Strategy implementation: what is the failure rate?

It is often claimed that 50–90% of strategic initiatives fail. Although these claims have had a significant impact on management theory and practice, they are controversial. We aim to clarify why this is the case. Towards this end, an extensive review of the literature is presented, assessed, compared and discussed. We conclude that while it is widely acknowledged that the implementation of a new strategy can be a difficult task, the true rate of implementation failure remains to be determined. Most of the estimates presented in the literature are based on evidence that is outdated, fragmentary, fragile or just absent. Careful consideration is advised before using current estimates to justify changes in the theory and practice. A set of guiding principles is presented for assisting researchers to produce better estimates of the rates of failure

Quality of life among people living with hypertension in a rural Vietnam community

Background - To respond to growing prevalence of hypertension in Vietnam, it is critical to have an in-depth understanding about quality of life (QOL) among people living with hypertension and related factors. This study aimed to measure QOL among hypertensive people in a rural community in Vietnam, and its association with socio-demographic characteristics and factors related to treatment. Methods - This study was conducted in a rural community located 60 km from Ho Chi Minh City. Face-to-face interviews were conducted among 275 hypertensive people aged 50 years and above using WHOQOL-BREF questionnaire. Descriptive statistics were used to examine mean scores of quality of life. Cronbach’s alpha coefficient and Pearson’s correlation coefficient were applied to estimate the internal consistency, and the level of agreement between different domains of WHOQOL-BREF, respectively. Independent T-test and ANOVA test followed by multiple linear regression analyses were used to measure the association between QOL domains and independent variables. Results - Both overall WHOQOL-BREF and each domain had a good internal consistency, ranging from 0.65 to 0.88. The QOL among hypertensive patients was found moderate in all domains, except for psychological domain that was fairly low (mean = 49.4). Backward multiple linear regressions revealed that being men, married, attainment of higher education, having physical activities at moderate level, and adherence to treatment were positively associated with QOL. However, older age and presence of co-morbidity were negatively associated with QOL. Conclusion - WHOQOL-BREF is a reliable instrument to measure QOL among hypertensive patients. The results revealed low QOL in psychological domain and inequality in QOL across socio-demographic characteristics. Given the results, encouraging physical activities and strengthening treatment adherence should be considered to improve QOL of hypertensive people, especially for psychological aspect. Actions to improve QOL among hypertensive patients targeted towards women, lower educated and unmarried patients are needed in the setting

Detecting intratumoral heterogeneity of EGFR activity by liposome-based in vivo transfection of a fluorescent biosensor

Despite decades of research in the epidermal growth factor receptor (EGFR) signalling field, and many targeted anti-cancer drugs that have been tested clinically, the success rate for these agents in the clinic is low, particularly in terms of the improvement of overall survival. Intratumoral heterogeneity is proposed as a major mechanism underlying treatment failure of these molecule-targeted agents. Here we highlight the application of fluorescence lifetime microscopy (FLIM)-based biosensing to demonstrate intratumoral heterogeneity of EGFR activity. For sensing EGFR activity in cells, we used a genetically encoded CrkII-based biosensor which undergoes conformational changes upon tyrosine-221 phosphorylation by EGFR. We transfected this biosensor into EGFR-positive tumour cells using targeted lipopolyplexes bearing EGFR-binding peptides at their surfaces. In a murine model of basal-like breast cancer, we demonstrated a significant degree of intratumoral heterogeneity in EGFR activity, as well as the pharmacodynamic effect of a radionuclide-labeled EGFR inhibitor in situ. Furthermore, a significant correlation between high EGFR activity in tumour cells and macrophage-tumour cell proximity was found to in part account for the intratumoral heterogeneity in EGFR activity observed. The same effect of macrophage infiltrate on EGFR activation was also seen in a colorectal cancer xenograft. In contrast, a non-small cell lung cancer xenograft expressing a constitutively active EGFR conformational mutant exhibited macrophage proximity-independent EGFR activity. Our study validates the use of this methodology to monitor therapeutic response in terms of EGFR activity. In addition, we found iNOS gene induction in macrophages that are cultured in tumour cell-conditioned media as well as an iNOS activity-dependent increase in EGFR activity in tumour cells. These findings point towards an immune microenvironment-mediated regulation that gives rise to the observed intratumoral heterogeneity of EGFR signalling activity in tumour cells in vivo

