Strategies to reduce the inappropriate prescription of antipsychotics have been the focus of recent attention but have shown considerable variation in their effectiveness.
To evaluate the ...effectiveness of academic detailing in nursing homes targeting appropriate prescribing of antipsychotics.
We conducted a pragmatic, cluster randomized clinical trial comparing the effect of academic detailing vs usual care on prescribing antipsychotics in 40 nursing homes with 5363 residents in Ontario, Canada. Data were collected from October 2015 to March 2016 and analyzed from April to August 2018. Primary analyses were conducted using intention to treat.
Academic detailing delivered by health professionals (eg, nurses or pharmacists) who arranged meetings (with administrators, physicians, pharmacists, nurses, and support workers), presentations, group visits (with 2-6 clinicians), and 1-on-1 visits (traditional academic detailing visits). Academic detailers had direct and ongoing contact with the nursing homes from the time of launch.
The primary outcome, defined at the level of the resident, was whether continuous antipsychotics were dispensed in the past week. Secondary outcomes included prescribing of other psychotropic medications and clinical outcomes and scores. Prescribing outcomes were assessed at baseline and at 3, 6, and 12 months, and clinical outcomes and scores were assessed at baseline and 3 and 6 months.
A total of 40 nursing homes with 5363 residents were randomized, with 18 intervention homes (45.0%; 2303 42.9% residents) and 22 control homes (55.0%; 3060 57.1% residents). Participants in the intervention and control groups had similar median (interquartile range) age (86 79-91 years vs 85 78-90 years) and sex (674 29.3% men vs 970 31.7% men). At 12 months, there was no statistically significant difference in the frequency of daily antipsychotic use (intervention: 569 patients 25.2%; control: 769 25.6%; odds ratio, 1.06; 95% CI, 0.93-1.20; P = .49). There were no significant differences in the rates of health care utilization, but the intervention group did experience a statistically significant reduction in pain compared with the control group (mean SD pain score, 0.30 0.59 vs 0.38 0.66; P < .001) and depression (mean SD Depression Rating Scale score, 2.18 2.37 vs 2.81 2.65; P < .001) at 6 months.
The intervention did not further reduce antipsychotic prescribing in nursing homes beyond system-level secular trends occurring alongside usual care. Our findings highlight the need for a more targeted approach to quality improvement strategies, including academic detailing, that account for the timing and topic of interventions.
ClinicalTrials.gov Identifier: NCT02604056.
Diverse genetic, epigenetic, and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here, we use an ...integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the The Cancer Genome Atlas (TCGA), functional approaches, and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4, EGFR, and PDGFRA loci and by mutations in the NF1 locus, which each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity, and their modulation by genetic drivers.
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•Four cellular states drive glioblastoma malignant cells heterogeneity•In vivo single-cell lineage tracing supports plasticity between these four states•Genetics and the microenvironment influence the frequency of cells in each state•TCGA subtypes reflect the highest-frequency malignant states and the microenvironment
Single-cell analyses of glioblastoma samples reveal multiple cellular states, their plasticity and the genetic underpinnings of state proportions in a given tumor.
Chronic allograft nephropathy has become the dominant cause of kidney-transplant failure in the present era of improved immunosuppression. This prospective study examined 961 kidney-transplant–biopsy ...specimens obtained sequentially during the first 10 years after transplantation from 120 recipients with type 1 diabetes. Nephrotoxicity, implicated in late, ongoing injury, was almost universal at 10 years, even in grafts with excellent early histologic findings.
Now the dominant cause of kidney-transplant failure.
Chronic allograft nephropathy, characterized by progressive renal dysfunction accompanied by chronic interstitial fibrosis, tubular atrophy, vascular occlusive changes, and glomerulosclerosis,
1
,
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is the chief cause of kidney-transplant failure despite improvements in immunosuppression. Although registry data can be used to define some risk factors, the pathophysiology of chronic allograft nephropathy remains poorly understood. A biopsy of a chronically failing kidney transplant usually shows nonspecific or end-stage changes, so the relative contributions of preexisting disease in the allograft and immunologic and nonimmunologic factors become difficult to distinguish. A major impediment has been the lack of prospective, longitudinal histologic data from studies of . . .
