A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions

Exploiting dynamic timing margins in microprocessors for frequency-over-scaling with instruction-based clock adjustment

Static timing analysis provides the basis for setting the clock period of a microprocessor core, based on its worst-case critical path. However, depending on the design, this critical path is not always excited and therefore dynamic timing margins exist that can theoretically be exploited for the benefit of better speed or lower power consumption (through voltage scaling). This paper introduces predictive instruction-based dynamic clock adjustment as a technique to trim dynamic timing margins in pipelined microprocessors. To this end, we exploit the different timing requirements for individual instructions during the dynamically varying program execution flow without the need for complex circuit-level measures to detect and correct timing violations. We provide a design flow to extract the dynamic timing information for the design using post-layout dynamic timing analysis and we integrate the results into a custom cycle-accurate simulator. This simulator allows annotation of individual instructions with their impact on timing (in each pipeline stage) and rapidly derives the overall code execution time for complex benchmarks. The design methodology is illustrated at the microarchitecture level, demonstrating the performance and power gains possible on a 6-stage OpenRISC in-order general purpose processor core in a 28nm CMOS technology. We show that employing instruction-dependent dynamic clock adjustment leads on average to an increase in operating speed by 38% or to a reduction in power consumption by 24%, compared to traditional synchronous clocking, which at all times has to respect the worst-case timing identified through static timing analysis

Automated High-level Modeling of Power, Temperature and Timing Variation for Microprocessor

The continued scaling of semiconductor technologies leads to diverse challenges such as power and temperature, which also forces reliability as another design metric of prime concern. There exists strong need to link reliability with physical metrics in a high-level architecture design environment, where estimation of reliability impacts can be performed in the early design stage. In this paper, we propose a joint modeling and simulation framework for power, thermal and timing variation, which is integrated into a commercial high-level processor design environment. A custom timing variation model is provided for estimation of dynamic timing variation, which is demonstrated using one nanoscale thermal effect known as Inverted Temperature Dependence. The complete modeling flow is automated for customized processor model with arbitrary architectural hierarchy, which assists designer to perform architectural and application-level design space exploration with power, thermal and reliability impacts

The CT Quadrate lobe hot spot sign

Intense enhancement of the quadrate lobe in the arterial phase may be seen on computed tomography in patients of superior vena cava syndrome. We present this imaging finding in a case of lymphoma causing superior vena cava syndrome and discuss the physiological cause and importance of this sign

Perivascular epithelioid cell tumour (PEComa) of the inferior vena cava presenting as an adrenal mass

A 54-year-old woman had a mass located in the right suprarenal area. On imaging, this mass appeared to be infiltrating the inferior vena cava (IVC). Exploratory laparotomy was undertaken and excision of the tumour was done with the sleeve of the involved IVC. The mass turned out to be a perivascular epithelioid cell tumour (PEComa) on histopathological examination. This report describes previously reported cases of PEComa in brief and highlights the problems associated with the management of this tumour

Late Middle Miocene volcanism in the Northern Borneo, Southeast Asia: Implications for tectonics, paleoclimate and stratigraphic marker

International audienceExplosive volcanic events often produce pyroclastic materials that can be recognized from the geological record. These discrete pyroclastics form regional marker beds. Here we report the occurrence of a tephra layer interbedded within very thick coal beds near Mukah, Sarawak, Borneo. Traceable for tens of kilometers in the Mukah area of Sarawak, this tephra layer can be considered as regional stratigraphic marker with precise chronostratigraphic control. Systematic sedimentological, mineralogical, geochemical and zircon UPb geochronological studies have revealed a major effusive volcanic event during the latest Middle Miocene, presumably contemporaneous and/or related to a magmatic event of an earlier phase of the Mt. Kinabalu pluton or magmatism in West Sarawak or East Sabah. The volcanic event had promoted catastrophic flooding of coastal swamps and fall-out from the ash clouds that formed a regionally monotonous tephra layer across the Serravallian- Tortonian boundary. In conjunction with the regional occurrences of trap rocks, structural trends and known tectonic events, we constrained the regional depositional environments, and climate. The tephra layer was deposited in a coastal plain-swamp,- seasonal, shallow, high-moderate energy, fluvial channel-lacustrine environmental setting, wherein atmospheric fallout and eroded material from regoliths formed over older basement and volcanic rocks of the hinterland which were mixed to produce the tephra layer. This tephra layer is sandwiched between the very thick coal beds. A pre-existent volcanic chamber that was active for a long time, also experienced periodic explosive activity from probably the same magma chamber and conduit and including a major explosive activity that recycled early-formed crystals and felsic magma (rhyolite-dacite) during the major effusive event are also recognized. Our findings provide robust evidence for the prevalence of intensive chemical weathering under a wet-humid climate, and relative tectonic quiescence before the major effusive event, and the existence of vast, monotonously gently-sloping coastal plains and luxuriant vegetation akin to the present