Standardization of in vitro digestibility and DIAAS method based on the static INFOGEST protocol

Background: The FAO recommends the digestible indispensable amino acid score (DIAAS) as the measure for protein quality, for which the true ileal digestibility needs to be assessed in humans or pigs. However, due to high costs and ethical concerns, the FAO strongly encourages as well the development of validated in vitro methods, which complement the in vivo experiments. Method: Recently, an in vitro workflow, based on the validated static INFOGEST protocol, was developed and compared towards in vivo data. In parallel to the validation with in vivo data, the repeatability and reproducibility of the in vitro protocol were tested in an international ring trial (RT) with the aim to establish an international ISO standard method within the International Dairy Federation (IDF). Five different dairy products (skim milk powder, whole milk powder, whey protein isolate, yoghurt, and cheese) were analyzed in 32 different laboratories from 18 different countries, across 4 continents. Results: in vitro protein digestibilities based on Nitrogen, free R-NH2, and total amino acids as well as DIAAS values were calculated and compared to in vivo data, where available. Conclusion: The in vitro method is suited for quantification of digestibility and will be further implemented to other food matricesinfo:eu-repo/semantics/publishedVersio

Precise interpolar phasing of abrupt climate change during the last ice age

The last glacial period exhibited abrupt Dansgaard–Oeschger climatic oscillations, evidence of which is preserved in a variety of Northern Hemisphere palaeoclimate archives¹. Ice cores show that Antarctica cooled during the warm phases of the Greenland Dansgaard–Oeschger cycle and vice versa[superscript 2,3], suggesting an interhemispheric redistribution of heat through a mechanism called the bipolar seesaw[superscript 4–6]. Variations in the Atlantic meridional overturning circulation (AMOC) strength are thought to have been important, but much uncertainty remains regarding the dynamics and trigger of these abrupt events[superscript 7–9]. Key information is contained in the relative phasing of hemispheric climate variations, yet the large, poorly constrained difference between gas age and ice age and the relatively low resolution of methane records from Antarctic ice cores have so far precluded methane-based synchronization at the required sub-centennial precision[superscript 2,3,10]. Here we use a recently drilled high-accumulation Antarctic ice core to show that, on average, abrupt Greenland warming leads the corresponding Antarctic cooling onset by 218 ± 92 years (2σ) for Dansgaard–Oeschger events, including the Bølling event; Greenland cooling leads the corresponding onset of Antarctic warming by 208 ± 96 years. Our results demonstrate a north-to-south directionality of the abrupt climatic signal, which is propagated to the Southern Hemisphere high latitudes by oceanic rather than atmospheric processes. The similar interpolar phasing of warming and cooling transitions suggests that the transfer time of the climatic signal is independent of the AMOC background state. Our findings confirm a central role for ocean circulation in the bipolar seesaw and provide clear criteria for assessing hypotheses and model simulations of Dansgaard–Oeschger dynamics

A multimodal cell census and atlas of the mammalian primary motor cortex

ABSTRACT We report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex (MOp or M1) as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties, and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Together, our results advance the collective knowledge and understanding of brain cell type organization: First, our study reveals a unified molecular genetic landscape of cortical cell types that congruently integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a unified taxonomy of transcriptomic types and their hierarchical organization that are conserved from mouse to marmoset and human. Third, cross-modal analysis provides compelling evidence for the epigenomic, transcriptomic, and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types and subtypes. Fourth, in situ single-cell transcriptomics provides a spatially-resolved cell type atlas of the motor cortex. Fifth, integrated transcriptomic, epigenomic and anatomical analyses reveal the correspondence between neural circuits and transcriptomic cell types. We further present an extensive genetic toolset for targeting and fate mapping glutamatergic projection neuron types toward linking their developmental trajectory to their circuit function. Together, our results establish a unified and mechanistic framework of neuronal cell type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Social dimensions of healing: A longitudinal study of outcomes of medical management of headaches

The social sciences have made few direct empirical contributions to the understanding of 'non-specific' benefits of treatment and generally the symbolic healing of indigenous non-Western medicine has received most attention in this field. This paper reports some results of a wider study of neurological clinics in England in which it is shown that a sample attending for headaches experienced considerable improvement in symptoms when followed up 1 year after attendance. Most of this improvement appeared not to be due to any intended treatments received at the clinics but could be attributed to the quality of patients' immediate responses to clinic attendance as assessed from research interviews conducted after their consultations. This relationship between immediate 'satisfied' response and subsequent symptomatic improvement is interpreted in terms of the general levels of expectancy and sense of potential control achieved by obtaining referral to a specialist which directly enhanced recovery in those patients who felt the doctor's actions to be directly relevant to their personal concerns. Disappointment with the doctor reduced the 'non-specific' therapeutic benefits of the hospital referral. The intimate connections of patient satisfaction, treatment received and subsequent outcomes need more careful consideration in social studies of Western medicine.

