Geriatric care physicians' perspectives on providing virtual care: a reflexive thematic synthesis of their online survey responses from Ontario, Canada.

BACKGROUND: During the COVID-19 pandemic, telemedicine was widely implemented to minimise viral spread. However, its use in the older adult patient population was not well understood. OBJECTIVE: To understand the perspectives of geriatric care providers on using telemedicine with older adults through telephone, videoconferencing and eConsults. DESIGN: Qualitative online survey study. SETTING AND PARTICIPANTS: We recruited geriatric care physicians, defined as those certified in Geriatric Medicine, Care of the Elderly (family physicians with enhanced skills training) or who were the most responsible physician in a long-term care home, in Ontario, Canada between 22 December 2020 and 30 April 2021. METHODS: We collected participants' perspectives on using telemedicine with older adults in their practice using an online survey. Two researchers jointly analysed free-text responses using the 6-phase reflexive thematic analysis. RESULTS: We recruited 29 participants. Participants identified difficulty using technology, patient sensory impairment, lack of hospital support and pre-existing high patient volumes as barriers against using telemedicine, whereas the presence of a caregiver and administrative support were facilitators. Perceived benefits of telemedicine included improved time efficiency, reduced travel, and provision of visual information through videoconferencing. Ultimately, participants felt telemedicine served various purposes in geriatric care, including improving accessibility of care, providing follow-up and obtaining collateral history. Main limitations are the absence of, or incomplete physical exams and cognitive testing. CONCLUSIONS: Geriatric care physicians identify a role for virtual care in their practice but acknowledge its limitations. Further work is required to ensure equitable access to virtual care for older adults.

Geriatric Specialists' Perspectives on Telemedicine during the COVID-19 Pandemic: a Concurrent Triangulation Mixed-Methods Study.

During the COVID-19 pandemic, physicians provided virtual care to minimize viral transmission. This concurrent triangulation mixed-methods study assesses the use of synchronous telephone and video visits with patients and asynchronous eConsults by geriatric providers, and explores their perspectives on telemedicine use during the pandemic. Participants included physicians practicing in Ontario, Canada who were certified in Geriatric Medicine, or Care of the Elderly, or who were the most responsible physician in a long-term care for at least 10 patients. Participants' perspectives were solicited using an online survey and themes were generated through a reflexive thematic analysis of survey responses. We assessed the current use of each telemedicine tool and compared the proportion of participants using telemedicine before the pandemic with self-predicted use after the pandemic. We received 29 surveys from eligible respondents (87.9% completion rate), with 75.9% being geriatricians. The telephone was most used (96.6%), followed by video (86.2%) and eConsults (64%). Most participants using telephone and video visits had newly implemented them during the pandemic and intend to continue using these tools post-pandemic. Our thematic analysis revealed that telemedicine plays an important role in the continuity of care during the pandemic, with increased self-reported positive perspectives and openness towards use of virtual care tools, although limited by inadequate physical exams or cognitive testing. Its ongoing use depends on the availability of continued remuneration.

Strategies for Improving Small-Molecule Biosensors in Bacteria.

In recent years, small-molecule biosensors have become increasingly important in synthetic biology and biochemistry, with numerous new applications continuing to be developed throughout the field. For many biosensors, however, their utility is hindered by poor functionality. Here, we review the known types of mechanisms of biosensors within bacterial cells, and the types of approaches for optimizing different biosensor functional parameters. Discussed approaches for improving biosensor functionality include methods of directly engineering biosensor genes, considerations for choosing genetic reporters, approaches for tuning gene expression, and strategies for incorporating additional genetic modules.

Barriers and facilitators for optimizing oral anticoagulant management: Perspectives of patients, caregivers, and providers.

