Multiomics Blood-Based Biomarkers Predict Alzheimer's Predementia with High Specificity in a Multicentric Cohort Study.

BACKGROUND: The primary criteria for diagnosing mild cognitive impairment (MCI) due to Alzheimer's Disease (AD) or probable mild AD dementia rely partly on cognitive assessments and the presence of amyloid plaques. Although these criteria exhibit high sensitivity in predicting AD among cognitively impaired patients, their specificity remains limited. Notably, up to 25% of non-demented patients with amyloid plaques may be misdiagnosed with MCI due to AD, when in fact they suffer from a different brain disorder. The introduction of anti-amyloid antibodies complicates this scenario. Physicians must prioritize which amyloid-positive MCI patients receive these treatments, as not all are suitable candidates. Specifically, those with non-AD amyloid pathologies are not primary targets for amyloid-modifying therapies. Consequently, there is an escalating medical necessity for highly specific blood biomarkers that can accurately detect pre-dementia AD, thus optimizing amyloid antibody prescription. OBJECTIVES: The objective of this study was to evaluate a predictive model based on peripheral biomarkers to identify MCI and mild dementia patients who will develop AD dementia symptoms in cognitively impaired population with high specificity. DESIGN: Peripheral biomarkers were identified in a gene transfer-based animal model of AD and then validated during a retrospective multi-center clinical study. SETTING: Participants from 7 retrospective cohorts (US, EU and Australia). PARTICIPANTS: This study followed 345 cognitively impaired individuals over up to 13 years, including 193 with MCI and 152 with mild dementia, starting from their initial visits. The final diagnoses, established during their last assessments, classified 249 participants as AD patients and 96 as having non-AD brain disorders, based on the specific diagnostic criteria for each disorder subtype. Amyloid status, assessed at baseline, was available for 82.9% of the participants, with 61.9% testing positive for amyloid. Both amyloid-positive and negative individuals were represented in each clinical group. Some of the AD patients had co-morbidities such as metabolic disorders, chronic diseases, or cardiovascular pathologies. MEASUREMENTS: We developed targeted mass spectrometry assays for 81 blood-based biomarkers, encompassing 45 proteins and 36 metabolites previously identified in AAV-AD rats. METHODS: We analyzed blood samples from study participants for the 81 biomarkers. The B-HEALED test, a machine learning-based diagnostic tool, was developed to differentiate AD patients, including 123 with Prodromal AD and 126 with mild AD dementia, from 96 individuals with non-AD brain disorders. The model was trained using 70% of the data, selecting relevant biomarkers, calibrating the algorithm, and establishing cutoff values. The remaining 30% served as an external test dataset for blind validation of the predictive accuracy. RESULTS: Integrating a combination of 19 blood biomarkers and participant age, the B-HEALED model successfully distinguished participants that will develop AD dementia symptoms (82 with Prodromal AD and 83 with AD dementia) from non-AD subjects (71 individuals) with a specificity of 93.0% and sensitivity of 65.4% (AUROC=81.9%, p<0.001) during internal validation. When the amyloid status (derived from CSF or PET scans) and the B-HEALED model were applied in association, with individuals being categorized as AD if they tested positive in both tests, we achieved 100% specificity and 52.8% sensitivity. This performance was consistent in blind external validation, underscoring the model's reliability on independent datasets. CONCLUSIONS: The B-HEALED test, utilizing multiomics blood-based biomarkers, demonstrates high predictive specificity in identifying AD patients within the cognitively impaired population, minimizing false positives. When used alongside amyloid screening, it effectively identifies a nearly pure prodromal AD cohort. These results bear significant implications for refining clinical trial inclusion criteria, facilitating drug development and validation, and accurately identifying patients who will benefit the most from disease-modifying AD treatments.

Two-Year Prognostic Utility of Plasma p217+tau across the Alzheimer's Continuum.