The role and burden of cyclosporine (CsA) nephrotoxicity in long-term progressive kidney graft dysfunction is poorly documented.
The authors evaluated 888 prospective protocol kidney biopsy specimens ...from 99 patients taken regularly until 10 years after transplantation for evidence of CsA nephrotoxicity.
The most sensitive histologic marker of CsA nephrotoxicity was arteriolar hyalinosis, predicted by CsA dose and functional CsA nephrotoxicity. Striped fibrosis was associated with early initiation of CsA and the need for posttransplant dialysis (both P < 0.05). The 10-year cumulative Kaplan-Meier prevalence of arteriolar hyalinosis, striped fibrosis, and tubular microcalcification was 100%, 88.0%, and 79.2% of kidneys, respectively. Beyond 1 year, 53.9% had two or more lesions of CsA nephrotoxicity. Structural CsA nephrotoxicity occurred in two phases, with different clinical and histologic characteristics. The acute phase occurred with a median onset 6 months after transplantation, was usually reversible, and was associated with functional CsA nephrotoxicity (P < 0.05), high CsA levels (P < 0.05), and mild arteriolar hyalinosis (P < 0.001). The chronic phase of CsA nephrotoxicity persisted over several biopsies, occurred at a median onset of 3 years, and was associated with lower CsA doses and trough levels (both P < 0.05). It was largely irreversible and accompanied by severe arteriolar hyalinosis and progressive glomerulosclerosis (both P < 0.001). A threshold CsA dose of 5 mg/kg/day predicted worsening of arteriolar hyalinosis on sequential histology.
Pathologic changes of CsA nephrotoxicity were virtually universal by 10 years and exacerbated chronic allograft nephropathy. CsA is unsuitable as a universal, long-term immunosuppressive agent for kidney transplantation. Strategies to ameliorate or avoid nephrotoxicity are thus urgently needed.
Summary
We report reference‐quality genome assemblies and annotations for two accessions of soybean (Glycine max) and for one accession of Glycine soja, the closest wild relative of G. max. The ...G. max assemblies provided are for widely used US cultivars: the northern line Williams 82 (Wm82) and the southern line Lee. The Wm82 assembly improves the prior published assembly, and the Lee and G. soja assemblies are new for these accessions. Comparisons among the three accessions show generally high structural conservation, but nucleotide difference of 1.7 single‐nucleotide polymorphisms (snps) per kb between Wm82 and Lee, and 4.7 snps per kb between these lines and G. soja. snp distributions and comparisons with genotypes of the Lee and Wm82 parents highlight patterns of introgression and haplotype structure. Comparisons against the US germplasm collection show placement of the sequenced accessions relative to global soybean diversity. Analysis of a pan‐gene collection shows generally high conservation, with variation occurring primarily in genomically clustered gene families. We found approximately 40–42 inversions per chromosome between either Lee or Wm82v4 and G. soja, and approximately 32 inversions per chromosome between Wm82 and Lee. We also investigated five domestication loci. For each locus, we found two different alleles with functional differences between G. soja and the two domesticated accessions. The genome assemblies for multiple cultivated accessions and for the closest wild ancestor of soybean provides a valuable set of resources for identifying causal variants that underlie traits for the domestication and improvement of soybean, serving as a basis for future research and crop improvement efforts for this important crop species.
Significance Statement
Accurate shared genome assemblies provide a framework and coordinate system for collaborative research, and provide essential genomic information, including genes, non‐coding regions and information on evolutionary histories. Here, we report high‐quality genome assemblies for two important soybean cultivars, including major improvements to the most widely used reference assembly, and also for a close wild relative of soybean.
Subclinical rejection (SCR) is defined as histologically proven acute rejection in the absence of immediate functional deterioration.
We evaluated the impact of SCR in 961 prospective protocol kidney ...biopsies from diabetic recipients of a kidney-pancreas transplant (n=119) and one kidney transplant alone taken regularly up to 10 years after transplantation.