BACKGROUND: Oral anticoagulants (OACs) are very commonly prescribed for prevention of serious vascular events, but are also associated with serious medication-related bleeding. Mitigation of harm is believed to require high-quality OAC management. This study aimed to identify barriers and facilitators for optimal OAC management from the perspective of patients, caregivers and healthcare providers. METHODS: Using a qualitative descriptive study design, we conducted five focus groups, three with patients and caregivers and two with health care providers, in two health regions in Southwestern Ontario. An expert facilitator led the discussions using a semi-structured interview guide. Each session was digitally recorded, transcribed verbatim and anonymized. Transcripts were analyzed in duplicate using conventional content analysis. RESULTS: Forty-two (19 patients, 7 caregivers, and 16 providers including physicians, nurses and pharmacists) participated. More than half of the patients received OAC for the treatment of venous thromboembolism (57.9%) and the majority (94.7%) were on chronic therapy (defined as >3 years). Data analysis organized codes describing barriers and facilitators into 4 main themes-medication-related, patient-related, provider-related, and system-related. Barriers highlighted were problems with medication access due to cost, patient difficulties with adherence, knowledge and adjusting their lifestyles to OAC therapy, provider expertise, time for adequate communication amongst providers and their patients, and health care system inadequacies in supporting communications and monitoring. Facilitators identified generally addressed these barriers. CONCLUSIONS: Many barriers to optimal OAC management exist even in the era of DOACs, many of which are amenable to facilitators of improved care coordination, patient education, and adherence monitoring.

Improved pyrrolysine biosynthesis through phage assisted non-continuous directed evolution of the complete pathway.

Pyrrolysine (Pyl, O) exists in nature as the 22nd proteinogenic amino acid. Despite being a fundamental building block of proteins, studies of Pyl have been hindered by the difficulty and inefficiency of both its chemical and biological syntheses. Here, we improve Pyl biosynthesis via rational engineering and directed evolution of the entire biosynthetic pathway. To accommodate toxicity of Pyl biosynthetic genes in Escherichia coli, we also develop Alternating Phage Assisted Non-Continuous Evolution (Alt-PANCE) that alternates mutagenic and selective phage growths. The evolved pathway provides 32-fold improved yield of Pyl-containing reporter protein compared to the rationally engineered ancestor. Evolved PylB mutants are present at up to 4.5-fold elevated levels inside cells, and show up to 2.2-fold increased protease resistance. This study demonstrates that Alt-PANCE provides a general approach for evolving proteins exhibiting toxic side effects, and further provides an improved pathway capable of producing substantially greater quantities of Pyl-proteins in E. coli.

Macrolide Biosensor Optimization through Cellular Substrate Sequestration.

Developing and optimizing small-molecule biosensors is a central goal of synthetic biology. Here we incorporate additional cellular components to improve biosensor sensitivity by preventing target molecules from diffusing out of cells. We demonstrate that trapping erythromycin within Escherichia coli through phosphorylation increases the sensitivity of its biosensor (MphR) by approximately 10-fold. When combined with prior engineering efforts, our optimized biosensor can detect erythromycin concentrations as low as 13 nM. We show that this strategy works with a range of macrolide substrates, enabling the potential usage of our optimized system for drug development and metabolic engineering. This strategy can be extended in future studies to improve the sensitivity of other biosensors. Our findings further suggest that many naturally evolved genes involved in resistance to multiple classes of antibiotics may increase intracellular drug concentrations to modulate their own expression, acting as a form of regulatory feedback.

A suppressor tRNA-mediated feedforward loop eliminates leaky gene expression in bacteria.

Ligand-inducible genetic systems are the mainstay of synthetic biology, allowing gene expression to be controlled by the presence of a small molecule. However, 'leaky' gene expression in the absence of inducer remains a persistent problem. We developed a leak dampener tool that drastically reduces the leak of inducible genetic systems while retaining signal in Escherichia coli. Our system relies on a coherent feedforward loop featuring a suppressor tRNA that enables conditional readthrough of silent non-sense mutations in a regulated gene, and this approach can be applied to any ligand-inducible transcription factor. We demonstrate proof-of-principle of our system with the lactate biosensor LldR and the arabinose biosensor AraC, which displayed a 70-fold and 630-fold change in output after induction of a fluorescence reporter, respectively, without any background subtraction. Application of the tool to an arabinose-inducible mutagenesis plasmid led to a 540-fold change in its output after induction, with leak decreasing to the level of background mutagenesis. This study provides a modular tool for reducing leak and improving the fold-induction within genetic circuits, demonstrated here using two types of biosensors relevant to cancer detection and genetic engineering.