BACKGROUND: Plasma p217+tau has shown high concordance with cerebrospinal fluid (CSF) and positron emission tomography (PET) measures of amyloid-ß (Aß) and tau in Alzheimer's Disease (AD). However, its association with longitudinal cognition and comparative performance to PET Aß and tau in predicting cognitive decline are unknown. OBJECTIVES: To evaluate whether p217+tau can predict the rate of cognitive decline observed over two-year average follow-up and compare this to prediction based on Aß (18F-NAV4694) and tau (18F-MK6240) PET. We also explored the sample size required to detect a 30% slowing in cognitive decline in a 2-year trial and selection test cost using p217+tau (pT+) as compared to PET Aß (A+) and tau (T+) with and without p217+tau pre-screening. DESIGN: A prospective observational cohort study. SETTING: Participants of the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and Australian Dementia Network (ADNeT). PARTICIPANTS: 153 cognitively unimpaired (CU) and 50 cognitively impaired (CI) individuals. MEASUREMENTS: Baseline p217+tau Simoa® assay, 18F-MK6240 tau-PET and 18F-NAV4694 Aß-PET with neuropsychological follow-up (MMSE, CDR-SB, AIBL-PACC) over 2.4 ± 0.8 years. RESULTS: In CI, p217+tau was a significant predictor of change in MMSE (ß = -0.55, p < 0.001) and CDR-SB (ß =0.61, p < 0.001) with an effect size similar to Aß Centiloid (MMSE ß = -0.48, p = 0.002; CDR-SB ß = 0.43, p = 0.004) and meta-temporal (MetaT) tau SUVR (MMSE: ß = -0.62, p < 0.001; CDR-SB: ß = 0.65, p < 0.001). In CU, only MetaT tau SUVR was significantly associated with change in AIBL-PACC (ß = -0.22, p = 0.008). Screening pT+ CI participants into a trial could lead to 24% reduction in sample size compared to screening with PET for A+ and 6-13% compared to screening with PET for T+ (different regions). This would translate to an 81-83% biomarker test cost-saving assuming the p217+tau test cost one-fifth of a PET scan. In a trial requiring PET A+ or T+, p217+tau pre-screening followed by PET in those who were pT+ would cost more in the CI group, compared to 26-38% biomarker test cost-saving in the CU. CONCLUSIONS: Substantial cost reduction can be achieved using p217+tau alone to select participants with MCI or mild dementia for a clinical trial designed to slow cognitive decline over two years, compared to participant selection by PET. In pre-clinical AD trials, p217+tau provides significant cost-saving if used as a pre-screening measure for PET A+ or T+ but in MCI/mild dementia trials this may add to cost both in testing and in the increased number of participants needed for testing.

Non-viral chimeric antigen receptor (CAR) T cells going viral.

Chimeric antigen receptor (CAR) T cell therapy has made significant strides in the treatment of B-cell malignancies, but its application in treating solid tumors still poses significant challenges. Particularly, the widespread use of viral vectors to deliver CAR transgenes into T cells comes with limitations, including high costs and regulatory restrictions, which hinder the translation of novel genetic engineering concepts into clinical applications. Non-viral methods, such as transposon/transposase and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas systems, offer promising alternatives for stable transgene insertion in CAR-T cells. These methods offer the potential to increase accessibility and efficiency in the development and delivery of CAR-T cell therapies. The main challenge in using non-viral methods, however, is their low knock-in efficiency, which leads to low transgene expression levels. In this review, we discuss recent developments in non-viral approaches for CAR-T cell production, the manufacturing requirements for clinical-grade production of non-viral CAR-T cells, and the adjustments needed in quality control for proper characterization of genomic features and evaluation of potential genotoxicity.

Carbon Ion Fluxes at Mars: First Results of Tailward Flows From MAVEN-STATIC.