Emergence of 3D Printed Dosage Forms: Opportunities and Challenges

The recent introduction of the first FDA approved 3D-printed drug has fuelled interest in 3D printing technology, which is set to revolutionize healthcare. Since its initial use, this rapid prototyping (RP) technology has evolved to such as extent that it is currently being used in a wide range of applications including in tissue engineering, dentistry, construction, automotive and aerospace. However, in the pharmaceutical industry this technology is still in its infancy and its potential yet to be fully explored. This paper presents various 3D printing technologies such as stereolithographic, powder based, selective laser sintering, fused deposition modelling and semi-solid extrusion 3D printing. It also provides a comprehensive review of previous attempts at using 3D printing technologies on the manufacturing dosage forms with a particular focus on oral tablets. Their advantages particularly with adaptability in the pharmaceutical field have been highlighted, including design flexibility and control and manufacture which enables the preparation of dosage forms with complex designs and geometries, multiple actives and tailored release profiles. An insight into the technical challenges facing the different 3D printing technologies such as the formulation and processing parameters is provided. Light is also shed on the different regulatory challenges that need to be overcome for 3D printing to fulfil its real potential in the pharmaceutical industry

Mechanism and disease-association of E2 conjugating enzymes:lessons from UBE2T and UBE2L3

Ubiquitin signalling is a fundamental eukaryotic regulatory system, controlling diverse cellular functions. A cascade of E1, E2, and E3 enzymes is required for assembly of distinct signals, whereas an array of deubiquitinases and ubiquitin-binding modules edit, remove, and translate the signals. In the centre of this cascade sits the E2-conjugating enzyme, relaying activated ubiquitin from the E1 activating enzyme to the substrate, usually via an E3 ubiquitin ligase. Many disease states are associated with dysfunction of ubiquitin signalling, with the E3s being a particular focus. However, recent evidence demonstrates that mutations or impairment of the E2s can lead to severe disease states, including chromosome instability syndromes, cancer predisposition, and immunological disorders. Given their relevance to diseases, E2s may represent an important class of therapeutic targets. In the present study, we review the current understanding of the mechanism of this important family of enzymes, and the role of selected E2s in disease

Tests of light-lepton universality in angular asymmetries of B0→D∗−ℓνB^0 \to D^{*-} \ell \nu decays

We present the first comprehensive tests of light-lepton universality in the angular distributions of semileptonic \Bz-meson decays to charged spin-1 charmed mesons. We measure five angular-asymmetry observables as functions of the decay recoil that are sensitive to lepton-universality-violating contributions. We use events where one neutral \B is fully reconstructed in \PUpsilonFourS{} \to\B\overline{B} decays in data corresponding to \lumion integrated luminosity from electron-positron collisions collected with the \belletwo detector. We find no significant deviation from the standard model expectations

Global burden of peripheral artery disease and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: Peripheral artery disease is a growing public health problem. We aimed to estimate the global disease burden of peripheral artery disease, its risk factors, and temporospatial trends to inform policy and public measures. Methods: Data on peripheral artery disease were modelled using the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2019 database. Prevalence, disability-adjusted life years (DALYs), and mortality estimates of peripheral artery disease were extracted from GBD 2019. Total DALYs and age-standardised DALY rate of peripheral artery disease attributed to modifiable risk factors were also assessed. Findings: In 2019, the number of people aged 40 years and older with peripheral artery disease was 113 million (95% uncertainty interval [UI] 99·2–128·4), with a global prevalence of 1·52% (95% UI 1·33–1·72), of which 42·6% was in countries with low to middle Socio-demographic Index (SDI). The global prevalence of peripheral artery disease was higher in older people, (14·91% [12·41–17·87] in those aged 80–84 years), and was generally higher in females than in males. Globally, the total number of DALYs attributable to modifiable risk factors in 2019 accounted for 69·4% (64·2–74·3) of total peripheral artery disease DALYs. The prevalence of peripheral artery disease was highest in countries with high SDI and lowest in countries with low SDI, whereas DALY and mortality rates showed U-shaped curves, with the highest burden in the high and low SDI quintiles. Interpretation: The total number of people with peripheral artery disease has increased globally from 1990 to 2019. Despite the lower prevalence of peripheral artery disease in males and low-income countries, these groups showed similar DALY rates to females and higher-income countries, highlighting disproportionate burden in these groups. Modifiable risk factors were responsible for around 70% of the global peripheral artery disease burden. Public measures could mitigate the burden of peripheral artery disease by modifying risk factors. Funding: Bill & Melinda Gates Foundation

