Predicting Mutation-Induced Changes in the Electronic Properties of Photosynthetic Proteins from First Principles: The Fenna-Matthews-Olson Complex Example.

Multiscale molecular modeling is utilized to predict optical absorption and circular dichroism spectra of two single-point mutants of the Fenna-Matthews-Olson photosynthetic pigment-protein complex. The modeling approach combines classical molecular dynamics simulations with structural refinement of photosynthetic pigments and calculations of their excited states in a polarizable protein environment. The only experimental input to the modeling protocol is the X-ray structure of the wild-type protein. The first-principles modeling reproduces changes in the experimental optical spectra of the considered mutants, Y16F and Q198V. Interestingly, the Q198V mutation has a negligible effect on the electronic properties of the targeted bacteriochlorophyll a pigment. Instead, the electronic properties of several other pigments respond to this mutation. The molecular modeling demonstrates that a single-point mutation can induce long-range effects on the protein structure, while extensive structural changes near a pigment do not necessarily lead to significant changes in the electronic properties of that pigment.

Evaluation of publication bias for 12 clinical trials of molnupiravir to treat SARS-CoV-2 infection in 13 694 patients with meta-analysis.

In response to the COVID-19 pandemic, Merck Sharp & Dohme (MSD) acquired the global licensing rights for the antiviral molnupiravir, promising affordable access via licensing deals. Numerous Indian pharmaceutical companies subsequently conducted trials of the drug. Registered trials of molnupiravir were searched on the Clinical Trials Registry-India (CTRI) and efforts made to detect resulting public data. Per the CTRI, 12 randomized trials of molnupiravir were conducted in 13 694 Indian patients, from mid-2021. By August 2022, only a preprint and medical conference presentation had resulted. Additionally, two trials were mentioned in press releases suggesting failure of treatment. The available data contain unexplained results that differ significantly from both the PANORAMIC and MSD MOVe-OUT trials. Approximately one-third of the global data on molnupiravir remain unpublished. We conducted a meta-analysis with four studies that provided results and observed that molnupiravir does not have a significant benefit for hospitalizations.

Chart based data as a resource for tracking and improving a person-centred palliative approach in long-term care.

AIMS AND OBJECTIVES: To enhance the practice of a person-centred palliative approach in long-term care. BACKGROUND: Implementing a person-centred palliative approach in long-term care entails placing residents at the centre of care planning that attends to the 'whole' person, rather than prioritising biomedical needs. DESIGN: We conducted a four-stage directed content analysis of long-term care progress notes to meet our study aims and applied the EQUATOR guidelines for qualitative research publication (COREQ). METHODS: We qualitatively analysed 78 resident charts across three long-term care homes in southern Ontario to capture the extent to which person-centred care was absent, initiated or implemented in different types of documented care interactions. RESULTS: Most residents had interactions related to daily care activities (65/78, 83%), social concerns (65/78, 83%) and treatment decisions (53/78, 68%). By contrast, interactions around pain and discomfort (34/78, 44%) and spirituality (27/78, 35%) were documented for less than half of the residents. Almost all (92%) residents had at least one progress note where staff initiated person-centred care by documenting their preference for a certain type of care, but only a third had at least one progress note that suggested their preference was implemented (35%). CONCLUSIONS: While person-centred care is often initiated by nurses and other allied health professionals, changes to care plans to address resident preferences are implemented less often. Nurses and other allied health professionals should be encouraged to elicit care preferences crucial for holistic care planning and equipped with the skills and support to enact collaborative care planning. RELEVANCE TO CLINICAL PRACTICE: Collaborative care planning appears relatively absent in charted progress notes, constraining the full implementation of a person-centred palliative approach to care. PATIENT OR PUBLIC CONTRIBUTION: An advisory group consisting of long-term care resident and staff representatives informed the overall study design and dissemination of the results.

"This is how I want it": Exploring the use of a workbook with persons with dementia to support advance care planning engagement.

