Synthesis and Characterization of a Terminal Iron(II)-PH2 Complex and a Series of Iron(II)-PH3 Complexes.

Reported is the reaction of a series of iron(II) bisphosphine complexes with PH3 in the presence of NaBArF4 [where BArF4 = tetrakis(3,5-bis(trifluoromethyl)phenyl)borate]. The iron(II) bisphosphine reagents bear two chlorides or a hydride and a chloride motif. We have isolated six different cationic terminal-bound PH3 complexes and undertaken rigorous characterization by NMR spectroscopy, single crystal X-ray diffraction, and mass spectrometry, where the PH3 often remains intact during the ionization process. Unusual bis- and tris-PH3 complexes are among the compounds isolated. Changing the monophosphine from PH3 to PMe3 results in the formation of an unusual Fe7 cluster, but with no PMe3 being ligated. Finally, by using an iron(0) source, we have provided a rare example of a terminally bound iron-PH2 complex.

Development of a conceptual framework to scale up co-managed care for older patients with hip fracture in China: a qualitative study.

BACKGROUND: Hip fracture creates a major burden on society due to high mortality, loss of independence and excess medical costs for older people. A multidisciplinary co-managed model of care is widely considered as the best practice for the management of older patients with hip fracture. The study aims to develop a conceptual framework to inform the future scale-up of this model of care through the identification of barriers and enablers that may influence successful uptake. METHODS: This qualitative study was conducted within an interventional study, which aimed to test the effectiveness of co-managed model of care for older patients with hip fracture. Health providers and health administrators from three hospitals were purposively selected and interviewed in-depth. The Consolidated Framework for Implementation Research (CFIR) was used to develop interview guides, collect and analyse data. Inductive and deductive approaches were used to generate enablers or barriers, aligned with the CFIR constructs. All barriers or enablers were inductively summarised to a conceptual framework with essential components to guide the implementation of co-managed model of care in other hospitals. RESULTS: A total of 13 health providers and 3 health administrators were recruited. The main barriers to co-managed care implementation included perceived complexity of implementation, insufficient international collaboration and incentives, the absence of national guideline support and lack of digital health applications for communication between health providers, insufficient number of health providers and beds, and poor understanding about the effectiveness of this care model. A conceptual framework for future scale-up was then developed, consisting of the following essential components: hospital authority support, enabling environment, adequate number of beds, sufficient and skilled health providers, use of digital health technology, regular quality supervision, evaluation and feedback, and external collaborations. CONCLUSIONS: Despite the complexity of the intervention, the co-managed model of care has the potential to be implemented and promoted in China and in similar settings, although there is a need to demonstrate feasibility in different settings.

Taming PH3: State of the Art and Future Directions in Synthesis.

Appetite for reactions involving PH3 has grown in the past few years. This in part is due to the ability to generate PH3 cleanly and safely via digestion of cheap metal phosphides with acids, thus avoiding pressurized cylinders and specialized equipment. In this perspective we highlight current trends in forming new P-C/P-OC bonds with PH3 and discuss the challenges involved with selectivity and product separation encumbering these reactions. We highlight the reactivity of PH3 with main group reagents, building on the early pioneering work with transition metal complexes and PH3. Additionally, we highlight the recent renewal of interest in alkali metal sources of H2P- which are proving to be useful synthons for chemistry across the periodic table. Such MPH2 sources are being used to generate the desired products in a more controlled fashion and are allowing access to unexplored phosphorus-containing species.

Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose monotherapy in patients with hypertension (QUARTET): a phase 3, randomised, double-blind, active-controlled trial.

