The challenge of admitting the very elderly to intensive care

The aging of the population has increased the demand for healthcare resources. The number of patients aged 80 years and older admitted to the intensive care unit (ICU) increased during the past decade, as has the intensity of care for such patients. Yet, many physicians remain reluctant to admit the oldest, arguing a "squandering" of societal resources, that ICU care could be deleterious, or that ICU care may not actually be what the patient or family wants in this instance. Other ICU physicians are strong advocates for admission of a selected elderly population. These discrepant opinions may partly be explained by the current lack of validated criteria to select accurately the patients (of any age) who will benefit most from ICU hospitalization. This review describes the epidemiology of the elderly aged 80 years and older admitted in the ICU, their long-term outcomes, and to discuss some of the solutions to cope with the burden of an aging population receiving acute care hospitalization

How communication of genetic information within the family is addressed in genetic counselling: a systematic review of research evidence

Supporting consultands to communicate risk information with their relatives is key to obtaining the full benefits of genetic health care. To understand how health-care professionals address this issue in clinical practice and what interventions are used specifically to assist consultands in their communication of genetic information to appropriate relatives, we conducted a systematic review. Four electronic databases and four subject-specific journals were searched for papers published, in English, between January 1997 and May 2014. Of 2926 papers identified initially, 14 papers met the inclusion criteria for the review and were heterogeneous in design, setting and methods. Thematic data analysis has shown that dissemination of information within families is actively encouraged and supported by professionals. Three overarching themes emerged: (1) direct contact from genetic services: sending letters to relatives of mutation carriers; (2) professionals' encouragement of initially reluctant consultands to share relevant information with at-risk relatives and (3) assisting consultands in communicating genetic information to their at-risk relatives, which included as subthemes (i) psychoeducational guidance and (ii) written information aids. Findings suggest that professionals' practice and interventions are predicated on the need to proactively encourage family communication. We discuss this in the context of what guidance of consultands by professionals might be appropriate, as best practices to facilitate family communication, and of the limits to non-directiveness in genetic counselling

Selection for antimicrobial resistance is reduced when embedded in a natural microbial community

This is the final version. Available from Springer Nature via the DOI in this record.Antibiotic resistance has emerged as one of the most pressing, global threats to public health. In single-species experiments selection for antibiotic resistance occurs at very low antibiotic concentrations. However, it is unclear how far these findings can be extrapolated to natural environments, where species are embedded within complex communities. We competed isogenic strains of Escherichia coli, differing exclusively in a single chromosomal resistance determinant, in the presence and absence of a pig faecal microbial community across a gradient of antibiotic concentration for two relevant antibiotics: gentamicin and kanamycin. We show that the minimal selective concentration was increased by more than one order of magnitude for both antibiotics when embedded in the community. We identified two general mechanisms were responsible for the increase in minimal selective concentration: an increase in the cost of resistance and a protective effect of the community for the susceptible phenotype. These findings have implications for our understanding of the evolution and selection of antibiotic resistance, and can inform future risk assessment efforts on antibiotic concentrations.Medical Research Council (MRC)European Commissio

Role of Sphingomyelin Synthase in Controlling the Antimicrobial Activity of Neutrophils against Cryptococcus neoformans

The key host cellular pathway(s) necessary to control the infection caused by inhalation of the environmental fungal pathogen Cryptococcus neoformans are still largely unknown. Here we have identified that the sphingolipid pathway in neutrophils is required for them to exert their killing activity on the fungus. In particular, using both pharmacological and genetic approaches, we show that inhibition of sphingomyelin synthase (SMS) activity profoundly impairs the killing ability of neutrophils by preventing the extracellular release of an antifungal factor(s). We next found that inhibition of protein kinase D (PKD), which controls vesicular sorting and secretion and is regulated by diacylglycerol (DAG) produced by SMS, totally blocks the extracellular killing activity of neutrophils against C. neoformans. The expression of SMS genes, SMS activity and the levels of the lipids regulated by SMS (namely sphingomyelin (SM) and DAG) are up-regulated during neutrophil differentiation. Finally, tissue imaging of lungs infected with C. neoformans using matrix-assisted laser desorption-ionization mass spectrometry (MALDI-MS), revealed that specific SM species are associated with neutrophil infiltration at the site of the infection. This study establishes a key role for SMS in the regulation of the killing activity of neutrophils against C. neoformans through a DAG-PKD dependent mechanism, and provides, for the first time, new insights into the protective role of host sphingolipids against a fungal infection