This mixed method sequential study reports focus group and pilot intervention findings that (1) explore the views of persons with dementia and their caregivers on using a self-directed advance care planning engagement workbook (Your Conversation Starter Kit) and (2) uncover the conditions that encouraged and hindered workbook use. In Phase 1, we conducted five focus groups consisting of 10 persons with dementia and eight family members/caregivers from two urban Canadian cities to explore overall impressions of the workbook and factors that might affect its use. In Phase 2, we empirically explored the factors identified in Phase 1 by distributing the workbook to 24 persons with dementia. The combined findings suggest that the workbook offers promise in supporting advance care planning engagement for persons with dementia in the early stages of their condition. Involving family/caregivers and clarifying some of the ranked questions might improve the workbook's use. Persons with dementia without familial support or those who have never contemplated advance care planning may require additional guidance prior to workbook distribution.

Evaluating the Implementation of the Conversation Starter Kit in Long Term Care.

INTRODUCTION: Advance care planning can improve the quality of life for residents in long-term care homes and reduce stress for families. However, care home staff and families often lack knowledge about advance care planning, making it especially difficult for residents with dementia to communicate their care plan wishes. A Conversation Starter Kit may increase advance care planning awareness among staff and families. OBJECTIVES: This study evaluated an advance care planning intervention, the Conversation Starter Kit booklet, for use in long term care homes. METHODS: Data were collected at three long-term care homes in southern Ontario. We collected data from 55 residents who were able to make decisions on their own paired with 11 family members of these residents. We also collected data from 24 family members of residents who were unable to make decisions on their own. This study used a quasi-experimental, one group pre/post design. Quantitative surveys were administered before and after a three-month advance care planning intervention. An additional structured interview was completed at the end of the intervention period, which included both closed and open-ended questions to assess perceptions about the booklet's use or non-use. RESULTS: Residents reported more engagement in advance care planning after completing the Conversation Starter Kit booklet, particularly related to asking questions to health care providers about health care decisions. Family members reported feeling very certain that they would be able to make decisions on behalf of the resident but felt less certain after completing the booklet, implying the booklet raised their awareness of the types of decisions they might need to make, hopefully prompting them to be more prepared for decisions in the future. CONCLUSIONS: An advance care planning intervention - The Conversation Starter Kit booklet - appears acceptable and easy to use for residents and family members/friends in long-term care and can improve resident engagement in advance care planning. Although using the booklet may decrease efficacy for decision making among family members of long-term care residents, it may highlight the importance of more actionable engagement in advance care planning among residents, their families/friends, and staff.

Using a self-directed workbook to support advance care planning with long term care home residents.

BACKGROUND: While advance care planning (ACP) has been shown to improve the quality of end-of-life (EOL) communication and palliative care, it is rarely practiced in long term care (LTC) homes, where staff time to support the process is limited. This study examines the potential of a publicly available self-directed ACP workbook distributed to LTC residents to encourage ACP reflection and communication. METHODS: Recruitment took place across three LTC homes, between June 2018 and July 2019. To be eligible, residents had to have medical stability, cognitive capacity, and English literacy. The study employed a mixed methods concurrent design using the combination of ranked (quantitative) and open (qualitative) workbook responses to examine documented care preferences and ACP reflections and communications. RESULTS: 58 residents initially agreed to participate in the study of which 44 completed self-directed ACP workbooks. Our combined quantitative and qualitative results suggested that the workbooks supported the elicitation of a range of resident care preferences of relevance for EOL care planning and decision making. For example, ranked data highlighted that most residents want to remain involved in decisions pertaining to their care (70%), even though less than half expect their wishes to be applied without discretion (48%). Ranked data further revealed many residents value quality of life over quantity of life (55%) but a sizable minority are concerned they will not receive enough care at EOL (20%). Open comments affirmed and expanded on ranked data by capturing care preferences not explored in the ranked data such as preferences around spiritual care and post mortem planning. Analysis of all open comments also suggested that while the workbook elicited many reflections that could be readily communicated to family/friends or staff, evidence that conversations had occurred was less evident in recorded workbook responses. CONCLUSIONS: ACP workbooks may be useful for supporting the elicitation of resident care preferences and concerns in LTC. Developing follow up protocols wherein residents are supported in communicating their workbook responses to families/friends and staff may be a critical next step in improving ACP engagement in LTC. Such protocols would require staff training and an organizational culture that empowers staff at all levels to engage in follow up conversations with residents.