BACKGROUND: Treatment inertia is a recognised barrier to blood pressure control, and simpler, more effective treatment strategies are needed. We hypothesised that a hypertension management strategy starting with a single pill containing ultra-low-dose quadruple combination therapy would be more effective than a strategy of starting with monotherapy. METHODS: QUARTET was a multicentre, double-blind, parallel-group, randomised, phase 3 trial among Australian adults (≥18 years) with hypertension, who were untreated or receiving monotherapy. Participants were randomly assigned to either treatment, that started with the quadpill (containing irbesartan at 37·5 mg, amlodipine at 1·25 mg, indapamide at 0·625 mg, and bisoprolol at 2·5 mg) or an indistinguishable monotherapy control (irbesartan 150 mg). If blood pressure was not at target, additional medications could be added in both groups, starting with amlodipine at 5 mg. Participants were randomly assigned using an online central randomisation service. There was a 1:1 allocation, stratified by site. Allocation was masked to all participants and study team members (including investigators and those assessing outcomes) except the manufacturer of the investigational product and one unmasked statistician. The primary outcome was difference in unattended office systolic blood pressure at 12 weeks. Secondary outcomes included blood pressure control (standard office blood pressure <140/90 mm Hg), safety, and tolerability. A subgroup continued randomly assigned allocation to 12 months to assess long-term effects. Analyses were per intention to treat. This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry, ACTRN12616001144404, and is now complete. FINDINGS: From June 8, 2017, to Aug 31, 2020, 591 participants were recruited, with 743 assessed for eligibility, 152 ineligible or declined, 300 participants randomly assigned to intervention of initial quadpill treatment, and 291 to control of initial standard dose monotherapy treatment. The mean age of the 591 participants was 59 years (SD 12); 356 (60%) were male and 235 (40%) were female; 483 (82%) were White, 70 (12%) were Asian, and 38 (6%) reported as other ethnicity; and baseline mean unattended office blood pressure was 141 mm Hg (SD 13)/85 mm Hg (SD 10). By 12 weeks, 44 (15%) of 300 participants had additional blood pressure medications in the intervention group compared with 115 (40%) of 291 participants in the control group. Systolic blood pressure was lower by 6·9 mm Hg (95% CI 4·9-8·9; p<0·0001) and blood pressure control rates were higher in the intervention group (76%) versus control group (58%; relative risk [RR] 1·30, 95% CI 1·15-1·47; p<0·0001). There was no difference in adverse event-related treatment withdrawals at 12 weeks (intervention 4·0% vs control 2·4%; p=0·27). Among the 417 patients who continued, uptitration occurred more frequently among control participants than intervention participants (p<0·0001). However, at 52 weeks mean unattended systolic blood pressure remained lower by 7·7 mm Hg (95% CI 5·2-10·3) and blood pressure control rates higher in the intervention group (81%) versus control group (62%; RR 1·32, 95% CI 1·16-1·50). In all randomly assigned participants up to 12 weeks, there were seven (3%) serious adverse events in the intervention group and three (1%) serious adverse events in the control group. INTERPRETATION: A strategy with early treatment of a fixed-dose quadruple quarter-dose combination achieved and maintained greater blood pressure lowering compared with the common strategy of starting monotherapy. This trial demonstrated the efficacy, tolerability, and simplicity of a quadpill-based strategy. FUNDING: National Health and Medical Research Council, Australia.

Dehydrocoupling Polymerization: Poly(silylether) Synthesis by Using an Iron ß-Diketiminate Catalyst.

We describe the iron-catalyzed polymerizations of diol and silane monomers to obtain fourteen different poly(silylether) products with number average molecular weights (Mn ) up to 36.3 kDa. The polymerization reactions developed in this study are operationally simple and applicable to 1° and 2° silane monomer substrates and a range of benzylic and aliphatic diol substrates as well as one polyol example. The polymers were characterized by IR spectroscopy, DSC and TGA and, where solubility allowed, 1 H, 13 C{1 H}, 29 Si{1 H} NMR spectroscopies, GPC and MALDI-TOF were also employed. The materials obtained displayed low Tg values (-70.6 to 19.1 °C) and were stable upon heating up to T-5%,Ar 421.6 °C. A trend in T-5%,Ar was observed whereby use of a 2° silane leads to higher T-5%,Ar compared to those obtained using a 1° silane. Reaction monitoring was undertaken by in situ gas evolution studies coupled with GPC analysis to follow the progression of chain-length growth which confirmed a condensation polymerization-type mechanism.