Characterizing C+ ions in the Martian ionosphere is important for understanding the history of the Martian atmosphere and surface due to its place in understanding carbon escape. Measuring minor ions, like C+, which are close in mass to major atmospheric ions, in this case O+, is difficult, requiring fitting algorithms and accurate background subtraction. Accurate measurement of these species is essential for understanding chemistry and transport in the ionosphere. In this paper, we use data from the Mars Atmospheric and Volatile EvolutioN SupraThermal And Thermal Ion Composition (MAVEN-STATIC) sensor to report the first C+ fluxes measured in the Martian magnetotail. We will describe a multistep method of background subtraction as well as fitting routines that are used to extract C+ fluxes from a 40-orbit subset of STATIC data. Our results show tailward fluxes in both optical shadow and the adjacent sunlit magnetotail at high altitudes ( > 3,000 km) and Mars-ward at low altitudes ( < 2,000 km) in shadow. These local flux values are similar to estimates of neutral carbon fluxes from photochemical escape. However, total carbon loss comparisons will require a more comprehensive study of integrated C+ loss over a larger data set from the Martian magnetotail.

A Conformational Variant of p53 (U-p53AZ) as Blood-Based Biomarker for the Prediction of the Onset of Symptomatic Alzheimer's Disease.

BACKGROUND: Ongoing research seeks to identify blood-based biomarkers able to predict onset and progression of Alzheimer's disease (AD). OBJECTIVE: The unfolded conformational variant of p53 (U-p53AZ), previously observed in AD individuals, was evaluated in plasma samples from individuals participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) cohort for diagnostic and prognostic assessment, validated on a neuropsychological-based diagnosis, over the course of six years. DESIGN: Retrospective Longitudinal Prognostic biomarker study. SETTING: Single-center study based on the AIBL cohort. PARTICIPANTS: 482 participants of the AIBL cohort, aged 60-85 years, without uncontrolled diabetes, vascular disease, severe depression or psychiatric illnesses. MEASUREMENTS: The AlzoSure® Predict test, consisting of immunoprecipitation (IP) followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS), was performed to quantify the AZ 284® peptide as readout of U-p53AZ and compared with an independent neuropsychological diagnosis. The amyloid load via amyloid ß-positron emission tomography (Aß-PET) and supporting clinical information were included where possible. RESULTS: U-p53AZ diagnostic and prognostic performance was assessed in both time-independent and time-dependent (36, 72 and 90 months following initial sampling) analyses. Prognostic performance of Aß-PET and survival analyses with different risk factors (gender, Aß-PET and APOE ε4 allele status) were also performed. U-p53AZ differentiated neuropsychologically graded AD from non-AD samples, and its detection at intermediate/high levels precisely identified present and future symptomatic AD. In both time-independent and time-dependent prognostic analyses U-p53AZ achieved area under the curve (AUC) >98%, significantly higher than Aß-PET AUCs (between 84% and 93%, P respectively <0.0001 and <0.001). As single factor, U-p53AZ could clearly determine the risk of AD neuropsychological diagnosis over time (low versus intermediate/high U-p53AZ hazard ratio=2.99). Proportional hazards regression analysis identified U-p53AZ levels as a major independent predictor of AD onset. CONCLUSIONS: These findings support use of U-p53AZ as blood-based biomarker predicting whether individuals would reach neuropsychologically-defined AD within six years prior to AD diagnosis. Integration of U-p53AZ in screening processes could support refined participant stratification for interventional studies.

Pharmacokinetic and pharmacodynamic properties of aerosolized ("vaped") THC in adolescent male and female rats.

