An illustrative analysis of atypical gas production profiles obtained from in vitro digestibility studies using fecal inoculum

14 páginas, 2 tablas, 6 figuras.Gas production profiles typically show a monotonically increasing monophasic pattern. However, atypical gas production profiles exist whereby at least two consecutive phases of gas production or additional extraneous features that distort the typical profile are present. Such profiles are more likely to occur with the use of a fecal inoculum and are much less well described. The presence of multiple phases or non-descript extraneous features makes it difficult to apply directly recommended modeling approaches such as standard response functions or classical growth functions. To overcome such difficulties, extensions of the Mitscherlich equation and a numerical modeling option also based on the Mitscherlich are explored. The numerical modeling option uses an estimate of relative rate obtained from the smoothed data profile and an estimate of maximum gas produced together with any lag time information drawn from the raw data to construct a simple Mitscherlich equation. In summary, this article illustrates the analysis of atypical gas production profiles obtained using a fecal inoculum and explores the methodology of numerical modeling to reconstruct equivalent typical growth-like trends.This research was funded in part by The Canada Research Chairs program, grant number 045867 (Natural Sciences and Engineering Research Council of Canada, Ottawa)

OREX-1038:A potential new treatment for pain with low abuse liability and limited adverse effects

Drugs targeting mu opioid receptors are the mainstay of clinical practice for treating moderate-to-severe pain. While they can offer excellent analgesia, their use can be limited by adverse effects, including constipation, respiratory depression, tolerance, and abuse liability. Multifunctional ligands acting at mu opioid and nociceptin/orphanin FQ peptide receptors might provide antinociception with substantially improved adverse-effect profiles. This study explored one of these ligands, OREX-1038 (BU10038), in several assays in rodents and nonhuman primates. Binding and functional studies confirmed OREX-1038 to be a low-efficacy agonist at mu opioid and nociceptin/orphanin FQ peptide receptors and an antagonist at delta and kappa opioid receptors with selectivity for opioid receptors over other proteins. OREX-1038 had long-acting antinociceptive effects in postsurgical and complete Freund's adjuvant (CFA)-induced thermal hyperalgesia assays in rats and a warm water tail-withdrawal assay in monkeys. OREX-1038 was active for at least 24 h in each antinociception assay, and its effects in monkeys did not diminish over 22 days of daily administration. This activity was coupled with limited effects on physiological signs (arterial pressure, heart rate, and body temperature) and no evidence of withdrawal after administration of naltrexone or discontinuation of treatment in monkeys receiving OREX-1038 daily. Over a range of doses, OREX-1038 was only transiently self-administered, which diminished rapidly to nonsignificant levels; overall, both OREX-1038 and buprenorphine maintained less responding than remifentanil. These results support the concept of dual mu and nociceptin/orphanin FQ peptide receptor partial agonists having improved pharmacological profiles compared with opioids currently used to treat pain.</p

Global health and foreign policy.

Health has long been intertwined with the foreign policies of states. In recent years, however, global health issues have risen to the highest levels of international politics and have become accepted as legitimate issues in foreign policy. This elevated political priority is in many ways a welcome development for proponents of global health, and it has resulted in increased funding for and attention to select global health issues. However, there has been less examination of the tensions that characterize the relationship between global health and foreign policy and of the potential effects of linking global health efforts with the foreign-policy interests of states. In this paper, the authors review the relationship between global health and foreign policy by examining the roles of health across 4 major components of foreign policy: aid, trade, diplomacy, and national security. For each of these aspects of foreign policy, the authors review current and historical issues and discuss how foreign-policy interests have aided or impeded global health efforts. The increasing relevance of global health to foreign policy holds both opportunities and dangers for global efforts to improve health

Follow-up of cancer in primary care versus secondary care: systematic review

Background Cancer follow-up has traditionally been undertaken in secondary care, but there are increasing calls to deliver it in primary care. Aim To compare the effectiveness and cost-effectiveness of primary versus secondary care follow-up of cancer patients, determine the effectiveness of the integration of primary care in routine hospital follow-up, and evaluate the impact of patient-initiated follow-up on primary care. Design of study Systematic review. Setting Primary and secondary care settings. Method A search was carried out of 19 electronic databases, online trial registries, conference proceedings, and bibliographies of included studies. The review included comparative studies or economic evaluations of primary versus secondary care follow-up, hospital follow-up with formal primary care involvement versus conventional hospital follow-up, and hospital follow-up versus patient-initiated or minimal follow-up if the study reported the impact on primary care. Results There was no statistically significant difference for patient wellbeing, recurrence rate, survival, recurrence-related serious clinical events, diagnostic delay, or patient satisfaction. GP-led breast cancer follow-up was cheaper than hospital follow-up. Intensified primary health care resulted in increased home-care nurse contact, and improved discharge summary led to increased GP contact. Evaluation of patient-initiated or minimal follow-up found no statistically significant impact on the number of GP consultations or cancer-related referrals. Conclusion Weak evidence suggests that breast cancer follow-up in primary care is effective. Interventions improving communication between primary and secondary care could lead to greater GP involvement. Discontinuation of formal follow-up may not increase GP workload. However, the quality of the data in general was poor, and no firm conclusions can be reached