Are We There Yet? Exploring the Use of Single-Pill Combination Therapy in the Management of Raised Blood Pressure in Australia.

OBJECTIVE: Single-pill combination (SPC) therapy is recommended as first-line therapy for most patients in global hypertension guidelines due to benefits of improved adherence and blood pressure (BP) control. We aimed to understand factors affecting SPC use in the management of raised BP in Australia. DESIGN: A mixed-method study comprising of qualitative (policy review and interviews) and quantitative (Pharmaceutical Benefits Scheme [PBS] data) approaches. MAIN OUTCOME MEASURES: Australian and international hypertension guideline recommendations regarding SPC use; the Australian registration and subsidy approval processes of SPCs; use of SPCs on the PBS; cost-analysis of PBS-listed SPCs compared to free-drug combinations; perceptions of healthcare providers towards SPCs. RESULTS: The 2016 Australian Heart Foundation's "Guideline for the diagnosis and management of hypertension in adults" does not recommend combination therapy (including SPCs) as first-line treatment. Additional challenges in the uptake of SPCs include: (1) the additional PBS requirements and barriers imposed for the listing of SPCs. (2) Script volumes for SPCs have not matched the rise in the number of SPCs listed for subsidy, have plateaued since 2016 and remained significantly lower than single constituent scripts. (3) SPCs are not subsidised by the PBS for initial treatment. Most SPCs provided substantial cost savings for individual patients compared to free-drug combinations. Health care providers were positive about the cost-saving and convenience of SPCs, however perceived negatives included inflexibility of SPCs during dose titration, medicine shortages, and potential adverse effects when initiating treatment with multiple drugs. CONCLUSION: The safety, efficacy and cost-saving potential of SPCs have been established in the literature but several roadblocks in the existing health system in Australia impede uptake. Interventions addressing these barriers may facilitate improved uptake, which may in turn improve blood pressure control in Australia.

An Iron-Catalyzed Route to Dewar 1,3,5-Triphosphabenzene and Subsequent Reactivity.

The application of an alkyne cyclotrimerization regime with an [Fe(salen)]2 -µ-oxo (1) catalyst to triphenylmethylphosphaalkyne (2) yields gram-scale quantities of 2,4,6-tris(triphenylmethyl)-Dewar-1,3,5-triphosphabenzene (3). Bulky lithium salt LiHMDS facilitates a rearrangement of 3 to the 1,3,5-triphosphabenzene valence isomer (3'), which subsequently undergoes an intriguing phosphorus migration reaction to form the ring-contracted species (3''). Density functional theory calculations provide a plausible mechanism for this rearrangement. Given the stability of 3, a diverse array of unprecedented transformations was investigated. We report novel crystallographically characterized products of successful nucleophilic/electrophilic addition and protonation/oxidation reactions.

Ultra-low-dose quadruple combination blood pressure-lowering therapy in patients with hypertension: The QUARTET randomized controlled trial protocol.