Canadian Guidelines on Benzodiazepine Receptor Agonist Use Disorder Among Older Adults Title.

BACKGROUND: Benzodiazepine receptor agonist (BZRA) use disorder among older adults is a relatively common and challenging clinical condition. METHOD: The Canadian Coalition for Seniors' Mental Health, with financial support from Health Canada, has produced evidence-based guidelines on the prevention, identification, assessment, and management of this form of substance use disorder. RESULTS: Inappropriate use of BZRAs should be avoided by considering non-pharmacological approaches to the management of late life insomnia, anxiety, and other common indications for the use of BZRA. Older persons should only be prescribed BZRAs after they are fully informed of alternatives, benefits, and risks associated with their use. Clinicians should have a high index of suspicion for the presence of BZRA use disorders. The full version of these guidelines can be accessed at www.ccsmh.ca. CONCLUSIONS: A person-centred, stepped care approach utilizing gradual dose reductions should be used in the management of BZRA use disorder.

Bacterial Killers Engineered to Exterminate Pathogenic Microbes.

A new study reports a synthetic bacterium that uses conjugation to transfer toxic genes that selectively kill pathogenic cells. The work represents a novel strategy for targeting pathogens, which could be the basis for a new generation of precision antimicrobials.

Comparative risk of harm associated with trazodone or atypical antipsychotic use in older adults with dementia: a retrospective cohort study.

BACKGROUND: Trazodone is increasingly prescribed for behavioural and psychological symptoms of dementia, but little is known about its risk of harm. Our objective was to describe the comparative risk of falls and fractures among older adults with dementia dispensed trazodone or atypical antipsychotics. METHODS: The study cohort included adults with dementia (excluding patients with chronic psychotic illnesses) living in long-term care and aged 66 years and older. Data were obtained from routinely collected, linked health administrative databases in Ontario, Canada. We compared new users of trazodone with new users of atypical antipsychotics (quetiapine, olanzapine or risperidone) between Dec. 1, 2009, and Dec. 31, 2015. The primary outcome was a composite of fall or major osteoporotic fracture within 90 days of first prescription. Secondary outcomes were falls, major osteoporotic fractures, hip fractures and all-cause mortality. RESULTS: We included 6588 older adults dispensed trazodone and 2875 dispensed an atypical antipsychotic, of whom 95.2% received a low dose of these medications. Compared with use of atypical antipsychotics, use of trazodone was associated with similar rates of falls or major osteoporotic fractures (weighted hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.73 to 1.07), major osteoporotic fracture (weighted HR 1.03, 95% CI 0.73 to 1.47), falls (weighted HR 0.91, 95% CI 0.75 to 1.11) and hip fractures (weighted HR 0.92, 95% CI 0.59 to 1.43). Use of trazodone was associated with a lower rate of mortality (weighted HR 0.75, 95% CI 0.66 to 0.85). INTERPRETATION: Trazodone is not a uniformly safer alternative to atypical antipsychotics, given the similar risk of falls and fractures among older adults with dementia.

A population-based study of the risk of osteoporosis and fracture with dutasteride and finasteride.