The effect of behaviour change interventions on changes in physical activity and anthropometrics in ambulatory hospital settings: a systematic review and meta-analysis.

BACKGROUND: The aim of this systematic review and meta-analysis was to investigate whether behaviour change interventions promote changes in physical activity and anthropometrics (body mass, body mass index and waist circumference) in ambulatory hospital populations. METHODS: Randomised controlled trials were collected from five bibliographic databases (MEDLINE, Embase, CINAHL, The Cochrane Central Register of Controlled Trials (CENTRAL) and PsycINFO). Meta-analyses were conducted using change scores from baseline to determine mean differences (MD), standardised mean differences (SMD) and 95% confidence intervals (95% CI). The Grades of Recommendation, Assessment, Development and Evaluation approach was used to evaluate the quality of the evidence. RESULTS: A total of 29 studies met the eligibility criteria and 21 were included in meta-analyses. Behaviour change interventions significantly increased physical activity (SMD: 1.30; 95% CI: 0.53 to 2.07, p < 0.01), and resulted in significant reductions in body mass (MD: -2.74; 95% CI: - 4.42 to - 1.07, p < 0.01), body mass index (MD: -0.99; 95% CI: - 1.48 to - 0.50, p < 0.01) and waist circumference (MD: -2.21; 95% CI: - 4.01 to - 0.42, p = 0.02). The GRADE assessment indicated that the evidence is very uncertain about the effect of behaviour change interventions on changes in physical activity and anthropometrics in ambulatory hospital patients. CONCLUSIONS: Behaviour change interventions initiated in the ambulatory hospital setting significantly increased physical activity and significantly reduced body mass, body mass index and waist circumference. Increased clarity in interventions definitions and assessments of treatment fidelity are factors that need attention in future research. PROSPERO registration number: CRD42020172140.

Quality assurance assessment of a specialized perinatal mental health clinic.

BACKGROUND: Mood and anxiety issues are the main mental health complaints of women during pregnancy and the postpartum period. Services targeting such women can reduce perinatal complications related to psychiatric difficulties. This quality assurance project aimed to examine changes in mood and anxiety symptoms in pregnant and postpartum women referred to the Women's Health Concerns Clinic (WHCC), a specialized outpatient women's mental health program. METHODS: We extracted patient characteristics and service utilization from electronic medical records of women referred between 2015 and 2016. We also extracted admission and discharge scores on the Edinburgh Postnatal Depression Scale (EPDS) and the Generalized Anxiety Disorder-7 (GAD-7) scale. RESULTS: Most patients accessed the WHCC during pregnancy (54%), had a diagnosis of major depressive disorder (54.9%), were prescribed a change in their medication or dose (61.9%), and accessed psychotherapy for perinatal anxiety (30.1%). There was a significant decrease in EPDS scores between admission and discharge (t(214) = 11.57; p = .000; effect size d = .86), as well as in GAD-7 scores (t(51) = 3.63; p = .001; effect size d = .61). A secondary analysis showed that patients with more severe depression and anxiety symptoms demonstrated even greater effect sizes. CONCLUSIONS: Changes in EPDS and GAD-7 scores indicate that the WHCC is effective in reducing mood and anxiety symptoms associated with the perinatal period. This project highlights the importance of quality assurance methods in evaluating the effectiveness of clinical services targeting perinatal mental health, in order to inform policy and funding strategies.

Two-Dimensional Crystallization of Poly( N-isopropylacrylamide)-Capped Gold Nanoparticles.

Surface-sensitive X-ray reflectivity and grazing incidence small-angle X-ray scattering reveal the structure of polymer-capped-gold nanoparticles (AuNPs that are grafted with poly( N-isopropylacrylamide); PNIPAM-AuNPs) as they self-assemble and crystallize at the aqueous suspension/vapor interface. Citrate-stabilized AuNPs (5 and 10 nm in nominal diameter) are ligand-exchanged by 6 kDa PNIPAM-thiol to form corona brushes around the AuNPs that are highly stable and dispersed in aqueous suspensions. Surprisingly, no clear evidence of thermosensitive effect on surface enrichment or self-assembly of the PNIPAM-AuNPs is observed in the 10-35 °C temperature range. However, addition of simple salts (in this case, NaCl) to the suspension induces migration of the PNIPAM-AuNPs to the aqueous surface, and above a threshold salt concentration, two-dimensional crystals are formed. The 10 nm PNIPAM-AuNPs form a highly ordered single layer with in-plane triangular structure, whereas the 5 nm capped NPs form short-range triangular structure that gradually becomes denser as salt concentration increases.