RATIONALE: Adolescent exposure to ∆9-tetrahydrocannabinol (THC), the psychotropic constituent of cannabis, might affect brain development, and in rodent models leads to long-term behavioral and physiological alterations. Yet, the basic pharmacology of this drug in adolescent rodents, especially when ingested via ecologically relevant routes like aerosol inhalation, commonly referred to as "vaping," is still poorly characterized. Moreover, sex differences exist in THC metabolism, kinetics, and behavioral effects, but these have not been rigorously examined after vapor dosing in adolescents. OBJECTIVES: We investigated the pharmacokinetics and pharmacodynamics of aerosolized THC (30 min inhalation exposure, 25 or 100 mg/ml) in adolescent Wistar rats of both sexes. METHODS: Liquid chromatography/mass spectrometry analysis of THC and its major metabolites was conducted on blood plasma and brain tissue at 5, 30, 60, and 120 min following a 30-min aerosol dosing session. Effects on activity in a novel environment for 120 min after aerosol, and temperature, were measured in separate rats. RESULTS: We found sex-dependent differences in the pharmacokinetics of THC and its active (11-OH-THC) and inactive (11-COOH-THC) metabolites in the blood and brain, along with dose- and sex-dependent effects on anxiety-like and exploratory behaviors; namely, greater 11-OH-THC levels accompanied by greater behavioral effects in females at the low dose but similar hypothermic effects in both sexes at the high dose. CONCLUSIONS: These results provide a benchmark for dosing adolescent rats with aerosolized (or "vaped") THC, which could facilitate adoption by other labs of this potentially human-relevant THC exposure model to understand cannabis effects on the developing brain.

An evaluation of clinical and quality of life outcomes after ventral hernia repair with poly-4-hydroxybutyrate mesh.

PURPOSE: Despite continued efforts, recurrence after ventral hernia repair (VHR) remains a common problem. Biosynthetic Phasix™ (Poly-4-Hydroxybutyrate, P4HB) mesh combines the durability of synthetic mesh with the bio-resistance of biologics. P4HB has shown promising early outcomes, but long-term data are lacking. We examine patients following VHR with P4HB with at least 3 years of follow-up to assess clinical and patient reported outcomes (PROs). METHODS: Adult patients (≥ 18 years old) undergoing VHR with P4HB mesh between 10/2015 and 01/2018 by a single surgeon were retrospectively identified. Patients with < 36 months of follow-up were excluded unless they had a documented recurrence. Clinical outcomes and quality of life using the Hernia-Related Quality of Life Survey (HerQLes) were assessed. RESULTS: Seventy-one patients were included with a median age and body mass index of 61.2 and 31 kg/m2, respectively. Mesh was placed in the retromuscular (79%) and onlay (21%) planes with 1/3 of patients having hernias repaired in contaminated fields. There were no mesh infections, enterocutaneous fistulas, or mesh explantations. Nine patients (12.7%) developed recurrence at a median follow-up of 43.1 months [38.2-49.1]. Mesh plane, fixation technique, and Ventral Hernia Working Group were not associated with recurrence. Significant improvement in disease-specific PROs was observed and maintained at 3-year follow-up. CONCLUSION: Longitudinal clinical and quality of life outcomes after clean and contaminated VHR with P4HB are limited. Here, we conclude that P4HB is an effective and versatile mesh option for use in abdominal wall reinforcement.

Fragment-Based Nuclear Magnetic Resonance Screen against a Regulator of G Protein Signaling Identifies a Binding "Hot Spot".

Regulator of G protein signaling (RGS) proteins have attracted attention as a result of their primary role in directing the specificity as well as the temporal and spatial aspects of G protein-coupled receptor signaling. In addition, alterations in RGS protein expression have been observed in a number of disease states, including certain cancers. In this area, RGS17 is of particular interest. It has been demonstrated that, while RGS17 is expressed primarily in the central nervous system, it has been found to be inappropriately expressed in lung, prostate, breast, cervical, and hepatocellular carcinomas. Overexpression of RGS17 leads to dysfunction in inhibitory G protein signaling and an overproduction of the intracellular second messenger cAMP, which in turn alters the transcription patterns of proteins known to promote various cancer types. Suppressing RGS17 expression with RNA interference (RNAi) has been found to decrease tumorigenesis and sufficiently prevents cancer cell migration, leading to the hypothesis that pharmacological blocking of RGS17 function could be useful in anticancer therapies. We have identified small-molecule fragments capable of binding the RGS homology (RH) domain of RGS17 by using a nuclear magnetic resonance fragment-based screening approach. By chemical shift mapping of the two-dimensional 15 N,1 H heteronuclear single quantum coherence (HSQC) spectra of the backbone-assigned 15 N-labeled RGS17-RH, we determined the fragment binding sites to be distant from the Gα interface. Thus, our study identifies a putative fragment binding site on RGS17 that was previously unknown.

