•Extant research on minimalism views consumers as homogeneous and not heterogeneous.•The antecedents and motives of minimalistic consumption are identified.•The research gap is addressed through ...developing a consumer typology.•Firms can design strategies to satisfy the unique goals for each consumer segment.
Minimalistic consumption has received increased attention during the last few years with a substantial segment of consumers having adopted this notion. Minimalism highlights subjective well-being, happiness, and increased quality of life. Despite minimalism gaining significance, we know little about minimalistic consumption, its various forms, its antecedents, and its impact on consumer behavior. Extant literature does not offer a clear or concise conceptualization of minimalism in consumption or the potential strategies to identify, target, and engage minimalistic consumers. This has been a major deterrent in advancing research on minimalistic consumption. This article provides a conceptualization of minimalism and offers a typology of consumers that engage in minimalistic consumption based on two dimensions: the conditional susceptibility and goal orientation of consumers. It presents a framework of brand engagement strategies for each type of consumer and shows how firms can potentially benefit in terms of sales, profitability, and customer relationships by engaging with minimalistic consumers.
Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles.
We determined ...subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas.
TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors.
Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.
BackgroundThis paper describes the methods and conceptual framework for Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study data collection. The National Institutes of Health, ...through the National Institute on Drug Abuse, is partnering with the Food and Drug Administration's (FDA) Center for Tobacco Products to conduct the PATH Study under a contract with Westat.MethodsThe PATH Study is a nationally representative, longitudinal cohort study of 45 971 adults and youth in the USA, aged 12 years and older. Wave 1 was conducted from 12 September 2013 to 15 December 2014 using Audio Computer-Assisted Self-Interviewing to collect information on tobacco-use patterns, risk perceptions and attitudes towards current and newly emerging tobacco products, tobacco initiation, cessation, relapse behaviours and health outcomes. The PATH Study's design allows for the longitudinal assessment of patterns of use of a spectrum of tobacco products, including initiation, cessation, relapse and transitions between products, as well as factors associated with use patterns. Additionally, the PATH Study collects biospecimens from consenting adults aged 18 years and older and measures biomarkers of exposure and potential harm related to tobacco use.ConclusionsThe cumulative, population-based data generated over time by the PATH Study will contribute to the evidence base to inform FDA's regulatory mission under the Family Smoking Prevention and Tobacco Control Act and efforts to reduce the Nation's burden of tobacco-related death and disease.
The EU, the USA, and Japan account for the majority of biological pharmacotherapy use worldwide. Biosimilar regulatory approval pathways were authorised in the EU (2006), in Japan (2009), and in the ...USA (2015), to facilitate approval of biological drugs that are highly similar to reference products and to encourage market competition. Between 2007 and 2020, 33 biosimilars for oncology were approved by the European Medicines Agency (EMA), 16 by the US Food and Drug Administration (FDA), and ten by the Japan Pharmaceuticals and Medical Devices Agency (PMDA). Some of these approved applications were initially rejected because of manufacturing concerns (four of 36 11% with the EMA, seven of 16 44% with the FDA, none of ten for the PMDA). Median times from initial regulatory submission before approval of oncology biosimilars were 1·5 years (EMA), 1·3 years (FDA), and 0·9 years (PMDA). Pharmacists can substitute biosimilars for reference biologics in some EU countries, but not in the USA or Japan. US regulation prohibits substitution, unless the biosimilar has been approved as interchangeable, a designation not yet achieved for any biosimilar in the USA. Japan does not permit biosimilar substitution, as prescribers must include the product name on each prescription and that specific product must be given to the patient. Policy Reviews published in 2014 and 2016 in The Lancet Oncology focused on premarket and postmarket policies for oncology biosimilars before most of these drugs received regulatory approval. In this Policy Review from the Southern Network on Adverse Reactions, we identify factors preventing the effective launch of oncology biosimilars. Introduction to the market has been more challenging with therapeutic than for supportive care oncology biosimilars. Addressing region-specific competition barriers and educational needs would improve the regulatory approval process and market launches for these biologics, therefore expanding patient access to these products in the EU, the USA, and Japan.
Summary Background Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease ...(GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs). Methods Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis. Findings Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350 000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient −0·37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa. Interpretation Rates of YLDs per 100 000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world. Funding Bill & Melinda Gates Foundation.