BACKGROUND: Dutasteride is a potent inhibitor of 5-alpha reductase enzymes that reduces concentrations of dihydrotestosterone to a greater extent than finasteride. Whether this has adverse implications for bone health is unknown. We compared the risk of osteoporosis and fractures in older men treated with dutasteride or finasteride. METHODS: We conducted a population-based retrospective cohort study with high-dimensional propensity score matching of Ontario men aged 66 years or older who started treatment with dutasteride or finasteride between January 1, 2006 and December 31, 2012. The primary outcome was a diagnosis of osteoporosis within 2 years of treatment initiation. A secondary outcome was osteoporotic or fragility fractures. RESULTS: We studied 31,615 men treated with dutasteride and an equal number of men treated with finasteride. Dutasteride-treated patients had a lower incidence of osteoporosis than those receiving finasteride [2.2 versus 2.6 per 100 person years; hazard ratio (HR) 0.82; 95% confidence interval (CI) 0.72 to 0.93]. This effect was no longer statistically significant following adjustment for specialty of prescribing physician (HR 0.90; 95% CI 0.78 to 1.02)]. There was no differential risk of fractures with dutasteride (HR 1.04; 95% 0.86 to 1.25). CONCLUSIONS: Despite differential effects on 5-alpha reductase, dutasteride is not associated with an increased risk of osteoporosis or fractures in older men relative to finasteride. These findings suggest that dutasteride does not adversely affect bone health.

Tuning the dynamic range of bacterial promoters regulated by ligand-inducible transcription factors.

One challenge for synthetic biologists is the predictable tuning of genetic circuit regulatory components to elicit desired outputs. Gene expression driven by ligand-inducible transcription factor systems must exhibit the correct ON and OFF characteristics: appropriate activation and leakiness in the presence and absence of inducer, respectively. However, the dynamic range of a promoter (i.e., absolute difference between ON and OFF states) is difficult to control. We report a method that tunes the dynamic range of ligand-inducible promoters to achieve desired ON and OFF characteristics. We build combinatorial sets of AraC-and LasR-regulated promoters containing -10 and -35 sites from synthetic and Escherichia coli promoters. Four sequence combinations with diverse dynamic ranges were chosen to build multi-input transcriptional logic gates regulated by two and three ligand-inducible transcription factors (LacI, TetR, AraC, XylS, RhlR, LasR, and LuxR). This work enables predictable control over the dynamic range of regulatory components.

Drugging tRNA aminoacylation.

Inhibition of tRNA aminoacylation has proven to be an effective antimicrobial strategy, impeding an essential step of protein synthesis. Mupirocin, the well-known selective inhibitor of bacterial isoleucyl-tRNA synthetase, is one of three aminoacylation inhibitors now approved for human or animal use. However, design of novel aminoacylation inhibitors is complicated by the steadfast requirement to avoid off-target inhibition of protein synthesis in human cells. Here we review available data regarding known aminoacylation inhibitors as well as key amino-acid residues in aminoacyl-tRNA synthetases (aaRSs) and nucleotides in tRNA that determine the specificity and strength of the aaRS-tRNA interaction. Unlike most ligand-protein interactions, the aaRS-tRNA recognition interaction represents coevolution of both the tRNA and aaRS structures to conserve the specificity of aminoacylation. This property means that many determinants of tRNA recognition in pathogens have diverged from those of humans-a phenomenon that provides a valuable source of data for antimicrobial drug development.

Comparative Effectiveness and Safety of Cognitive Enhancers for Treating Alzheimer's Disease: Systematic Review and Network Metaanalysis.

