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"Bell, John"
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Do less better : the power of strategic sacrifice in a complex world
\"In Do Less Better, John Bell draws on personal experiences from his days in the C-suite and the boardrooms of his consulting clients. He culls his experience to make a convincing case that, in business, sacrifice is the surprising secret to successful focus and long-term viability. Business complexity has never been greater, but it is not the phenomenon itself but rather the inability to cut through the clutter that comes in the way of resurrecting clarity and coherence. Bell demonstrates how the best business strategies all require this sacrifice. He emphasizes, through case studies and personal anecdotes, the importance of specializing--of a company's willingness to focus on a particular area, vision, or identity in order to create and maintain its value. According to Bell, the specialist always beats the generalist. Doing less, better ensures viability and strengthens a company's competitive edge. Do Less Better will teach business leaders how to keep their company nimble--willing and able to sacrifice and evolve in order to remain relevant and competitive. This smart sacrifice and nimbleness--dumping a pet project that's not profitable anymore, taking your partner's name off the door, altering some beloved company formulae, for example--can be incredibly difficult. However, maintaining this prioritization of nimbleness is crucial as it gives you a hugely significant advantage over companies that are more reactive and slow-to-change. Bell shows business leaders how, in a corporation, you don't have to be an entrepreneur to think like one. But he also asserts that, in order to act like one, you'll have to sacrifice your aversion to risk. You'll have to fight off certain strongly-help or sacred inclinations, such as the tendency to generalize rather than specialize and the desire to preserve and maintain (practices, products, ways of doing business) rather than sacrifice, let go, and innovate. He discusses several disciplines and examples in entrepreneurship, strategy, marketing and branding that help to clear the fog of company complexity. Within problem/solution scenarios, he demonstrate how people and companies succeed or fail at these practices. According to Bell, doing less, better should by no means lead to doing less work. More often than not, those who embrace the notion of focus, specialization, and streamlining work harder because they are more passionate and emotionally connected to their vision. This is a book for business leaders, innovators, and entrepreneurs who are just starting out and need help embracing the practices and philosophy that will allow them to be lean, farsighted, adaptable, and resilient. It is also a book for leaders of established business, who are looking to reduce clutter and encumbering complexity in order to stay nimble and focused enough to maintain a competitive edge. \"-- Provided by publisher.
Book
Effect of Delta variant on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK
The effectiveness of the BNT162b2 and ChAdOx1 vaccines against new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections requires continuous re-evaluation, given the increasingly dominant B.1.617.2 (Delta) variant. In this study, we investigated the effectiveness of these vaccines in a large, community-based survey of randomly selected households across the United Kingdom. We found that the effectiveness of BNT162b2 and ChAdOx1 against infections (new polymerase chain reaction (PCR)-positive cases) with symptoms or high viral burden is reduced with the B.1.617.2 variant (absolute difference of 10–13% for BNT162b2 and 16% for ChAdOx1) compared to the B.1.1.7 (Alpha) variant. The effectiveness of two doses remains at least as great as protection afforded by prior natural infection. The dynamics of immunity after second doses differed significantly between BNT162b2 and ChAdOx1, with greater initial effectiveness against new PCR-positive cases but faster declines in protection against high viral burden and symptomatic infection with BNT162b2. There was no evidence that effectiveness varied by dosing interval, but protection was higher in vaccinated individuals after a prior infection and in younger adults. With B.1.617.2, infections occurring after two vaccinations had similar peak viral burden as those in unvaccinated individuals. SARS-CoV-2 vaccination still reduces new infections, but effectiveness and attenuation of peak viral burden are reduced with B.1.617.2.
A large, community-based study in the United Kingdom indicates that the effectiveness of BNT162b2 and ChAdOx1 vaccines against SARS-CoV-2 infections with symptoms or high viral burden is reduced with the Delta variant compared to the Alpha variant.
Journal Article
Impact of vaccination on new SARS-CoV-2 infections in the United Kingdom
The effectiveness of COVID-19 vaccination in preventing new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the general community is still unclear. Here, we used the Office for National Statistics COVID-19 Infection Survey—a large community-based survey of individuals living in randomly selected private households across the United Kingdom—to assess the effectiveness of the BNT162b2 (Pfizer–BioNTech) and ChAdOx1 nCoV-19 (Oxford–AstraZeneca; ChAdOx1) vaccines against any new SARS-CoV-2 PCR-positive tests, split according to self-reported symptoms, cycle threshold value (<30 versus ≥30; as a surrogate for viral load) and gene positivity pattern (compatible with B.1.1.7 or not). Using 1,945,071 real-time PCR results from nose and throat swabs taken from 383,812 participants between 1 December 2020 and 8 May 2021, we found that vaccination with the ChAdOx1 or BNT162b2 vaccines already reduced SARS-CoV-2 infections ≥21 d after the first dose (61% (95% confidence interval (CI) = 54–68%) versus 66% (95% CI = 60–71%), respectively), with greater reductions observed after a second dose (79% (95% CI = 65–88%) versus 80% (95% CI = 73–85%), respectively). The largest reductions were observed for symptomatic infections and/or infections with a higher viral burden. Overall, COVID-19 vaccination reduced the number of new SARS-CoV-2 infections, with the largest benefit received after two vaccinations and against symptomatic and high viral burden infections, and with no evidence of a difference between the BNT162b2 and ChAdOx1 vaccines.