Summary Background Measuring disease and injury burden in populations requires a composite metric that captures both premature mortality and the prevalence and severity of ill-health. The 1990 Global ...Burden of Disease study proposed disability-adjusted life years (DALYs) to measure disease burden. No comprehensive update of disease burden worldwide incorporating a systematic reassessment of disease and injury-specific epidemiology has been done since the 1990 study. We aimed to calculate disease burden worldwide and for 21 regions for 1990, 2005, and 2010 with methods to enable meaningful comparisons over time. Methods We calculated DALYs as the sum of years of life lost (YLLs) and years lived with disability (YLDs). DALYs were calculated for 291 causes, 20 age groups, both sexes, and for 187 countries, and aggregated to regional and global estimates of disease burden for three points in time with strictly comparable definitions and methods. YLLs were calculated from age-sex-country-time-specific estimates of mortality by cause, with death by standardised lost life expectancy at each age. YLDs were calculated as prevalence of 1160 disabling sequelae, by age, sex, and cause, and weighted by new disability weights for each health state. Neither YLLs nor YLDs were age-weighted or discounted. Uncertainty around cause-specific DALYs was calculated incorporating uncertainty in levels of all-cause mortality, cause-specific mortality, prevalence, and disability weights. Findings Global DALYs remained stable from 1990 (2·503 billion) to 2010 (2·490 billion). Crude DALYs per 1000 decreased by 23% (472 per 1000 to 361 per 1000). An important shift has occurred in DALY composition with the contribution of deaths and disability among children (younger than 5 years of age) declining from 41% of global DALYs in 1990 to 25% in 2010. YLLs typically account for about half of disease burden in more developed regions (high-income Asia Pacific, western Europe, high-income North America, and Australasia), rising to over 80% of DALYs in sub-Saharan Africa. In 1990, 47% of DALYs worldwide were from communicable, maternal, neonatal, and nutritional disorders, 43% from non-communicable diseases, and 10% from injuries. By 2010, this had shifted to 35%, 54%, and 11%, respectively. Ischaemic heart disease was the leading cause of DALYs worldwide in 2010 (up from fourth rank in 1990, increasing by 29%), followed by lower respiratory infections (top rank in 1990; 44% decline in DALYs), stroke (fifth in 1990; 19% increase), diarrhoeal diseases (second in 1990; 51% decrease), and HIV/AIDS (33rd in 1990; 351% increase). Major depressive disorder increased from 15th to 11th rank (37% increase) and road injury from 12th to 10th rank (34% increase). Substantial heterogeneity exists in rankings of leading causes of disease burden among regions. Interpretation Global disease burden has continued to shift away from communicable to non-communicable diseases and from premature death to years lived with disability. In sub-Saharan Africa, however, many communicable, maternal, neonatal, and nutritional disorders remain the dominant causes of disease burden. The rising burden from mental and behavioural disorders, musculoskeletal disorders, and diabetes will impose new challenges on health systems. Regional heterogeneity highlights the importance of understanding local burden of disease and setting goals and targets for the post-2015 agenda taking such patterns into account. Because of improved definitions, methods, and data, these results for 1990 and 2010 supersede all previously published Global Burden of Disease results. Funding Bill & Melinda Gates Foundation.
CONTEXT While the delivery of cell therapy after ST-segment elevation myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the ...effect on left ventricular function has not been analyzed. OBJECTIVES To determine the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery after STEMI on recovery of global and regional left ventricular function and whether timing of BMC delivery (3 days vs 7 days after reperfusion) influences this effect. DESIGN, SETTING, AND PATIENTS A randomized, 2 × 2 factorial, double-blind, placebo-controlled trial, Timing In Myocardial infarction Evaluation (TIME) enrolled 120 patients with left ventricular dysfunction (left ventricular ejection fraction LVEF ≤ 45%) after successful primary percutaneous coronary intervention (PCI) of anterior STEMI between July 17, 2008, and November 15, 2011, as part of the Cardiovascular Cell Therapy Research Network sponsored by the National Heart, Lung, and Blood Institute. INTERVENTIONS Intracoronary infusion of 150 × 106 BMCs or placebo (randomized 2:1) within 12 hours of aspiration and cell processing administered at day 3 or day 7 (randomized 1:1) after treatment with PCI. MAIN OUTCOME MEASURES The primary end points were change in global (LVEF) and regional (wall motion) left ventricular function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and change in left ventricular function as affected by timing of treatment on day 3 vs day 7. The secondary end points included major adverse cardiovascular events as well as changes in left ventricular volumes and infarct size. RESULTS The mean (SD) patient age was 56.9 (10.9) years and 87.5% of participants were male. At 6 months, there was no significant increase in LVEF for the BMC group (45.2% 95% CI, 42.8% to 47.6% to 48.3% 95% CI, 45.3% to 51.3%) vs the placebo group (44.5% 95% CI, 41.0% to 48.0% to 47.8% 95% CI, 43.4% to 52.2%) (P = .96). There was no significant treatment effect on regional left ventricular function observed in either infarct or border zones. There were no significant differences in change in global left ventricular function for patients treated at day 3 (−0.9% 95% CI, −6.6% to 4.9%, P = .76) or day 7 (1.1% 95% CI, −4.7% to 6.9%, P = .70). The timing of treatment had no significant effect on regional left ventricular function recovery. Major adverse events were rare among all treatment groups. CONCLUSION Among patients with STEMI treated with primary PCI, the administration of intracoronary BMCs at either 3 days or 7 days after the event had no significant effect on recovery of global or regional left ventricular function compared with placebo. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00684021
Phenotypic screening of a Medicines for Malaria Venture compound library against
(
) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various ...tool strains of
suggested a novel mechanism of action. The compounds were bactericidal against replicating
and retained potency against clinical isolates of
. Although selected MmpL3 mutant strains of
showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure-activity relationship studies identified potent compounds with good physicochemical properties and
microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.