SCR was present in 60.8%, 45.7%, 25.8%, and 17.7% of biopsies at 1, 3, 12, and greater than 12 months after transplantation. Banff scores for acute interstitial inflammation and tubulitis declined exponentially with time. SCR was predicted by prior acute cellular rejection and type of immunosuppressive therapy (P<0.05-0.001). Tacrolimus reduced interstitial infiltration (P<0.001), whereas mycophenolate reduced tubulitis (P<0.05), and the combination effectively eliminated SCR (P<0.001). Persistent SCR of less than 2 years duration on sequential biopsies occurred in 29.2% of patients and was associated with prior acute interstitial rejection (P<0.001) and requirement for antilymphocyte therapy (P<0.05). It resolved by 0.49 +/- 0.33 years and resulted in higher grades of chronic allograft nephropathy (CAN, P<0.05). True chronic rejection, defined as persistent SCR of 2 years or more duration and implying continuous immunologic activation was found in only 5.8% of patients. The presence of SCR increased chronic interstitial fibrosis, tubular atrophy, and CAN scores on subsequent biopsies (P<0.05-0.001). SCR preceded and was correlated with CAN (P<0.001) on sequential analysis.
Histologic evidence of acute rejection in the absence of clinical suspicion resulted in significant tubulointerstitial damage to transplanted kidneys and contributed to CAN.
Abstract
Background
Although much of the public health effort to combat coronavirus disease 2019 (COVID-19) has focused on disease control strategies in public settings, transmission of severe acute ...respiratory syndrome coronavirus 2 (SARS-CoV-2) within households remains an important problem. The nature and determinants of household transmission are poorly understood.
Methods
To address this gap, we gathered and analyzed data from 22 published and prepublished studies from 10 countries (20 291 household contacts) that were available through 2 September 2020. Our goal was to combine estimates of the SARS-CoV-2 household secondary attack rate (SAR) and to explore variation in estimates of the household SAR.
Results
The overall pooled random-effects estimate of the household SAR was 17.1% (95% confidence interval CI, 13.7–21.2%). In study-level, random-effects meta-regressions stratified by testing frequency (1 test, 2 tests, >2 tests), SAR estimates were 9.2% (95% CI, 6.7–12.3%), 17.5% (95% CI, 13.9–21.8%), and 21.3% (95% CI, 13.8–31.3%), respectively. Household SARs tended to be higher among older adult contacts and among contacts of symptomatic cases.
Conclusions
These findings suggest that SARs reported using a single follow-up test may be underestimated, and that testing household contacts of COVID-19 cases on multiple occasions may increase the yield for identifying secondary cases.
Chronic viral infections present serious public health challenges; however, direct-acting antivirals (DAAs) are now able to cure nearly all patients infected with hepatitis C virus (HCV), ...representing the only cure of a human chronic viral infection to date. DAAs provide a valuable opportunity to study immune pathways in the reversal of chronic immune failures in an in vivo human system.
To leverage this opportunity, we used plate-based single-cell RNA-seq to deeply profile myeloid cells from liver fine needle aspirates in patients with HCV before and after DAA treatment. We comprehensively characterised liver neutrophils, eosinophils, mast cells, conventional dendritic cells, plasmacytoid dendritic cells, classical monocytes, non-classical monocytes, and macrophages, and defined fine-grained subpopulations of several cell types.
We discovered cell type-specific changes post-cure, including an increase in MCM7+STMN1+ proliferating CD1C+ conventional dendritic cells, which may support restoration from chronic exhaustion. We observed an expected downregulation of interferon-stimulated genes (ISGs) post-cure as well as an unexpected inverse relationship between pre-treatment viral load and post-cure ISG expression in each cell type, revealing a link between viral loads and sustained modifications of the host’s immune system. We found an upregulation of PD-L1/L2 gene expression in ISG-high neutrophils and IDO1 expression in eosinophils, pinpointing cell subpopulations crucial for immune regulation. We identified three recurring gene programmes shared by multiple cell types, distilling core functions of the myeloid compartment.
This comprehensive single-cell RNA-seq atlas of human liver myeloid cells in response to cure of chronic viral infections reveals principles of liver immunity and provides immunotherapeutic insights.
This study is registered at ClinicalTrials.gov (NCT02476617).