Results from the Office of National Statistics COVID-19 Infection Survey in the United Kingdom demonstrate that the ChAdOx1 nCoV-19 and BNT162b2 vaccines reduce the incidence of new SARS-CoV-2 infections by up to 65% with a single dose and up to 80% after two doses, with no significant differences in efficacy observed between the two vaccines.
Journal Article
Antibody responses and correlates of protection in the general population after two doses of the ChAdOx1 or BNT162b2 vaccines
Antibody responses are an important part of immunity after Coronavirus Disease 2019 (COVID-19) vaccination. However, antibody trajectories and the associated duration of protection after a second vaccine dose remain unclear. In this study, we investigated anti-spike IgG antibody responses and correlates of protection after second doses of ChAdOx1 or BNT162b2 vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the United Kingdom general population. In 222,493 individuals, we found significant boosting of anti-spike IgG by the second doses of both vaccines in all ages and using different dosing intervals, including the 3-week interval for BNT162b2. After second vaccination, BNT162b2 generated higher peak levels than ChAdOX1. Older individuals and males had lower peak levels with BNT162b2 but not ChAdOx1, whereas declines were similar across ages and sexes with ChAdOX1 or BNT162b2. Prior infection significantly increased antibody peak level and half-life with both vaccines. Anti-spike IgG levels were associated with protection from infection after vaccination and, to an even greater degree, after prior infection. At least 67% protection against infection was estimated to last for 2–3 months after two ChAdOx1 doses, for 5–8 months after two BNT162b2 doses in those without prior infection and for 1–2 years for those unvaccinated after natural infection. A third booster dose might be needed, prioritized to ChAdOx1 recipients and those more clinically vulnerable.
A large study in the United Kingdom shows that virus-specific antibody levels associated with at least 67% protection against SARS-CoV-2 Delta variant infection last longer after two doses of BNT162b2 vaccine than after two doses of ChAdOx1 vaccine in previously uninfected individuals.
Journal Article
Oncolytic viruses as engineering platforms for combination immunotherapy
To effectively build on the recent successes of immune checkpoint blockade, adoptive T cell therapy and cancer vaccines, it is critical to rationally design combination strategies that will increase and extend efficacy to a larger proportion of patients. For example, the combination of anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and anti-programmed cell death protein 1 (PD1) immune checkpoint inhibitors essentially doubles the response rate in certain patients with metastatic melanoma. However, given the heterogeneity of cancer, it seems likely that even more complex combinations of immunomodulatory agents may be required to obtain consistent, durable therapeutic responses against a broad spectrum of cancers. This carries serious implications in terms of toxicities for patients, feasibility for care providers and costs for health-care systems. A compelling solution is offered by oncolytic viruses (OVs), which can be engineered to selectively replicate within and destroy tumour tissue while simultaneously augmenting antitumour immunity. In this Opinion article, we argue that the future of immunotherapy will include OVs that function as multiplexed immune-modulating platforms expressing factors such as immune checkpoint inhibitors, tumour antigens, cytokines and T cell engagers. We illustrate this concept by following the trials and tribulations of tumour-reactive T cells from their initial priming through to the execution of cytotoxic effector function in the tumour bed. We highlight the myriad opportunities for OVs to help overcome critical barriers in the T cell journey, leading to new synergistic mechanisms in the battle against cancer.
Journal Article
Oncolytic virotherapy
Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Recent advances include preclinical proof of feasibility for a single-shot virotherapy cure, identification of drugs that accelerate intratumoral virus propagation, strategies to maximize the immunotherapeutic action of oncolytic viruses and clinical confirmation of a critical viremic threshold for vascular delivery and intratumoral virus replication. The primary clinical milestone has been completion of accrual in a phase 3 trial of intratumoral herpes simplex virus therapy using talimogene laherparepvec for metastatic melanoma. Key challenges for the field are to select 'winners' from a burgeoning number of oncolytic platforms and engineered derivatives, to transiently suppress but then unleash the power of the immune system to maximize both virus spread and anticancer immunity, to develop more meaningful preclinical virotherapy models and to manufacture viruses with orders-of-magnitude higher yields than is currently possible.
Journal Article