An African Salmonella Typhimurium ST313 sublineage with extensive drug-resistance and signatures of host adaptation

Abstract: Bloodstream infections by Salmonella enterica serovar Typhimurium constitute a major health burden in sub-Saharan Africa (SSA). These invasive non-typhoidal (iNTS) infections are dominated by isolates of the antibiotic resistance-associated sequence type (ST) 313. Here, we report emergence of ST313 sublineage II.1 in the Democratic Republic of the Congo. Sublineage II.1 exhibits extensive drug resistance, involving a combination of multidrug resistance, extended spectrum β-lactamase production and azithromycin resistance. ST313 lineage II.1 isolates harbour an IncHI2 plasmid we name pSTm-ST313-II.1, with one isolate also exhibiting decreased ciprofloxacin susceptibility. Whole genome sequencing reveals that ST313 II.1 isolates have accumulated genetic signatures potentially associated with altered pathogenicity and host adaptation, related to changes observed in biofilm formation and metabolic capacity. Sublineage II.1 emerged at the beginning of the 21st century and is involved in on-going outbreaks. Our data provide evidence of further evolution within the ST313 clade associated with iNTS in SSA

Longitudinal associations of DNA methylation and sleep in children : a meta-analysis

Publisher Copyright: © 2022, The Author(s).Background: Sleep is important for healthy functioning in children. Numerous genetic and environmental factors, from conception onwards, may influence this phenotype. Epigenetic mechanisms such as DNA methylation have been proposed to underlie variation in sleep or may be an early-life marker of sleep disturbances. We examined if DNA methylation at birth or in school age is associated with parent-reported and actigraphy-estimated sleep outcomes in children. Methods: We meta-analysed epigenome-wide association study results. DNA methylation was measured from cord blood at birth in 11 cohorts and from peripheral blood in children (4–13 years) in 8 cohorts. Outcomes included parent-reported sleep duration, sleep initiation and fragmentation problems, and actigraphy-estimated sleep duration, sleep onset latency and wake-after-sleep-onset duration. Results: We found no associations between DNA methylation at birth and parent-reported sleep duration (n = 3658), initiation problems (n = 2504), or fragmentation (n = 1681) (p values above cut-off 4.0 × 10–8). Lower methylation at cg24815001 and cg02753354 at birth was associated with longer actigraphy-estimated sleep duration (p = 3.31 × 10–8, n = 577) and sleep onset latency (p = 8.8 × 10–9, n = 580), respectively. DNA methylation in childhood was not cross-sectionally associated with any sleep outcomes (n = 716–2539). Conclusion: DNA methylation, at birth or in childhood, was not associated with parent-reported sleep. Associations observed with objectively measured sleep outcomes could be studied further if additional data sets become available.Peer reviewe

Périgord black truffle genome uncovers evolutionary origins and mechanisms of symbiosis

LetterInternational audienceThe Périgord black truffle ($Tuber\ melanosporum$ Vittad.) and the Piedmont white truffle dominate today's truffle market. The hypogeous fruiting body of $T.\ melanosporum$ is a gastronomic delicacy produced by an ectomycorrhizal symbiont endemic to calcareous soils in southern Europe. The worldwide demand for this truffle has fuelled intense efforts at cultivation. Identification of processes that condition and trigger fruit body and symbiosis formation, ultimately leading to efficient crop production, will be facilitated by a thorough analysis of truffle genomic traits. In the ectomycorrhizal $Laccaria\ bicolor$, the expansion of gene families may have acted as a 'symbiosis toolbox'. This feature may however reflect evolution of this particular taxon and not a general trait shared by all ectomycorrhizal species. To get a better understanding of the biology and evolution of the ectomycorrhizal symbiosis, we report here the sequence of the haploid genome of $T.\ melanosporum$, which at $\sim$125 megabases is the largest and most complex fungal genome sequenced so far. This expansion results from a proliferation of transposable elements accounting for $\sim$58% of the genome. In contrast, this genome only contains $\sim$7,500 protein-coding genes with very rare multigene families. It lacks large sets of carbohydrate cleaving enzymes, but a few of them involved in degradation of plant cell walls are induced in symbiotic tissues. The latter feature and the upregulation of genes encoding for lipases and multicopper oxidases suggest that $T.\ melanosporum$ degrades its host cell walls during colonization. Symbiosis induces an increased expression of carbohydrate and amino acid transporters in both $L.\ bicolor$ and $T.\ melanosporum$, but the comparison of genomic traits in the two ectomycorrhizal fungi showed that genetic predispositions for symbiosis $-$'the symbiosis toolbox'$-$ evolved along different ways in ascomycetes and basidiomycete