Face Name Associative Memory Exam and biomarker status in the ARMADA study: Advancing reliable measurement in Alzheimer's disease and cognitive aging

Abstract The Face Name Associative Memory Exam (FNAME) was introduced into the NIH Toolbox as part of the ARMADA study and establishes normative data for diverse participants, ages 64 to 85+, and proposes cutoff scores between biomarker positive versus negative (+/−) groups. The FNAME was administered to 257 participants across the clinical spectrum with 122 having amyloid biomarkers. Linear regression explored the association between demographics and FNAME and between amyloid (+/−) groups. Receiver operating characteristic curves (ROC) identified performance thresholds that best discriminated between biomarker (+/−) individuals. Lower FNAME scores occurred in males, older ages, Black/African Americans, Hispanics, and biomarker‐positive participants. ROC analyses demonstrated acceptable accuracy (0.73 to 0.77) but only when combined with clinical status. The diagnostic discrimination of amyloid positivity was acceptable but not excellent, suggesting the FNAME may be a better screening indicator of clinical status rather than amyloid deposition in cognitively normal individuals. Normative data are provided

Reducing Health Risk Behaviors and Improving Depression in Adolescents: A Randomized Controlled Trial in Primary Care Clinics

ObjectivePrimary care (PC) is a major service delivery setting that can provide preventive behavioral health care to youths. To explore the hypothesis that reducing health risk behaviors (HRBs) would lower depressive symptoms, and that health risk and depression can be efficiently targeted together in PC, this study (1) evaluates an intervention designed to reduce HRBs among adolescent PC patients with depressive symptoms and (2) examines prospective links between HRBs and depressive symptoms.MethodA Randomized controlled trial was conducted comparing a behavioral health intervention with enhanced Usual PC (UC+). Participants were 187 adolescents (ages 13-18 years) with past-year depression, assessed at baseline, 6 months, and 12 months. Primary outcome was the Health Risk Behavior Index (HRBI), a composite score indexing smoking, substance use, unsafe sex, and obesity risk. Secondary/exploratory outcomes were an index of the first three most correlated behaviors (HRBI-S), each HRB, depressive symptoms, and satisfaction with mental health care.ResultsOutcomes were similar at 6 and 12 months, with no significant between-group differences. HRBI, HRBI-S, and depressive symptoms decreased, and satisfaction with mental health care increased across time in both groups. HRBI, HRBI-S, and smoking predicted later severe depression. Conversely, severe depression predicted later HRBI-S and substance use.ConclusionsUC+ and the behavioral health intervention yielded similar benefits in reducing HRBs and depressive symptoms. Findings underscore the bidirectional links between depression and HRBs, supporting the importance of monitoring for HRBs and depression in PC to allow for effective intervention in both areas

Expanding the Family of Tetrahalide Iron Complexes: Synthesis, Structure and Biological Applications.

A neutral octahedral mononuclear iron(II) tetrabromide complex, [Fe(Hampy)2Br4], that consists of equatorial bromide and protonated aminopyrazinium axial ligands is successfully synthesised through redox chemistry and analysed using X-ray crystallography. The iron(II) oxidation state is balanced by the protonated pyrazinium nitrogen just outside the coordination sphere. The biological properties of this and two other related complexes are investigated using both Gram-negative and Gram-positive bacteria as well as methicillin resistant strains. They all exhibit some antimicrobial properties albeit at moderate to poor concentrations. However, the tetrahalide complexes analysed exhibit excellent anti biofilm properties well below cytotoxic levels

Time Costs Associated with Informal Care for Colorectal Cancer: An Investigation of the Impact of Alternative Valuation Methods

Background A societal perspective in economic evaluation necessitates that all resources associated with a disease or intervention should be valued; however, informal care time costs are rarely considered. Objective We estimated time allocated to care by informal carers of colorectal cancer survivors; and investigated the impact of applying alternative valuation methods to this time. Methods Colorectal cancer cases (ICD10 C18-C20) diagnosed 6–30 months previously and identified from the National Cancer Registry Ireland were invited to provide details of informal carers. Carers completed a postal questionnaire. Time estimates per week associated with hospital-related and domestic-related care activities were collected for two phases: diagnosis and initial treatment (initial 3 months) and ongoing care (previous 30 days). Seven valuation scenarios, based on variants of the opportunity cost approach (OCA), and the proxy good approach (PGA), were considered. The base-case was OCA with all carer time valued at the average national wage. Results We received 154 completed questionnaires (response rate = 68 %). Average weekly time allocated to caring was 42.5 h in the diagnosis and initial treatment phase and 16.9 h in the ongoing care phase. Under the base-case, average weekly time costs were €295 (95 % CI 255–344) for hospital-related activities and €630 (95 % CI 543–739) for domestic-related activities in the diagnosis and initial treatment phase and €359 (95 % CI 293–434) in the ongoing care phase. PGA estimates were 23 % below the base-case. Only one alternative scenario (occupation and gender-specific wages for carers in paid work and replacement wages for non-working carers) surpassed base-case costs, and the difference was modest. Conclusions Overall, significant time is associated with informal caring in colorectal cancer. Different time valuation methods can produce quite different cost estimates. A standardised methodology for estimating informal care costs would facilitate better integration of these into economic evaluations