The Feeding Practices and Structure Questionnaire: development and validation of age appropriate versions for infants and toddlers.

BACKGROUND: In order to measure and understand trajectories of parental feeding practices and their relationship with child eating and weight, it is desirable to perform assessment from infancy and across time, in age-appropriate ways. While many feeding practices questionnaires exist, none is presently available that enables tracking of feeding practices from infancy through childhood. The aim of the study was to develop a version of the Feeding Practices and Structure Questionnaire (FPSQ) for parents with infants and toddlers (< 2 years) to be used in conjunction with the original FPSQ for older children (≥2 years) to measure feeding practices related to non-responsiveness and structure across childhood. METHODS: Constructs and items for the FPSQ for infants and toddlers were derived from the existing and validated FPSQ for older children and supplemented by a review of the literature on infant feeding questionnaires. Following expert review, two versions of the questionnaire were developed, one for milk feeding parents and one for solid feeding parents. Data from two studies were combined (child ages 0-24 months) to test the derived constructs with Confirmatory Factor Analysis for the milk feeding (N = 731) and solid feeding (N = 611) versions. RESULTS: The milk feeding version consisted of four factors (18 items) and showed acceptable model fit and good internal reliability: 'feeding on demand vs. feeding routine' (α = 0.87), 'using food to calm' (α = 0.87), 'persuasive feeding' (α = 0.71), 'parent-led feeding' (α = 0.79). The same four factors showed acceptable model fit for the solid feeding version (21 items), likewise with good internal reliability (α = 0.74, 0.86, 0.85, 0.84 respectively). Two additional factors (13 items) were developed for the solid feeding version that appeared developmentally appropriate only for children aged 12 months or older: 'family meal environment' (α = 0.81) and 'using (non-)food rewards' (α = 0.92). The majority of factor-factor correlations were in line with those of the original FPSQ. CONCLUSIONS: The FPSQ milk and solid feeding versions are the first measures specifically developed as precursors to the FPSQ to measure parental feeding practices in children < 2 years, particularly practices related to non-responsiveness and structure. Further validation in more diverse samples is required.

In Situ Measurements of Thermal Ion Temperature in the Martian Ionosphere.

In situ measurements of ionospheric and thermospheric temperatures are experimentally challenging because orbiting spacecraft typically travel supersonically with respect to the cold gas and plasma. We present O 2 + temperatures in Mars' ionosphere derived from data measured by the SupraThermal And Thermal Ion Composition instrument onboard the Mars Atmosphere and Volatile EvolutioN spacecraft. We focus on data obtained during nine special orbit maneuvers known as Deep Dips, during which MAVEN lowered its periapsis altitude from the nominal 150 to 120 km for 1 week in order to sample the ionospheric main peak and approach the homopause. We use two independent techniques to calculate ion temperatures from the measured energy and angular widths of the supersonic ram ion beam. After correcting for background and instrument response, we are able to measure ion temperatures as low as 100 K with associated uncertainties as low as 10%. It is theoretically expected that ion temperatures will converge to the neutral temperature at altitudes below the exobase region (∼180-200 km) due to strong collisional coupling; however, no evidence of the expected thermalization is observed. We have eliminated several possible explanations for the observed temperature difference between ions and neutrals, including Coulomb collisions with electrons, Joule heating, and heating caused by interactions with the spacecraft. The source of the energy maintaining the high ion temperatures remains unclear, suggesting that a fundamental piece of physics is missing from existing models of the Martian ionosphere.

The endocannabinoid system - current implications for drug development.

