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From email to smart phones, and from social media to Google searches, digital technologies have transformed the way we learn, entertain ourselves, socialize, and work. Despite their usefulness, these technologies have often led to information overload, stress, and distraction. David M. Levy, who has lived his life between the \"fast world\" of high tech and the \"slow world\" of contemplation, offers a welcome guide to being more relaxed, attentive, and emotionally balanced while online. In a series of exercises carefully designed to help readers observe and reflect on their own use., Levy has readers observe themselves while emailing and while multitasking , and also to experiment with unplugging for a specified period.

Autophagy allows for cellular material to be delivered to lysosomes for degradation resulting in basal or stress-induced turnover of cell components that provide energy and macromolecular precursors. These activities are thought to be particularly important in cancer where both tumor-promoting and tumor-inhibiting functions of autophagy have been described. Autophagy has also been intricately linked to apoptosis and programmed cell death, and understanding these interactions is becoming increasingly important in improving cancer therapy and patient outcomes. In this review, we consider how recent discoveries about how autophagy manipulation elicits its effects on cancer cell behavior can be leveraged to improve therapeutic responses. ▓

Key Points Macroautophagy (known as autophagy) is a highly regulated multi-step process that is involved in the bulk degradation of cellular proteins and organelles to provide macromolecular precursors that are recycled or that are used to fuel metabolic pathways. Autophagy can be targeted for both stimulation and inhibition. Stimulation can be achieved through cellular stress (nutrient deprivation) and mTOR inhibition, and inhibition can be achieved through multiple targets both upstream (ULK1, Beclin 1 and VPS34 inhibitors) and downstream of the site of lysosomal fusion with the autophagosome. Early clinical trials have demonstrated the feasibility and potential benefit of clinically inhibiting autophagy in multiple cancer types, including glioblastoma, pancreatic cancer, melanoma, sarcoma and multiple myeloma. Ongoing studies are developing novel clinical biomarkers that can be used to monitor autophagy in patients, including electron microscopy evaluation of autophagosome number in peripheral blood mononuclear cells and tumour samples, LC3II and ATG13 puncta by immunohistochemistry, and novel imaging techniques that use positron emission tomography and metabolomics profiles. The role of autophagy in regulating tumour immune responses is unclear, with arguments both for and against autophagy inhibition. Further research is needed to define the safety and utility of autophagy inhibition while also maximizing tumour immune responses for improved clinical outcomes. Markers of autophagy dependence have the potential to identify patients who will best respond to autophagy inhibition therapy. Such markers include altered RAS signalling, BRAF mutations, signal transducer and activator of transcription 3 (STAT3) activation, autophagy-dependent secretion of interleukins and p53 status. Autophagy can be an effective cancer escape mechanism and has been implicated in the development of resistance in multiple cancer types, including BRAF-mutated central nervous system (CNS) tumours and melanoma, non-small-cell lung cancer (NSCLC), bladder cancer and thyroid cancer. Combination therapy with autophagy inhibition in these cancers has the potential to reduce and reverse resistance to therapy. Autophagy is a process that delivers cytoplasmic components to lysosomes for degradation. This Review discusses clinical interventions to target autophagy in cancer and explains how understanding the context-dependent role of autophagy in cancer should dictate future clinical trial design. Autophagy is a mechanism by which cellular material is delivered to lysosomes for degradation, leading to the basal turnover of cell components and providing energy and macromolecular precursors. Autophagy has opposing, context-dependent roles in cancer, and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. This has led to the therapeutic targeting of autophagy in cancer to be sometimes viewed as controversial. In this Review, we suggest a way forwards for the effective targeting of autophagy by understanding the context-dependent roles of autophagy and by capitalizing on modern approaches to clinical trial design.