Mapping subnational HIV mortality in six Latin American countries with incomplete vital registration systems

Background: Human immunodeficiency virus (HIV) remains a public health priority in Latin America. While the burden of HIV is historically concentrated in urban areas and high-risk groups, subnational estimates that cover multiple countries and years are missing. This paucity is partially due to incomplete vital registration (VR) systems and statistical challenges related to estimating mortality rates in areas with low numbers of HIV deaths. In this analysis, we address this gap and provide novel estimates of the HIV mortality rate and the number of HIV deaths by age group, sex, and municipality in Brazil, Colombia, Costa Rica, Ecuador, Guatemala, and Mexico. Methods: We performed an ecological study using VR data ranging from 2000 to 2017, dependent on individual country data availability. We modeled HIV mortality using a Bayesian spatially explicit mixed-effects regression model that incorporates prior information on VR completeness. We calibrated our results to the Global Burden of Disease Study 2017. Results: All countries displayed over a 40-fold difference in HIV mortality between municipalities with the highest and lowest age-standardized HIV mortality rate in the last year of study for men, and over a 20-fold difference for women. Despite decreases in national HIV mortality in all countries—apart from Ecuador—across the period of study, we found broad variation in relative changes in HIV mortality at the municipality level and increasing relative inequality over time in all countries. In all six countries included in this analysis, 50% or more HIV deaths were concentrated in fewer than 10% of municipalities in the latest year of study. In addition, national age patterns reflected shifts in mortality to older age groups—the median age group among decedents ranged from 30 to 45 years of age at the municipality level in Brazil, Colombia, and Mexico in 2017. Conclusions: Our subnational estimates of HIV mortality revealed significant spatial variation and diverging local trends in HIV mortality over time and by age. This analysis provides a framework for incorporating data and uncertainty from incomplete VR systems and can help guide more geographically precise public health intervention to support HIV-related care and reduce HIV-related deaths

Measurement of C ⁣PC\!P asymmetries and branching-fraction ratios for B±→DK±B^\pm \to DK^\pm and Dπ±D\pi^\pm with D→KS0K±π∓D\to K^0_{\rm S} K^\pm\pi^\mp using Belle and Belle II data

We measure $C\!P$ asymmetries and branching-fraction ratios for $B^\pm \to DK^\pm$ and $D\pi^\pm$ decays with $D\to K^0_{\rm S} K^\pm\pi^\mp$, where $D$ is a superposition of $D^0$ and $\bar{D}^0$. We use the full data set of the Belle experiment, containing $772\times 10^6~B\bar{B}$ pairs, and data from the Belle~II experiment, containing $387\times 10^6~B\bar{B}$ pairs, both collected in electron-positron collisions at the $\Upsilon(4S)$ resonance. Our results provide model-independent information on the unitarity triangle angle $\phi_3$.Comment: 26 pages, 8 figure

Search for an invisible Z′Z^\prime in a final state with two muons and missing energy at Belle II

The $L_{\mu}-L_{\tau}$ extension of the standard model predicts the existence of a lepton-flavor-universality-violating $Z^{\prime}$ boson that couples only to the heavier lepton families. We search for such a $Z^\prime$ through its invisible decay in the process $e^+ e^- \to \mu^+ \mu^- Z^{\prime}$. We use a sample of electron-positron collisions at a center-of-mass energy of 10.58GeV collected by the Belle II experiment in 2019-2020, corresponding to an integrated luminosity of 79.7fb$^{-1}$. We find no excess over the expected standard-model background. We set 90$\%$-confidence-level upper limits on the cross section for this process as well as on the coupling of the model, which ranges from $3 \times 10^{-3}$ at low $Z^{\prime}$ masses to 1 at $Z^{\prime}$ masses of 8$GeV/c^{2}$