The HCV NS5B RNA dependent RNA polymerase plays an essential role in viral replication. The discovery of a novel class of inhibitors based on an N,N-disubstituted phenylalanine scaffold and ...structure−activity relationships studies to improve potency are described.
Herein, we describe the structure–activity relationship (SAR) of
N,N-disubstituted phenylalanine series of NS5B polymerase inhibitors of hepatitis C. The NS5B polymerase inhibitory activity of the ...most active compound exhibited an IC
50 of 2.7 μM.
The structure–activity relationship (SAR) of NS5B polymerase inhibitor (
1) with an IC
50 of 3.5 μM is reported.
HCV NS5B RNA-dependent RNA polymerase (NS5B) is essential for viral replication and is therefore considered a target for antiviral drug development. From our ongoing screening effort in the search ...for new anti-HCV agents, a novel inhibitor 1 with low microM activity against the HCV NS5B polymerase was identified. SAR analysis indicated the optimal substitution pattern required for activity, for example, carboxylic acid group at 2-position of thiophene ring. We describe the steps taken to identify and solve the bioactive conformation of derivative 6 through the use of the transferred NOE method (trNOE).
We have recently described the discovery of new leads in the area of anti-HCMV research. Further structure - activity relationship studies have allowed us to identify potent and selective anti-HCMV ...nucleotide analogs. The synthesis as well as structure - activity relationship studies are described.
Both the
cis and
trans isomer of the guanine phosphonate analog were found to exhibit potent in vitro HCMV activity. The in vivo efficacy of the
cis isomer was also demonstrated in a surrogate model.
Following the identification of first pass metabolism issues with our recently described anti-HCMV compounds, the naphthyridines and isoquinolines, we have designed a class of novel metabolically ...stable and orally bioavailable anti-HCMV agents, the dihydroisoquinolines.
Programmable nucleases, such as Cas9, are used for precise genome editing by homology-dependent repair (HDR). However, HDR efficiency is constrained by competition from other double-strand break ...(DSB) repair pathways, including non-homologous end-joining (NHEJ). We report the discovery of a genetically encoded inhibitor of 53BP1 that increases the efficiency of HDR-dependent genome editing in human and mouse cells. 53BP1 is a key regulator of DSB repair pathway choice in eukaryotic cells and functions to favor NHEJ over HDR by suppressing end resection, which is the rate-limiting step in the initiation of HDR. We screened an existing combinatorial library of engineered ubiquitin variants for inhibitors of 53BP1. Expression of one variant, named i53 (inhibitor of 53BP1), in human and mouse cells, blocked accumulation of 53BP1 at sites of DNA damage and improved gene targeting and chromosomal gene conversion with either double-stranded DNA or single-stranded oligonucleotide donors by up to 5.6-fold. Inhibition of 53BP1 is a robust method to increase efficiency of HDR-based precise genome editing.
Little is known about the decision-making experiences of seniors and informal caregivers facing decisions about seniors' housing decisions when objective decision making measures are used.
To report ...on seniors' and caregivers' experiences of housing decisions.
A cross-sectional study with a quantitative approach supplemented by qualitative data.
Sixteen health jurisdictions providing home care services, Quebec province, Canada.
Two separate samples of seniors aged ≥ 65 years and informal caregivers of cognitively impaired seniors who had made a decision about housing.
Information on preferred choice and actual choice about housing, role assumed in the decision, decisional conflict and decision regret was obtained through closed-ended questionnaires. Research assistants paraphrased participants' narratives about their decision-making experiences and made other observations in standardized logbooks.
Thirty-one seniors (median age: 85.5 years) and 48 caregivers (median age: 65.1 years) were recruited. Both seniors and caregivers preferred that the senior stay at home (64.5% and 71.7% respectively). Staying home was the actual choice for only 32.2% of participating seniors and 36.2% of the seniors cared for by the participating caregivers. Overall, 93% seniors and 71% caregivers reported taking an active or collaborative role in the decision-making process. The median decisional conflict score was 23/100 for seniors and 30/100 for caregivers. The median decision regret score was the same for both (10/100). Qualitative analysis revealed that the housing decision was influenced by factors such as seniors' health and safety concerns and caregivers' burden of care. Some caregivers felt sad and guilty when the decision did not match the senior's preference.