In this review, the state of the art for compounds affecting the endocannabinoid (eCB) system is described with a focus on the treatment of pain. Amongst directly acting CB receptor ligands, clinical experience with ∆9 -tetrahydracannabinol and medical cannabis in chronic non-cancer pain indicates that there are differences between the benefits perceived by patients and the at best modest effect seen in meta-analyses of randomized controlled trials. The reason for this difference is not known but may involve differences in the type of patients that are recruited, the study conditions that are chosen and the degree to which biases such as reporting bias are operative. Other directly acting CB receptor ligands such as biased agonists and allosteric receptor modulators have not yet reached the clinic. Amongst indirectly acting compounds targeting the enzymes responsible for the synthesis and catabolism of the eCBs anandamide and 2-arachidonoylglycerol, fatty acid amide hydrolase (FAAH) inhibitors have been investigated clinically but were per se not useful for the treatment of pain, although they may be useful for the treatment of post-traumatic stress disorder and cannabis use disorder. Dual-acting compounds targeting this enzyme and other targets such as cyclooxygenase-2 or transient potential vanilloid receptor 1 may be a way forward for the treatment of pain.

A unified call to action from Australian nursing and midwifery leaders: ensuring that Black lives matter.

Nurses and midwives of Australia now is the time for change! As powerfully placed, Indigenous and non-Indigenous nursing and midwifery professionals, together we can ensure an effective and robust Indigenous curriculum in our nursing and midwifery schools of education. Today, Australia finds itself in a shifting tide of social change, where the voices for better and safer health care ring out loud. Voices for justice, equity and equality reverberate across our cities, our streets, homes, and institutions of learning. It is a call for new songlines of reform. The need to embed meaningful Indigenous health curricula is stronger now than it ever was for Australian nursing and midwifery. It is essential that nursing and midwifery leadership continue to build an authentic collaborative environment for Indigenous curriculum development. Bipartisan alliance is imperative for all academic staff to be confident in their teaching and learning experiences with Indigenous health syllabus. This paper is a call out. Now is the time for Indigenous and non-Indigenous nurses and midwives to make a stand together, for justice and equity in our teaching, learning, and practice. Together we will dismantle systems, policy, and practices in health that oppress. The Black Lives Matter movement provides us with a 'now window' of accepted dialogue to build a better, culturally safe Australian nursing and midwifery workforce, ensuring that Black Lives Matter in all aspects of health care.

Report of a Delphi exercise to inform the design of a research programme on screening for thoracic aortic disease.

OBJECTIVES: To inform the design of a clinical trial of a targeted screening programme for relatives of individuals affected by thoracic aortic disease, we performed a consensus exercise as to the acceptability of screening, the optimal sequence and choice of tests, long-term patient management, and choice of trial design. METHODS: Working with the Aortic Dissection Awareness UK & Ireland patient association, we performed a Delphi exercise with clinical experts, patients, and carers, consisting of three rounds of consultation followed by a final multi-stakeholder face-to-face workshop. RESULTS: Thirty-five experts and 84 members of the public took part in the surveys, with 164 patients and clinicians attending the final workshop. There was substantial agreement on the need for a targeted screening pathway that would employ a combined approach (imaging + genetic testing). The target population would include the first- and second-degree adult (> 15 years) relatives, with no upper age limit of affected patients. Disagreement persisted about the screening process, sequence, personnel, the imaging method to adopt, computed tomography (CT) scan vs magnetic resonance imaging (MRI), and the specifics of a potential trial, including willingness to undergo randomisation, and measures of effectiveness and acceptability. CONCLUSION: A Delphi process, initiated by patients, identified areas of uncertainty with respect to behaviour, process, and the design of a targeted screening programme for thoracic aortic disease that requires further research prior to any future trial.