High blood pressure is the leading cause of preventable morbidity and mortality globally. Many patients remain on single-drug treatment with poor control, although guidelines recognize that most require combination therapy for blood pressure control. Our hypothesis is that a single-pill combination of 4 blood pressure-lowering agents each at a quarter dose may provide a simple, safe, and effective blood pressure-lowering solution which may also improve long-term adherence. The Quadruple UltrA-low-dose tReaTment for hypErTension (QUARTET) double-blind, active-controlled, randomized clinical trial will examine whether ultra-low-dose quadruple combination therapy is more effective than guideline-recommended standard care in lowering blood pressure. QUARTET will enroll 650 participants with high blood pressure either on no treatment or on monotherapy. Participants will be randomized 1:1 and allocated to intervention therapy of a single pill (quadpill) containing irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg or to control therapy of a single identical-appearing pill containing irbesartan 150 mg. In both arms, step-up therapy of open-label amlodipine 5 mg will be provided if blood pressure is >140/90 at 6 weeks. The primary outcome is the difference between groups in the change from baseline in mean unattended automated office systolic blood pressure at 12-week follow-up. The primary outcome and some secondary outcomes will be assessed at 12 weeks; there is an optional 12-month extension phase to assess longer-term efficacy and tolerability. Our secondary aims are to assess if this approach is safe, has fewer adverse effects, and has better tolerability compared to standard care control. QUARTET will therefore provide evidence for the effectiveness and safety of a new paradigm in the management of high blood pressure.

Polymerization of Allenes by Using an Iron(II) ß-Diketiminate Pre-Catalyst to Generate High Mn Polymers.

Herein, we report an iron(II)-catalyzed polymerization of arylallenes. This reaction proceeds rapidly at room temperature in the presence of a hydride co-catalyst to generate polymers of weight up to Mn =189 000 Da. We have determined the polymer structure and chain length for a range of monomers through a combination of NMR, differential scanning calorimetry (DSC) and gel permeation chromatography (GPC) analysis. Mechanistically, we postulate that the co-catalyst does not react to form an iron(II) hydride in situ, but instead the chain growth is proceeding via a reactive Fe(III) species. We have also performed kinetic and isotopic experiments to further our understanding. The formation of a highly unusual 1,3-substituted cyclobutane side-product is also investigated.

Iron Catalyzed Double Bond Isomerization: Evidence for an FeI /FeIII Catalytic Cycle.

Iron-catalyzed isomerization of alkenes is reported using an iron(II) ß-diketiminate pre-catalyst. The reaction proceeds with a catalytic amount of a hydride source, such as pinacol borane (HBpin) or ammonia borane (H3 N⋅BH3 ). Reactivity with both allyl arenes and aliphatic alkenes has been studied. The catalytic mechanism was investigated by a variety of means, including deuteration studies, Density Functional Theory (DFT) and Electron Paramagnetic Resonance (EPR) spectroscopy. The data obtained support a pre-catalyst activation step that gives access to an η2 -coordinated alkene FeI complex, followed by oxidative addition of the alkene to give an FeIII intermediate, which then undergoes reductive elimination to allow release of the isomerization product.

Hydrogen/Halogen Exchange of Phosphines for the Rapid Formation of Cyclopolyphosphines.

The hydrogen/halogen exchange of phosphines has been exploited to establish a truly useable substrate scope and straightforward methodology for the formation of cyclopolyphosphines. Starting from a single dichlorophosphine, a sacrificial proton "donor phosphine" makes the rapid, mild synthesis of cyclopolyphosphines possible: reactions are complete within 10 min at room temperature. Novel (aryl)cyclopentaphosphines (ArP)5 have been formed in good conversion, with the crystal structures presented. The use of catalytic quantities of iron(III) acetylacetonate provides significant improvements in conversion in the context of diphosphine (Ar2P)2 and alkyl-substituted cyclotetra- or cyclopentaphosphine ((AlkylP)n, where n = 4 or 5) formation. Both iron-free and iron-mediated reactions show high levels of selectivity for one specific ring size. Finally, investigations into the reactivity of Fe(acac)3 suggest that the iron species is acting as a sink for the hydrochloric acid byproduct of the reaction.

An electronic decision support-based complex intervention to improve management of cardiovascular risk in primary health care: a cluster randomised trial (INTEGRATE).