The actual housing decision made for seniors frequently did not match their preferred housing option. Advanced care planning regarding housing and better decision support are needed for these difficult decisions.
Inertial measurement units (IMUs) have been increasingly popular in rehabilitation research. However, despite their accessibility and potential advantages, their uptake and acceptance by health ...professionals remain a big challenge. The development of an IMU-based clinical tool must bring together engineers, researchers and clinicians. This study is part of a developmental process with the investigation of clinicians' perspectives about IMUs. Clinicians from four rehabilitation centers were invited to a 30-minute presentation on IMUs. Then, two one-hour focus groups were conducted with volunteer clinicians in each rehabilitation center on: 1) IMUs and their clinical usefulness, and 2) IMUs data analysis and visualization interface. Fifteen clinicians took part in the first focus groups. They expressed their thoughts on: 1) categories of variables that would be useful to measure with IMUs in clinical practice, and 2) desired characteristics of the IMUs. Twenty-three clinicians participated to the second focus groups, discussing: 1) functionalities, 2) display options, 3) clinical data reported and associated information, and 4) data collection duration. Potential influence of IMUs on clinical practice and added value were discussed in both focus groups. Clinicians expressed positive opinions about the use of IMUs, but their expectations were high before considering using IMUs in their practice.
ObjectiveTo compare facility-level influenza vaccination rates in long-term care (LTC) homes from four countries and to identify factors associated with influenza vaccination among residents.Design ...and settingRetrospective cross-sectional study of individuals residing in LTC homes in New Brunswick (Canada), New Zealand, Switzerland, and the Netherlands between 2017 and 2020.ParticipantsLTC home residents assessed with interRAI assessment system instruments as part of routine practice in New Brunswick (n=7006) and New Zealand (n=34 518), and national pilot studies in Switzerland (n=2760) and the Netherlands (n=1508). End-of-life residents were excluded from all country cohorts.OutcomesInfluenza vaccination within the past year.ResultsInfluenza vaccination rates among LTC home residents were highest in New Brunswick (84.9%) and lowest in Switzerland (63.5%). For all jurisdictions where facility-level data were available, substantial interfacility variance was observed. There was approximately a fourfold difference in the coefficient of variation for facility-level vaccination rates with the highest in Switzerland at 37.8 and lowest in New Brunswick at 9.7. Resident-level factors associated with vaccine receipt included older age, severe cognitive impairment, medical instability, health conditions affecting a greater number of organ systems and social engagement. Residents who displayed aggressive behaviours and smoke tobacco were less likely to be vaccinated.ConclusionThere are opportunities to increase influenza vaccine uptake at both overall country and individual facility levels. Enhanced vaccine administration monitoring programmes in LTC homes that leverage interRAI assessment systems should be widely adopted.
Long-term care (LTC) residents, isolated because of the COVID-19 pandemic, are at increased risk for negative mental health outcomes. The purpose of our article is to demonstrate how the interRAI LTC ...facility (LTCF) assessment can inform clinical care and evaluate the effect of strategies to mitigate worsening mental health outcomes during the COVID-19 pandemic. We present a supporting analysis of the effects of lockdown in homes without COVID-19 outbreaks on depression, delirium, and behavior problems in a network of 7 LTC homes in New Brunswick, Canada, where mitigative strategies were deployed to minimize poor mental health outcomes (eg, virtual visits and increased student volunteers). This network meets regularly to review performance on risk-adjusted quality of care indicators from the interRAI LTCF and share learning through a community of practice model. We included 4209 assessments from 765 LTC residents between January 2017 to June 2020 and modeled the change within and between residents for depression, delirium, and behavioral problems over time with longitudinal generalized estimating equations. Though the number of residents who had in-person visits with family decreased from 73.2% before to 17.9% during lockdown (chi square, P < .001), the number of residents experiencing delirium (4.5%-3.5%, P = .51) and behavioral problems (35.5%-30.2%, P = .19) did not change. The proportion of residents with indications of depression decreased from 19.9% before to 11.5% during lockdown (P < .002). The final multivariate models indicate that the effect of lockdown was not statistically significant on depression, delirium, or behavioral problems. Our analyses demonstrate that poor mental health outcomes associated with lockdown can be mitigated with thoughtful intervention and ongoing evaluation with clinical information systems. Policy makers can use outputs to guide resource deployment, and researchers can examine the data to identify better management strategies for when pandemic strikes again.
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