Guías de práctica clínica basadas en la evidencia para el manejo de la sedoanalgesia y delirium en el paciente adulto críticamente enfermo / Evidence-based clinical practice guidelines for the management of sedoanalgesia and delirium in critically ill adult patients

Dada la importancia del manejo de la sedación, analgesia y delirium en las unidades de cuidados intensivos, y con el fin de actualizar las guías publicadas anteriormente, se decidió elaborar una nueva guía de práctica clínica con los soportes, manejos e intervenciones más relevantes acordes con las publicaciones recientes. Para elaborar esta guía, se reunió un grupo de 24 intensivistas procedentes de 9 países de la Federación Panamericana e Ibérica de Sociedades de Medicina Crítica y Terapia Intensiva. Se acogió la propuesta del Grading of Recommendations Assessment, Development and Evaluation Working Group para emitir el grado de recomendación y evaluar la calidad de la evidencia. Se realizó una búsqueda sistemática de la literatura utilizándose: MEDLINE, las siguientes bases de datos de la biblioteca Cochrane: Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects, National Health Service Economic Evaluation Database, y la base de datos de Literatura Latinoamericana y del Caribe en Ciencias de la Salud (LILACS). Finalmente, se seleccionaron 438 referencias, permitiendo realizar 47 recomendaciones fuertes con evidencia alta y moderada, 14 recomendaciones condicionales con evidencia moderada y 65 recomendaciones condicionales con evidencia baja. Se confirma la importancia del manejo inicial y multimodal del dolor, se hace énfasis en la disminución de los niveles de sedación y la utilización de sedación profunda solo en casos específicos. Aumenta la evidencia y recomendaciones para el uso de medicamentos como dexmedetomidina, remifentanil, ketamina, entre otros

Given the importance of the management of sedation, analgesia and delirium in Intensive Care Units, and in order to update the previously published guidelines, a new clinical practice guide is presented, addressing the most relevant management and intervention aspects based on the recent literature. A group of 24 intensivists from 9 countries of the Pan-American and Iberian Federation of Societies of Critical Medicine and Intensive Therapy met to develop the guidelines. Assessment of evidence quality and recommendations was made according to the Grading of Recommendations Assessment, Development and Evaluation Working Group. A systematic search of the literature was carried out using MEDLINE, Cochrane Library databases such as the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of Abstracts of Reviews of Effects, the National Health Service Economic Evaluation Database and the database of Latin American and Caribbean Literature in Health Sciences (LILACS). A total of 438 references were selected. After consensus, 47 strong recommendations with high and moderate quality evidence, 14 conditional recommendations with moderate quality evidence, and 65 conditional recommendations with low quality evidence were established. Finally, the importance of initial and multimodal pain management was underscored. Emphasis was placed on decreasing sedation levels and the use of deep sedation only in specific cases. The evidence and recommendations for the use of drugs such as dexmedetomidine, remifentanil, ketamine and others were incremented

Evidence-based clinical practice guidelines for the management of sedoanalgesia and delirium in critically ill adult patients. / Guías de práctica clínica basadas en la evidencia para el manejo de la sedoanalgesia y delirium en el paciente adulto críticamente enfermo.

Given the importance of the management of sedation, analgesia and delirium in Intensive Care Units, and in order to update the previously published guidelines, a new clinical practice guide is presented, addressing the most relevant management and intervention aspects based on the recent literature. A group of 24 intensivists from 9 countries of the Pan-American and Iberian Federation of Societies of Critical Medicine and Intensive Therapy met to develop the guidelines. Assessment of evidence quality and recommendations was made according to the Grading of Recommendations Assessment, Development and Evaluation Working Group. A systematic search of the literature was carried out using MEDLINE, Cochrane Library databases such as the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of Abstracts of Reviews of Effects, the National Health Service Economic Evaluation Database and the database of Latin American and Caribbean Literature in Health Sciences (LILACS). A total of 438 references were selected. After consensus, 47 strong recommendations with high and moderate quality evidence, 14 conditional recommendations with moderate quality evidence, and 65 conditional recommendations with low quality evidence were established. Finally, the importance of initial and multimodal pain management was underscored. Emphasis was placed on decreasing sedation levels and the use of deep sedation only in specific cases. The evidence and recommendations for the use of drugs such as dexmedetomidine, remifentanil, ketamine and others were incremented.

HbA1c determination from HemaSpot™ blood collection devices: comparison of home prepared dried blood spots with standard venous blood analysis.