CONTEXT Clinical trial results suggest that intracoronary delivery of autologous bone marrow mononuclear cells (BMCs) may improve left ventricular (LV) function when administered within the first ...week following myocardial infarction (MI). However, because a substantial number of patients may not present for early cell delivery, the efficacy of autologous BMC delivery 2 to 3 weeks post-MI warrants investigation. OBJECTIVE To determine if intracoronary delivery of autologous BMCs improves global and regional LV function when delivered 2 to 3 weeks following first MI. DESIGN, SETTING, AND PATIENTS A randomized, double-blind, placebo-controlled trial (LateTIME) of the National Heart, Lung, and Blood Institute–sponsored Cardiovascular Cell Therapy Research Network of 87 patients with significant LV dysfunction (LV ejection fraction LVEF ≤45%) following successful primary percutaneous coronary intervention (PCI) between July 8, 2008, and February 28, 2011. INTERVENTIONS Intracoronary infusion of 150 × 106 autologous BMCs (total nucleated cells) or placebo (BMC:placebo, 2:1) was performed within 12 hours of bone marrow aspiration after local automated cell processing. MAIN OUTCOME MEASURES Changes in global (LVEF) and regional (wall motion) LV function in the infarct and border zone between baseline and 6 months, measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volumes and infarct size. RESULTS A total of 87 patients were randomized (mean SD age, 57 11 years; 83% men). Harvesting, processing, and intracoronary delivery of BMCs in this setting was feasible. Change between baseline and 6 months in the BMC group vs placebo for mean LVEF (48.7% to 49.2% vs 45.3% to 48.8%; between-group mean difference, −3.00; 95% CI, −7.05 to 0.95), wall motion in the infarct zone (6.2 to 6.5 mm vs 4.9 to 5.9 mm; between-group mean difference, −0.70; 95% CI, −2.78 to 1.34), and wall motion in the border zone (16.0 to 16.6 mm vs 16.1 to 19.3 mm; between-group mean difference, −2.60; 95% CI, −6.03 to 0.77) were not statistically significant. No significant change in LV volumes and infarct volumes was observed; both groups decreased by a similar amount at 6 months vs baseline. CONCLUSION Among patients with MI and LV dysfunction following reperfusion with PCI, intracoronary infusion of autologous BMCs vs intracoronary placebo infusion, 2 to 3 weeks after PCI, did not improve global or regional function at 6 months. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00684060
Molecular recognition reagents are key tools for understanding biological processes and are used universally by scientists to study protein expression, localisation and interactions. Antibodies ...remain the most widely used of such reagents and many show excellent performance, although some are poorly characterised or have stability or batch variability issues, supporting the use of alternative binding proteins as complementary reagents for many applications. Here we report on the use of Affimer proteins as research reagents. We selected 12 diverse molecular targets for Affimer selection to exemplify their use in common molecular and cellular applications including the (a) selection against various target molecules; (b) modulation of protein function in vitro and in vivo; (c) labelling of tumour antigens in mouse models; and (d) use in affinity fluorescence and super-resolution microscopy. This work shows that Affimer proteins, as is the case for other alternative binding scaffolds, represent complementary affinity reagents to antibodies for various molecular and cell biology applications.
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