OBJECTIVES: To determine whether a multifaceted primary health care intervention better controlled cardiovascular disease (CVD) risk factors in patients with high risk of CVD than usual care. DESIGN, SETTING: Parallel arm, cluster randomised trial in 71 Australian general practices, 5 December 2016 - 13 September 2019. PARTICIPANTS: General practices that predominantly used an electronic medical record system compatible with the HealthTracker electronic decision support tool, and willing to implement all components of the INTEGRATE intervention. INTERVENTION: Electronic point-of-care decision support for general practices; combination cardiovascular medications (polypills); and a pharmacy-based medication adherence program. MAIN OUTCOME MEASURES: Proportion of patients with high CVD risk not on an optimal preventive medication regimen at baseline who had achieved both blood pressure and low-density lipoprotein (LDL) cholesterol goals at study end. RESULTS: After a median 15 months' follow-up, primary outcome data were available for 4477 of 7165 patients in the primary outcome cohort (62%). The proportion of patients who achieved both treatment targets was similar in the intervention (423 of 2156; 19.6%) and control groups (466 of 2321; 20.1%; relative risk, 1.06; 95% CI, 0.85-1.32). Further, no statistically significant differences were found for a number of secondary outcomes, including risk factor screening, preventive medication prescribing, and risk factor levels. Use of intervention components was low; it was highest for HealthTracker, used at least once for 347 of 3236 undertreated patients with high CVD risk (10.7%). CONCLUSIONS: Despite evidence for the efficacy of its individual components, the INTEGRATE intervention was not broadly implemented and did not improve CVD risk management in participating Australian general practices. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12616000233426 (prospective).

Amine-Boranes as Transfer Hydrogenation and Hydrogenation Reagents: A Mechanistic Perspective.

Transfer hydrogenation (TH) has historically been dominated by Meerwein-Ponndorf-Verley (MPV) reactions. However, with growing interest in amine-boranes, not least ammonia-borane (H3 N⋅BH3 ), as potential hydrogen storage materials, these compounds have also started to emerge as an alternative reagent in TH reactions. In this Review we discuss TH chemistry using H3 N⋅BH3 and their analogues (amine-boranes and metal amidoboranes) as sacrificial hydrogen donors. Three distinct pathways were considered: 1) classical TH, 2) nonclassical TH, and 3) hydrogenation. Simple experimental mechanistic probes can be employed to distinguish which pathway is operating and computational analysis can corroborate or discount mechanisms. We find that the pathway in operation can be perturbed by changing the temperature, solvent, amine-borane, or even the substrate used in the system, and subsequently assignment of the mechanism can become nontrivial.

Highly Sensitive Real-Time Isotopic Quantification of Water by ATR-FTIR.

A method has been developed to reliably quantify the isotopic composition of liquid water, requiring only immersion of a "ReactIR" probe in the sample under test. The accuracy and robustness of this method has been extensively tested using a deuterium/protium system, and substantial improvements in sensitivity were obtained using highly novel chemical signal amplification methods demonstrating a standard deviation of 247 ppb D (a δD of 1.6 ‰). This compares favorably with other more costly and time-consuming techniques and is over 20 times more sensitive than any previously published FTIR study. Computational simulations of a model system match the experimental data and show how these methods can be adapted to a tritium/protium system.

Room Temperature Iron-Catalyzed Transfer Hydrogenation and Regioselective Deuteration of Carbon-Carbon Double Bonds.