BACKGROUND/OBJECTIVES: To examine the comparative effectiveness and safety of cognitive enhancers for Alzheimer's disease (AD). DESIGN: Systematic review and Bayesian network metaanalysis (NMA). SETTING: MEDLINE, EMBASE, Cochrane Library, CINAHL, Ageline (inception-March 2016). PARTICIPANTS: Individuals with AD in randomized controlled trials (RCTs), quasi-RCTs, and nonrandomized studies. INTERVENTION: Any combination of donepezil, rivastigmine, galantamine, or memantine. MEASUREMENTS: Two reviewers independently screened titles, abstracts, and full-texts; abstracted data; and appraised risk of bias. RESULTS: Twenty thousand three hundred forty-three citations were screened, and 142 studies were included (110 RCTs, 21 non-RCTs, 11 cohort studies). NMA found that donepezil (Mini-Mental State Examination: mean difference (MD) = 1.39, 95% credible interval (CrI) = 0.53-2.24), donepezil+memantine (2.59, 95% CrI = 0.12-4.98), and transdermal rivastigmine (2.02, 95% CrI = 0.02-4.08) improved cognition more than placebo. NMA found that donepezil (Alzheimer's Disease Assessment Scale-cognitive: MD = -3.29, 95% CrI = -4.57 to -1.99) and galantamine (MD = -2.13, 95% CrI = -3.91 to -0.27) improved cognition more than placebo. NMA found that donepezil+memantine (MD = -5.23, 95% CrI = -8.72 to -1.56) improved behavior more than placebo. NMA found that donepezil (MD = -0.32, 95% CrI = -0.46 to -0.19), donepezil+memantine (MD = -0.57, 95% CrI = -0.95 to -0.21), oral rivastigmine (MD = -0.38, 95% CrI = -0.56 to -0.17), and galantamine (MD = -3.79, 95% CrI = -6.98 to -0.59) improved global status more than placebo. NMA found that galantamine decreased the odds of mortality (odds ratio = 0.56, 95% CrI = 0.36-0.87). No agent increased risk of serious adverse events, falls, or bradycardia. Some increased risk of headache (oral rivastigmine), diarrhea (oral rivastigmine, donepezil), nausea (oral rivastigmine, donepezil, galantamine), and vomiting (oral rivastigmine, donepezil, galantamine). CONCLUSION: An exhaustive review of the literature involving 142 studies demonstrated that cognitive enhancers in general have minimal effects on cognition according to minimal clinically important difference and global ratings. The drugs appear safe, but this must be interpreted cautiously because trial participants may have less comorbidity and fewer adverse effects than those treated with these drugs in clinical practice.

Tunable NF-κB Oscillations in Yeast.

Studies of genetic networks in situ are confounded by unknown interactions with native networks. In Zhang et al. (2017), the authors capitalize on the fact that yeast lacks the NF-κB pathway to study the human NF-κB pathway in isolation and develop a predictive model.

Crystal structures reveal an elusive functional domain of pyrrolysyl-tRNA synthetase.

Pyrrolysyl-tRNA synthetase (PylRS) is a major tool in genetic code expansion using noncanonical amino acids, yet its structure and function are not completely understood. Here we describe the crystal structure of the previously uncharacterized essential N-terminal domain of this unique enzyme in complex with tRNAPyl. This structure explains why PylRS remains orthogonal in a broad range of organisms, from bacteria to humans. The structure also illustrates why tRNAPyl recognition by PylRS is anticodon independent: the anticodon does not contact the enzyme. Then, using standard microbiological culture equipment, we established a new method for laboratory evolution-a noncontinuous counterpart of the previously developed phage-assisted continuous evolution. With this method, we evolved novel PylRS variants with enhanced activity and amino acid specificity. Finally, we employed an evolved PylRS variant to determine its N-terminal domain structure and show how its mutations improve PylRS activity in the genetic encoding of a noncanonical amino acid.

Pregabalin and heart failure: A population-based study.

PURPOSE: The anticonvulsant pregabalin is increasingly prescribed for pain, seizures, and psychiatric disorders. Although evidence suggests pregabalin can cause edema and heart failure, its cardiac safety profile in clinical practice is unknown. We sought to examine the risk of heart failure among older patients receiving pregabalin compared to those receiving gabapentin. METHODS: We conducted a population-based cohort study of Ontarians aged 66 and older with a history of seizure who received pregabalin or gabapentin between April 2013 and March 2014. We used propensity scores to match patients commencing pregabalin to those commencing gabapentin. The primary outcome was an emergency department visit or hospitalization for heart failure within 90 days. RESULTS: We studied 9855 patients who initiated pregabalin and an equal number treated with gabapentin. In the primary analysis, we found no difference in the risk of heart failure with pregabalin compared to gabapentin (1.2% versus 1.3%, hazard ratio of 0.77; 95% CI 0.58-1.03). Secondary analyses stratified for baseline history of heart failure yielded similar findings. CONCLUSION: In a large cohort of older patients with a seizure disorder, pregabalin was not associated with an increased risk of heart failure relative to gabapentin.