AIM: To assess the clinical performance and patient acceptance of HemaSpot™ blood collection devices as an alternative blood collection method. METHODS: Adult men and women with any type of diabetes, routinely carrying out self-monitoring of blood glucose were recruited (n = 128). Participants provided a venous blood sample and prepared two HemaSpot dried blood spots, one at clinics and one at home. HbA1c analysis was by Tosoh G8 high-performance liquid chromatography. Participants also completed a questionnaire. RESULTS: Strong linear relationships been HbA1c levels in dried blood spots and venous blood were observed and a linear model was fitted to the data. Time between dried blood spot preparation and testing did not impact the model. Participants were accepting of the approach: 69.2% would use this system if available and 60.7% would be more likely to use this system than going to their general practitioner. CONCLUSIONS: The combination of a robust desiccating dried blood spot device, home sample preparation and return by post produces HbA1c data that support the use of a time-independent linear calibration of dried blood spot to venous blood HbA1c . A robust remote sample collection service would be valuable to people living with diabetes in urban areas who are working or house-bound as well as those living in remote or rural locations.

High-resolution structure of RGS17 suggests a role for Ca2+ in promoting the GTPase-activating protein activity by RZ subfamily members.

Regulator of G protein signaling (RGS) proteins are negative regulators of G protein-coupled receptor (GPCR) signaling through their ability to act as GTPase-activating proteins (GAPs) for activated Gα subunits. Members of the RZ subfamily of RGS proteins bind to activated Gαo, Gαz, and Gαi1-3 proteins in the nervous system and thereby inhibit downstream pathways, including those involved in Ca2+-dependent signaling. In contrast to other RGS proteins, little is known about RZ subfamily structure and regulation. Herein, we present the 1.5-Å crystal structure of RGS17, the most complete and highest-resolution structure of an RZ subfamily member to date. RGS17 cocrystallized with Ca2+ bound to conserved positions on the predicted Gα-binding surface of the protein. Using NMR chemical shift perturbations, we confirmed that Ca2+ binds in solution to the same site. Furthermore, RGS17 had greater than 55-fold higher affinity for Ca2+ than for Mg2+ Finally, we found that Ca2+ promotes interactions between RGS17 and activated Gα and decreases the Km for GTP hydrolysis, potentially by altering the binding mechanism between these proteins. Taken together, these findings suggest that Ca2+ positively regulates RGS17, which may represent a general mechanism by which increased Ca2+ concentration promotes the GAP activity of the RZ subfamily, leading to RZ-mediated inhibition of Ca2+ signaling.

Benefits of introduction of Oncotype DX® testing.

INTRODUCTION: Decisions regarding adjuvant chemotherapy in women with oestrogen receptor positive, human epidermal growth factor receptor 2 negative, node negative, early invasive breast cancer are unclear. The Recurrence Score® (RS) from Oncotype DX® (ODX) testing guides decisions based on individual cancer genomics. The aim of this study was to evaluate the impact of introducing ODX results on adjuvant treatment decisions and its potential economic benefits. METHODS: Patients offered the test were identified from the ODX requesting system. Information on reasons behind chemotherapy treatment decisions were collected from clinical letters and the pathology system. The Nottingham prognostic index (NPI) scores were calculated for each individual patient. RESULTS: A total of 101 patients were identified as having undergone ODX testing over 21 months. The median age was 57 years (range: 41-72 years), the median NPI was 3.70 (range: 3.40-5.26) and the median RS was 17 (range: 0-59). NPI did not predict the risk category. All of the patients in the high risk group, 35.1% in the intermediate risk group and 5.4% in the low risk group received chemotherapy. The majority of low risk patients who received chemotherapy made a decision prior to the ODX result. CONCLUSIONS: In our unit, RS aided our decision making regarding adjuvant chemotherapy. Patients with a higher RS were more likely to receive chemotherapy. If NPI had been used alone, more women would have been offered chemotherapy. Good communication with patients prior to testing is important to ensure it is cost effective.