The Sequential Organ Failure Assessment or SOFA score was developed to assess the acute morbidity of critical illness at a population level and has been widely validated as a tool for this purpose across a range of healthcare settings and environments. In recent years, the SOFA score has become extensively used in a range of other applications. A change in the SOFA score of 2 or more is now a defining characteristic of the sepsis syndrome, and the European Medicines Agency has accepted that a change in the SOFA score is an acceptable surrogate marker of efficacy in exploratory trials of novel therapeutic agents in sepsis. The requirement to detect modest serial changes in a patients’ SOFA score therefore means that increased clarity on how the score should be assessed in different circumstances is required. This review explores the development of the SOFA score, its applications and the challenges associated with measurement. In addition, it proposes guidance designed to facilitate the consistent and valid assessment of the score in multicentre sepsis trials involving novel therapeutic agents or interventions. Conclusion The SOFA score is an increasingly important tool in defining both the clinical condition of the individual patient and the response to therapies in the context of clinical trials. Standardisation between different assessors in widespread centres is key to detecting response to treatment if the SOFA score is to be used as an outcome in sepsis clinical trials.

A theoretical black carbon (BC) aging model is developed to account for three typical evolution stages, namely, freshly emitted aggregates, BC coated by soluble material, and BC particles undergoing further hygroscopic growth. The geometric-optics surface-wave (GOS) approach is employed to compute the BC single-scattering properties at each aging stage, which are subsequently compared with laboratory measurements. Theoretical calculations are consistent with measurements in extinction and absorption cross sections for fresh BC aggregates with different BC sizes (i.e., mobility diameters of 155, 245, and 320 nm), with differences of ≤ 25 %. The measured optical cross sections for BC coated by sulfuric acid and for that undergoing further hygroscopic growth are generally captured (differences < 30 %) by theoretical calculations using a concentric core-shell structure, with an overestimate in extinction and absorption of the smallest BC size and an underestimate in scattering of the largest BC size. We find that the absorption and scattering cross sections of fresh BC aggregates vary by 20–40 and 50–65 %, respectively, due to the use of upper (1.95–0.79i) and lower (1.75–0.63i) bounds of BC refractive index, while the variations are < 20 % in absorption and < 50 % in scattering in the case of coated BC particles. Sensitivity analyses of the BC morphology show that the optical properties of fresh BC aggregates are more sensitive to fractal dimension than primary spherule size. The absorption and scattering cross sections of coated BC particles vary by more than a factor of 2 due to different coating structures. We find an increase of 20–250 % in absorption and a factor of 3–15 in scattering during aging, significantly depending on coating morphology and aging stages. This study suggests that an accurate estimate of BC radiative effects requires the incorporation of a dynamic BC aging process that accounts for realistic coating structures in climate models.

When Italian Renaissance professor Allison Levy takes up residency in the palazzo of her dreams - the Palazzo Rucellai in Florence - she finds herself consumed by the space and swept into the vortex of its history. She spends every waking moment in dustry Florentine libraries and exploring the palazzo's myriad rooms seeking to uncover its secrets. As she unearths the stories of those who have lived behind its celebrated facade, she discovers that it has been witness to weddings, suicides, orgies and even a murder. Entwining Levy's own experiences with the ghosts of the Palazzo Rucellai's past, House of Secrets paints a scintillating portrait of a family, a palace and one of the most iconic cities in the world.

In an analysis including nearly 50,000 patients with sepsis treated at 149 New York hospitals, more rapid delivery of a 3-hour sepsis-care bundle (a protocol recommending blood cultures, broad-spectrum antibiotics, and lactate measurement within 3 hours) was associated with lower mortality. More than 1.5 million cases of sepsis occur in the United States annually, and many patients with sepsis present to the emergency department. 1 International clinical practice guidelines and the Centers for Medicare and Medicaid Services (CMS) recommend the prompt identification of sepsis and treatment with broad-spectrum antibiotic agents and intravenous fluids. 2 , 3 These recommendations are supported by preclinical and observational studies suggesting that early treatment with antibiotics and intravenous fluids could reduce the number of avoidable deaths. 4 , 5 Yet, considerable controversy exists about how rapidly sepsis must be treated. 6 Some clinicians question the potential benefit of rapid treatment, citing the . . .