An iron catalyst has been developed for the transfer hydrogenation of carbon-carbon multiple bonds. Using a well-defined ß-diketiminate iron(II) precatalyst, a sacrificial amine and a borane, even simple, unactivated alkenes such as 1-hexene undergo hydrogenation within 1 h at room temperature. Tuning the reagent stoichiometry allows for semi- and complete hydrogenation of terminal alkynes. It is also possible to hydrogenate aminoalkenes and aminoalkynes without poisoning the catalyst through competitive amine ligation. Furthermore, by exploiting the separate protic and hydridic nature of the reagents, it is possible to regioselectively prepare monoisotopically labeled products. DFT calculations define a mechanism for the transfer hydrogenation of propene with nBuNH2 and HBpin that involves the initial formation of an iron(II)-hydride active species, 1,2-insertion of propene, and rate-limiting protonolysis of the resultant alkyl by the amine N-H bond. This mechanism is fully consistent with the selective deuteration studies, although the calculations also highlight alkene hydroboration and amine-borane dehydrocoupling as competitive processes. This was resolved by reassessing the nature of the active transfer hydrogenation agent: experimentally, a gel is observed in catalysis, and calculations suggest this can be formulated as an oligomeric species comprising H-bonded amine-borane adducts. Gel formation serves to reduce the effective concentrations of free HBpin and nBuNH2 and so disfavors both hydroboration and dehydrocoupling while allowing alkene migratory insertion (and hence transfer hydrogenation) to dominate.

Process evaluation in the field: global learnings from seven implementation research hypertension projects in low-and middle-income countries.

BACKGROUND: Process evaluation is increasingly recognized as an important component of effective implementation research and yet, there has been surprisingly little work to understand what constitutes best practice. Researchers use different methodologies describing causal pathways and understanding barriers and facilitators to implementation of interventions in diverse contexts and settings. We report on challenges and lessons learned from undertaking process evaluation of seven hypertension intervention trials funded through the Global Alliance of Chronic Diseases (GACD). METHODS: Preliminary data collected from the GACD hypertension teams in 2015 were used to inform a template for data collection. Case study themes included: (1) description of the intervention, (2) objectives of the process evaluation, (3) methods including theoretical basis, (4) main findings of the study and the process evaluation, (5) implications for the project, policy and research practice and (6) lessons for future process evaluations. The information was summarized and reported descriptively and narratively and key lessons were identified. RESULTS: The case studies were from low- and middle-income countries and Indigenous communities in Canada. They were implementation research projects with intervention arm. Six theoretical approaches were used but most comprised of mixed-methods approaches. Each of the process evaluations generated findings on whether interventions were implemented with fidelity, the extent of capacity building, contextual factors and the extent to which relationships between researchers and community impacted on intervention implementation. The most important learning was that although process evaluation is time consuming, it enhances understanding of factors affecting implementation of complex interventions. The research highlighted the need to initiate process evaluations early on in the project, to help guide design of the intervention; and the importance of effective communication between researchers responsible for trial implementation, process evaluation and outcome evaluation. CONCLUSION: This research demonstrates the important role of process evaluation in understanding implementation process of complex interventions. This can help to highlight a broad range of system requirements such as new policies and capacity building to support implementation. Process evaluation is crucial in understanding contextual factors that may impact intervention implementation which is important in considering whether or not the intervention can be translated to other contexts.

Putting polypills into practice: challenges and lessons learned.

Regulatory approvals for cardiovascular polypills are increasing rapidly across more than 30 countries. The evidence clearly shows polypills improve adherence and cardiovascular disease risk factors for patients with indications for use of polypill components-ie, those with established cardiovascular disease or at high risk. However, the implementation of polypills into clinical practice has many challenges. The clinical trials literature provides insights into the clinical impact of a polypill strategy, including cost-effectiveness, safety of use, substantial improvement in adherence, and better risk factor control than usual care. Despite the clear need for such a strategy and the available clinical data backing up the use of the polypill in different patient populations, challenges to widespread implementation, such as an absence of government reimbursement and poor physician uptake (identified from on the ground experience in countries following commercial rollout), have greatly obstructed real-world implementation. Obtaining the full public health benefit of polypills will require education, advocacy, endorsement, and implementation by key global agencies such as WHO and national clinical bodies, as well as endorsement from governments.

Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review.