Is there a role for pharmacokinetic/pharmacodynamic-guided dosing for novel oral anticoagulants?

The novel direct oral anticoagulants (NOACs) represent a major advance in oral anticoagulant therapy and are replacing vitamin K antagonists as the preferred options for many indications. Given in fixed doses without routine laboratory monitoring, they have been shown to be at least as effective in reducing thromboembolic stroke as dose-adjusted warfarin in phase 3 randomized trials and less likely to cause hemorrhagic stroke. Pharmacokinetic and/or pharmacodynamic subanalyses of the major NOAC trials in patients with atrial fibrillation have established relationships between clinical characteristics, and drug levels and/or pharmacodynamic responses with both efficacy and safety. Based on these analyses, pharmaceutical manufacturers and regulatory authorities have provided contraindications and dosing recommendations based on clinical characteristics that are associated with drug levels and/or pharmacodynamic responses, stroke reduction, and bleeding risk to optimize the risk-benefit profile of the NOACs in the real world. The current fixed-dosing strategy of NOACs has triggered discussions about the potential value of laboratory monitoring and dose adjustment in customizing drug exposure to further improve the safety and efficacy of the NOACs in patients with atrial fibrillation. As there is neither high-quality evidence nor consensus about the potential role of laboratory monitoring and dose adjustment for the NOACs, a Cardiac Research Safety Consortium "Think Tank" meeting was held at the American College of Cardiology Heart House in December 2015 to discussions these issues. This manuscript reports on the deliberations and the conclusions reached at that meeting.

Cost-effectiveness of Apixaban Compared With Edoxaban for Stroke Prevention in Nonvalvular Atrial Fibrillation.

PURPOSE: The purpose of this analysis was to assess the cost-effectiveness of apixaban 5 mg BID versus high- and low-dose edoxaban (60 mg and 30 mg once daily) as intended starting dose strategies for stroke prevention in patients from a UK National Health Service perspective. METHODS: A previously developed and validated Markov model was adapted to evaluate the lifetime clinical and economic impact of apixaban 5 mg BID versus edoxaban (high and low dose) in patients with nonvalvular atrial fibrillation. A pairwise indirect treatment comparison was conducted for clinical end points, and price parity was assumed between apixaban and edoxaban. Costs in 2012 British pounds, life-years, and quality-adjusted life-years (QALYs) gained, discounted at 3.5% per annum, were estimated. FINDINGS: Apixaban was predicted to increase life expectancy and QALYs versus low- and high-dose edoxaban. These gains were achieved at cost-savings versus low-dose edoxaban, thus being dominant and nominal increases in costs versus high-dose edoxaban. The incremental cost-effectiveness ratio of apixaban versus high-dose edoxaban was £6763 per QALY gained. IMPLICATIONS: Apixaban was deemed to be dominant (less costly and more effective) versus low-dose edoxaban and a cost-effective alternative to high-dose edoxaban.

Clinical events after transitioning from apixaban versus warfarin to warfarin at the end of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.