Toward an operative diagnosis in sepsis: a latent class approach

<p>Abstract</p> <p>Background</p> <p>Recent data have suggested that 18 million of new sepsis cases occur each year worldwide, with a mortality rate of almost 30%. There is not consensus on the clinical definition of sepsis and, because of lack of training or simply unawareness, clinicians often miss or delay this diagnosis. This is especially worrying; since there is strong evidence supporting that early treatment is associated with greater clinical success. There are some difficulties for sepsis diagnosis such as the lack of an appropriate gold standard to identify this clinical condition. This situation has hampered the assessment of the accuracy of clinical signs and biomarkers to diagnose sepsis.</p> <p>Methods/design</p> <p>Cross-sectional study to determine the operative characteristics of three biological markers of inflammation and coagulation (D-dimer, C-reactive protein and Procalcitonin) as diagnostic tests for sepsis, in patients admitted to hospital care with a presumptive infection as main diagnosis.</p> <p>Discussion</p> <p>There are alternative techniques that have been used to assess the accuracy of tests without gold standards, and they have been widely used in clinical disciplines such as psychiatry, even though they have not been tested in sepsis diagnosis. Considering the main importance of diagnosis as early as possible, we propose a latent class analysis to evaluate the accuracy of three biomarkers to diagnose sepsis.</p

Rescue of Dystrophic Skeletal Muscle by PGC-1α Involves a Fast to Slow Fiber Type Shift in the mdx Mouse

Increased utrophin expression is known to reduce pathology in dystrophin-deficient skeletal muscles. Transgenic over-expression of PGC-1α has been shown to increase levels of utrophin mRNA and improve the histology of mdx muscles. Other reports have shown that PGC-1α signaling can lead to increased oxidative capacity and a fast to slow fiber type shift. Given that it has been shown that slow fibers produce and maintain more utrophin than fast skeletal muscle fibers, we hypothesized that over-expression of PGC-1α in post-natal mdx mice would increase utrophin levels via a fiber type shift, resulting in more slow, oxidative fibers that are also more resistant to contraction-induced damage. To test this hypothesis, neonatal mdx mice were injected with recombinant adeno-associated virus (AAV) driving expression of PGC-1α. PGC-1α over-expression resulted in increased utrophin and type I myosin heavy chain expression as well as elevated mitochondrial protein expression. Muscles were shown to be more resistant to contraction-induced damage and more fatigue resistant. Sirt-1 was increased while p38 activation and NRF-1 were reduced in PGC-1α over-expressing muscle when compared to control. We also evaluated if the use a pharmacological PGC-1α pathway activator, resveratrol, could drive the same physiological changes. Resveratrol administration (100 mg/kg/day) resulted in improved fatigue resistance, but did not achieve significant increases in utrophin expression. These data suggest that the PGC-1α pathway is a potential target for therapeutic intervention in dystrophic skeletal muscle

Year in review 2007: Critical Care – multiple organ failure and sepsis

Several research papers published in Critical Care throughout 2007 examined the pathogenesis, diagnosis, treatment and prognosis of sepsis and multiorgan failure. The present review summarizes the findings and implications of the papers published on sepsis and multiorgan failure and places the research in the context of other work in the field

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019 : a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10-14 and 50-54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings The global TFR decreased from 2.72 (95% uncertainty interval [UI] 2.66-2.79) in 2000 to 2.31 (2.17-2.46) in 2019. Global annual livebirths increased from 134.5 million (131.5-137.8) in 2000 to a peak of 139.6 million (133.0-146.9) in 2016. Global livebirths then declined to 135.3 million (127.2-144.1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2.1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27.1% (95% UI 26.4-27.8) of global livebirths. Global life expectancy at birth increased from 67.2 years (95% UI 66.8-67.6) in 2000 to 73.5 years (72.8-74.3) in 2019. The total number of deaths increased from 50.7 million (49.5-51.9) in 2000 to 56.5 million (53.7-59.2) in 2019. Under-5 deaths declined from 9.6 million (9.1-10.3) in 2000 to 5.0 million (4.3-6.0) in 2019. Global population increased by 25.7%, from 6.2 billion (6.0-6.3) in 2000 to 7.7 billion (7.5-8.0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58.6 years (56.1-60.8) in 2000 to 63.5 years (60.8-66.1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019. Interpretation Over the past 20 years, fertility rates have been dropping steadily and life expectancy has been increasing, with few exceptions. Much of this change follows historical patterns linking social and economic determinants, such as those captured by the GBD Socio-demographic Index, with demographic outcomes. More recently, several countries have experienced a combination of low fertility and stagnating improvement in mortality rates, pushing more populations into the late stages of the demographic transition. Tracking demographic change and the emergence of new patterns will be essential for global health monitoring. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd.Peer reviewe