BACKGROUND: Globally, most patients with hypertension are treated with monotherapy, and control rates are poor because monotherapy only reduces blood pressure by around 9/5 mm Hg on average. There is a pressing need for blood pressure-control strategies with improved efficacy and tolerability. We aimed to assess whether ultra-low-dose combination therapy could meet these needs. METHODS: We did a randomised, placebo-controlled, double-blind, crossover trial of a quadpill-a single capsule containing four blood pressure-lowering drugs each at quarter-dose (irbesartan 37·5 mg, amlodipine 1·25 mg, hydrochlorothiazide 6·25 mg, and atenolol 12·5 mg). Participants with untreated hypertension were enrolled from four centres in the community of western Sydney, NSW, Australia, mainly by general practitioners. Participants were randomly allocated by computer to either the quadpill or matching placebo for 4 weeks; this treatment was followed by a 2-week washout, then the other study treatment was administered for 4 weeks. Study staff and participants were unaware of treatment allocations, and masking was achieved by use of identical opaque capsules. The primary outcome was placebo-corrected 24-h systolic ambulatory blood pressure reduction after 4 weeks and analysis was by intention to treat. We also did a systematic review of trials evaluating the efficacy and safety of quarter-standard-dose blood pressure-lowering therapy against placebo. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614001057673. The trial ended after 1 year and this report presents the final analysis. FINDINGS: Between November, 2014, and December, 2015, 55 patients were screened for our randomised trial, of whom 21 underwent randomisation. Mean age of participants was 58 years (SD 11) and mean baseline office and 24-h systolic and diastolic blood pressure levels were 154 (14)/90 (11) mm Hg and 140 (9)/87 (8) mm Hg, respectively. One individual declined participation after randomisation and two patients dropped out for administrative reasons. The placebo-corrected reduction in systolic 24-h blood pressure with the quadpill was 19 mm Hg (95% CI 14-23), and office blood pressure was reduced by 22/13 mm Hg (p<0·0001). During quadpill treatment, 18 (100%) of 18 participants achieved office blood pressure less than 140/90 mm Hg, compared with six (33%) of 18 during placebo treatment (p=0·0013). There were no serious adverse events and all patients reported that the quadpill was easy to swallow. Our systematic review identified 36 trials (n=4721 participants) of one drug at quarter-dose and six trials (n=312) of two drugs at quarter-dose, against placebo. The pooled placebo-corrected blood pressure-lowering effects were 5/2 mm Hg and 7/5 mm Hg, respectively (both p<0·0001), and there were no side-effects from either regimen. INTERPRETATION: The findings of our small trial in the context of previous randomised evidence suggest that the benefits of quarter-dose therapy could be additive across classes and might confer a clinically important reduction in blood pressure. Further examination of the quadpill concept is needed to investigate effectiveness against usual treatment options and longer term tolerability. FUNDING: National Heart Foundation, Australia; University of Sydney; and National Health and Medical Research Council of Australia.

Fixed Low-Dose Triple Combination Antihypertensive Medication vs Usual Care for Blood Pressure Control in Patients With Mild to Moderate Hypertension in Sri Lanka: A Randomized Clinical Trial.