BACKGROUND: We sought to assess the occurrence of events after blinded study drug discontinuation and transition to open-label vitamin K antagonist (VKA) in ARISTOTLE. METHODS: At the end of ARISTOTLE, blinded study drug was stopped, and open-label VKA was recommended. For patients completing the trial on blinded study drug, a 2-day bridging period with apixaban or apixaban placebo was recommended (while beginning open-label VKA). Outcomes were assessed during the 30 days after stopping blinded study drug. RESULTS: Of the 6,809 patients in the apixaban group and 6,588 in the warfarin group who completed the trial on study drug, there were 21 strokes or systemic emboli (4.02%/year) and 26 major bleeding (4.97%/year) events in the apixaban group (transitioning to VKA) and 5 strokes or systemic emboli (0.99%/year) and 10 major bleeding (1.97%/year) events in the warfarin group (continuing on VKA), with most of the imbalance between groups being after the first week. Similar results were seen in the first 30 days of the trial where warfarin-naive patients starting warfarin had a higher rate of stroke or systemic emboli (5.41%/year) than warfarin-experienced patients (1.42%/year), a pattern not seen when starting apixaban. No similar increase in events with apixaban versus warfarin was seen during temporary or permanent study drug discontinuation during the trial. CONCLUSIONS: The excess in thrombotic and bleeding events in the apixaban group after study drug discontinuation appears to be related to an increased risk associated with the initiation of a VKA rather than a direct effect of apixaban. Whether ≥2 days of apixaban bridging improves outcomes during VKA transition is unknown and deserves further evaluation.

Documentation of study medication dispensing in a prospective large randomized clinical trial: experiences from the ARISTOTLE Trial.

BACKGROUND: In ARISTOTLE, apixaban resulted in a 21% reduction in stroke, a 31% reduction in major bleeding, and an 11% reduction in death. However, approval of apixaban was delayed to investigate a statement in the clinical study report that "7.3% of subjects in the apixaban group and 1.2% of subjects in the warfarin group received, at some point during the study, a container of the wrong type." METHODS: Rates of study medication dispensing error were characterized through reviews of study medication container tear-off labels in 6,520 participants from randomly selected study sites. The potential effect of dispensing errors on study outcomes was statistically simulated in sensitivity analyses in the overall population. RESULTS: The rate of medication dispensing error resulting in treatment error was 0.04%. Rates of participants receiving at least 1 incorrect container were 1.04% (34/3,273) in the apixaban group and 0.77% (25/3,247) in the warfarin group. Most of the originally reported errors were data entry errors in which the correct medication container was dispensed but the wrong container number was entered into the case report form. Sensitivity simulations in the overall trial population showed no meaningful effect of medication dispensing error on the main efficacy and safety outcomes. CONCLUSIONS: Rates of medication dispensing error were low and balanced between treatment groups. The initially reported dispensing error rate was the result of data recording and data management errors and not true medication dispensing errors. These analyses confirm the previously reported results of ARISTOTLE.

Apixaban with antiplatelet therapy after acute coronary syndrome.

BACKGROUND: Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome. METHODS: We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events. RESULTS: The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P=0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P=0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo. CONCLUSIONS: The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events. (Funded by Bristol-Myers Squibb and Pfizer; APPRAISE-2 ClinicalTrials.gov number, NCT00831441.).

Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment.

BACKGROUND: Many patients with atrial fibrillation (AF) at moderate or high risk for stroke are not treated with a vitamin K antagonist (VKA). Presently, the only alternative to a VKA with a labeled indication for AF is antiplatelet therapy with acetylsalicylic acid (ASA), which is much less effective than a VKA for prevention of stroke. The novel oral factor Xa inhibitor, apixaban, is being developed for prevention of stroke in AF. A noninferiority trial of apixaban versus a VKA (warfarin) is being conducted but does not address the large unmet need of AF patients at risk of stroke who are unsuitable for or unwilling to take a VKA. Apixaban may be an attractive alternative to ASA for prevention of stroke in patients with AF who cannot or will not take a VKA. DESIGN: AVERROES is a double-blind, double-dummy superiority trial of apixaban 5 mg twice daily (2.5 mg twice daily in selected patients) compared with ASA 81 to 324 mg once daily in patients with AF and at least 1 risk factor for stroke who have failed or are unsuitable for VKA therapy. The primary outcome is stroke or systemic embolism, and the primary safety outcome is major bleeding. The trial is event driven and is expected to enroll at least 5,600 patients. CONCLUSIONS: By evaluating the use of apixaban as a replacement for ASA in AF patients who are not treated with a VKA, the AVERROES study is addressing an important unmet clinical need. The results of AVERROES will be complementary to those of a parallel noninferiority trial comparing apixaban with VKA therapy in patients with AF who are able to receive a VKA.