Chronic viral liver infections continue to be a major public health problem. Single-cell characterisation of liver immune cells during hepatitis C and post-cure provides unique insights into the architecture of liver immunity contributing to the resolution of the first curable chronic viral infection of humans. Multiple layers of innate immune regulation during chronic infections and persistent immune modifications after cure are revealed. Researchers and clinicians may leverage these findings to develop methods to optimise the post-cure environment for HCV and develop novel therapeutic approaches for other chronic viral infections.
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•A comprehensive definition of human liver myeloid cell subsets in chronic viral hepatitis and post-cure.•MCM7+STMN1+ proliferating conventional dendritic cells were increased post-cure.•PD-L1+ ISG-high neutrophils and IDO1-high eosinophils may be immunoregulatory during chronic infections.•S100, MHC-II, and ISG were recurring gene programmes in the myeloid compartment.•Pre-treatment viral load was inversely related to post-cure ISG expression in each cell type in the host.
Tubulointerstitial damage (TID) is a key feature of chronic kidney transplant failure; however, the associated gene expression changes are poorly defined.
This pilot study used RNA from 59 protocol ...kidney transplant biopsies at implantation, 1, 3, and 12 months (n=18 patients), processed into cDNA and hybridized to 8K human cDNA microarrays. Gene expression was correlated with graft histology categorized by the Banff schema.
Gene and pathway expression were differentially activated according to the time after transplantation. Immune pathway activity peaked at 1 month, fibrotic expression at 3 months, wound healing-remodelling and cell proliferation-repair processes were activated between 3 and 12 months, whereas macrophage-related gene expression occurred late by 12 months. Forty percent of genes and 50% pathways initially activated persisted to 3 months. Biopsies with TID displayed 262 differentially expressed genes (P<0.001, B>2 compared with implantation), dominated by upregulated fibrogenic and immune-related genes reflecting unique immune (10% to 15% of genes) and fibrotic (15% vs. 4% in normal) pathway activation. Profibrotic genes were expressed before interstitial fibrosis was observed by sequential microscopic analysis. Kidneys progressing to TID by 3 months demonstrated 30 unique genes (B>1, P<0.05) versus nonprogressors with 95 genes (B>1, P<0.009). Fourteen of these progressor genes also occurred in the top decile from an independent validation set.
Allografts display predictable immune and fibrotic gene expression profiles, with patterns of expression gradually varying by time after transplantation. The pathology reflects differential activation of intrinsic pathways. Gene expression predated histologic damage, suggesting its possible use in early diagnostic testing.
Subclinical rejection (SCR) causes chronic allograft damage, which may be prevented by antirejection therapy.
A pilot study of the effect of routine treatment of SCR was performed in 88 recipients of ...either a kidney (n=59) or combined kidney-pancreas transplant (n=29) undergoing protocol biopsy (PBX) surveillance at 1 and 3 months, using calcineurin inhibitors, mycophenolate mofetil, and corticosteroid therapy.
SCR was seen in 46.6% (41/88 patients), as 30 borderline and 11 acute SCR. From 279 transplant biopsies, the prevalence of SCR was 25% (22/88) at 1 month, 10.2% (9/88) at 3 months, and 8.3% (2/24) at 12 months PBX. Treatment included bolus intravenous or oral corticosteroids (n=20) and augmented immunosuppression, either by conversion to tacrolimus (n=6) or increased doses of maintenance therapy (n=14), whereas OKT3 was used in one case of subclinical vascular rejection. Borderline episodes were not treated in 12 patients. In biopsies taken to assess therapeutic response, persistent SCR was present in 46.1% (6/13). Treatment of SCR at 1 month was followed by lower acute Banff sum scores at 3 months PBX (P<0.01-0.0001). Early chronic damage was already present in the 1 month PBX, associated with SCR (P<0.0005 versus without SCR), although by 3 months these differences were lost. Rates of opportunistic infections and BK nephropathy were not increased by SCR treatment.
Early chronic allograft damage was associated with SCR and therapy appeared to ameliorate further immune-mediated injury, although the efficacy of corticosteroids alone may be inadequate. A controlled trial of therapy for SCR is warranted.
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