Importance: Poorly controlled hypertension is a leading global public health problem requiring new treatment strategies. Objective: To assess whether a low-dose triple combination antihypertensive medication would achieve better blood pressure (BP) control vs usual care. Design, Setting, and Participants: Randomized, open-label trial of a low-dose triple BP therapy vs usual care for adults with hypertension (systolic BP >140 mm Hg and/or diastolic BP >90 mm Hg; or in patients with diabetes or chronic kidney disease: >130 mm Hg and/or >80 mm Hg) requiring initiation (untreated patients) or escalation (patients receiving monotherapy) of antihypertensive therapy. Patients were enrolled from 11 urban hospital clinics in Sri Lanka from February 2016 to May 2017; follow-up ended in October 2017. Interventions: A once-daily fixed-dose triple combination pill (20 mg of telmisartan, 2.5 mg of amlodipine, and 12.5 mg of chlorthalidone) therapy (n = 349) or usual care (n = 351). Main Outcomes and Measures: The primary outcome was the proportion achieving target systolic/diastolic BP (<140/90 mm Hg or <130/80 mm Hg in patients with diabetes or chronic kidney disease) at 6 months. Secondary outcomes included mean systolic/diastolic BP difference during follow-up and withdrawal of BP medications due to an adverse event. Results: Among 700 randomized patients (mean age, 56 years; 58% women; 29% had diabetes; mean baseline systolic/diastolic BP, 154/90 mm Hg), 675 (96%) completed the trial. The triple combination pill increased the proportion achieving target BP vs usual care at 6 months (70% vs 55%, respectively; risk difference, 12.7% [95% CI, 3.2% to 22.0%]; P < .001). Mean systolic/diastolic BP at 6 months was 125/76 mm Hg for the triple combination pill vs 134/81 mm Hg for usual care (adjusted difference in postrandomization BP over the entire follow-up: systolic BP, -9.8 [95% CI, -7.9 to -11.6] mm Hg; diastolic BP, -5.0 [95% CI, -3.9 to -6.1] mm Hg; P < .001 for both comparisons). Overall, 419 adverse events were reported in 255 patients (38.1% for triple combination pill vs 34.8% for usual care) with the most common being musculoskeletal pain (6.0% and 8.0%, respectively) and dizziness, presyncope, or syncope (5.2% and 2.8%). There were no significant between-group differences in the proportion of patient withdrawal from BP-lowering therapy due to adverse events (6.6% for triple combination pill vs 6.8% for usual care). Conclusions and Relevance: Among patients with mild to moderate hypertension, treatment with a pill containing low doses of 3 antihypertensive drugs led to an increased proportion of patients achieving their target BP goal vs usual care. Use of such medication as initial therapy or to replace monotherapy may be an effective way to improve BP control. Trial Registration: anzctr.org.au Identifier: ACTRN12612001120864; slctr.lk Identifier: SLCTR/2015/020.

Opioid suppression of conditioned anticipatory brain responses to breathlessness.

Opioid painkillers are a promising treatment for chronic breathlessness, but are associated with potentially fatal side effects. In the treatment of breathlessness, their mechanisms of action are unclear. A better understanding might help to identify safer alternatives. Learned associations between previously neutral stimuli (e.g. stairs) and repeated breathlessness induce an anticipatory threat response that may worsen breathlessness, contributing to the downward spiral of decline seen in clinical populations. As opioids are known to influence associative learning, we hypothesized that they may interfere with the brain processes underlying a conditioned anticipatory response to breathlessness in relevant brain areas, including the amygdala and the hippocampus. Healthy volunteers viewed visual cues (neutral stimuli) immediately before induction of experimental breathlessness with inspiratory resistive loading. Thus, an association was formed between the cue and breathlessness. Subsequently, this paradigm was repeated in two identical neuroimaging sessions with intravenous infusions of either low-dose remifentanil (0.7ng/ml target-controlled infusion) or saline (randomised). During saline infusion, breathlessness anticipation activated the right anterior insula and the adjacent operculum. Breathlessness was associated with activity in a network including the insula, operculum, dorsolateral prefrontal cortex, anterior cingulate cortex and the primary sensory and motor cortices. Remifentanil reduced breathlessness unpleasantness but not breathlessness intensity. Remifentanil depressed anticipatory activity in the amygdala and the hippocampus that correlated with reductions in breathlessness unpleasantness. During breathlessness, remifentanil decreased activity in the anterior insula, anterior cingulate cortex and sensory motor cortices. Remifentanil-induced reduction in breathlessness unpleasantness was associated with increased activity in the rostral anterior cingulate cortex and nucleus accumbens, components of the endogenous opioid system known to decrease the perception of aversive stimuli. These findings suggest that in addition to effects on brainstem respiratory control, opioids palliate breathlessness through an interplay of altered associative learning mechanisms. These mechanisms provide potential targets for novel ways to develop and assess treatments for chronic breathlessness.