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In patients with treatment resistant depression (TRD), the ESCAPE-TRD study showed esketamine nasal spray was superior to quetiapine extended release.
Aims
To determine the robustness of the ESCAPE-TRD results and confirm the superiority of esketamine nasal spray over quetiapine extended release.
Method
ESCAPE-TRD was a randomised, open-label, rater-blinded, active-controlled phase IIIb trial. Patients had TRD (i.e. non-response to two or more antidepressive treatments within a major depressive episode). Patients were randomised 1:1 to flexibly dosed esketamine nasal spray or quetiapine extended release, while continuing an ongoing selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor. The primary end-point was achieving a Montgomery–Åsberg Depression Rating Scale score of ≤10 at Week 8, while the key secondary end-point was remaining relapse free through Week 32 after achieving remission at Week 8. Sensitivity analyses were performed on these end-points by varying the definition of remission based on timepoint, threshold and scale.
Results
Of 676 patients, 336 were randomised to esketamine nasal spray and 340 to quetiapine extended release. All sensitivity analyses on the primary and key secondary end-point favoured esketamine nasal spray over quetiapine extended release, with relative risks ranging from 1.462 to 1.737 and from 1.417 to 1.838, respectively (all p < 0.05). Treatment with esketamine nasal spray shortened time to first and confirmed remission (hazard ratio: 1.711 [95% confidence interval 1.402, 2.087], p < 0.001; 1.658 [1.337, 2.055], p < 0.001).
Conclusion
Esketamine nasal spray consistently demonstrated significant superiority over quetiapine extended release using all pre-specified definitions for remission and relapse. Sensitivity analyses supported the conclusions of the primary ESCAPE-TRD analysis and demonstrated robustness of the results.
The incidence of cognitive decline is rising, leading to increased attention on the preventive role of healthy foods on brain function. Previous reviews including primarily observational studies suggested that dietary proteins may improve cognitive performance, but evidence from individual randomised controlled trials (RCT) is less consistent. Therefore, this systematic review examined the long-term effects of dietary proteins from RCT, considering both their amount and type, on cognitive performance (psychomotor speed and attention, executive function, memory and global cognition). Alterations in cerebral blood flow (CBF) – a validated brain vascular function marker – were also considered. A total of 4747 studies were identified through a systematic search, resulting in twenty-three included papers reporting effects on cognitive performance (n = 23) and CBF (n = 3). Improvements were observed in three out of the nine studies that evaluated psychomotor speed which compared a dietary protein intervention with a non-protein or lower-protein control. Of the six beneficial observations on working memory (n = 12), declarative memory (n = 10) and visuospatial memory (n = 10), five were nut interventions from three different trials. Limited studies focusing on global cognition suggested that specific target populations, namely subacute stroke or dementia, may benefit more than healthy individuals from increased dietary protein intake. From the three studies involving CBF, improvements in regional blood flow were associated with most cognitive performance outcomes. The comparative effects of different protein types warrant further investigation. Overall, this review encourages additional research into protein-rich foods or supplements which could potentially prevent or mitigate cognitive decline.
In this paper, we apply standard zooarchaeological methods and novel osteological approaches to analyse faunal remains from five Middle–Late Holocene sites in the southern Tibetan Plateau (STP). Framed by direct radiocarbon dates on taxonomically classified bioarchaeological remains and compared with published palaeoclimate data, our findings revealed a three-stage process of agro-pastoral development in the STP ca. 5.5 to 1.0 ka. In the first phase, habitation was restricted to the lower southeastern part of the plateau and human subsistence essentially based on foraging and low-level pig–millet farming. With the onset of colder and drier climatic conditions ca. 3.8 ka, the study area witnessed a growing human presence at higher elevations in its central and western parts, together with a shift towards bovid husbandry and barley cultivation, that is, agricultural practices that originated in west Asia; these were likely introduced to the STP following the eastern margin of the TP and/or arrived by sub-Himalayan transfer. Climate and ecological degradation might have contributed to the decline of local game in favour of cold-and-dry-tolerant pastoral livestock and crops. Our work shows that Middle–Late Holocene climate change, ecological change, human subsistence shifts, and prehistoric cultural transmissions are intimately connected.
Little is known about the early history of the chicken (Gallus gallus domesticus), including the timing and circumstances of its introduction into new cultural environments. To evaluate its spatio-temporal spread across Eurasia and north-west Africa, the authors radiocarbon dated 23 chicken bones from presumed early contexts. Three-quarters returned dates later than those suggested by stratigraphy, indicating the importance of direct dating. The results indicate that chickens did not arrive in Europe until the first millennium BC. Moreover, a consistent time-lag between the introduction of chickens and their consumption by humans suggests that these animals were initially regarded as exotica and only several centuries later recognised as a source of ‘food’.
As part of a project to implement antimicrobial dashboards at select facilities, we assessed physician attitudes and knowledge regarding antibiotic prescribing.
Design:
An online survey explored attitudes toward antimicrobial use and assessed respondents’ management of four clinical scenarios: cellulitis, community-acquired pneumonia, non–catheter-associated asymptomatic bacteriuria, and catheter-associated asymptomatic bacteriuria.
Setting:
This study was conducted across 16 Veterans’ Affairs (VA) medical centers in 2017.
Participants:
Physicians working in inpatient settings specializing in infectious diseases (ID), hospital medicine, and non-ID/hospitalist internal medicine.
Methods:
Scenario responses were scored by assigning +1 for answers most consistent with guidelines, 0 for less guideline-concordant but acceptable answers and −1 for guideline-discordant answers. Scores were normalized to 100% guideline concordant to 100% guideline discordant across all questions within a scenario, and mean scores were calculated across respondents by specialty. Differences in mean score per scenario were tested using analysis of variance (ANOVA).
Results:
Overall, 139 physicians completed the survey (19 ID physicians, 62 hospitalists, and 58 other internists). Attitudes were similar across the 3 groups. We detected a significant difference in cellulitis scenario scores (concordance: ID physicians, 76%; hospitalists, 58%; other internists, 52%; P = .0087). Scores were numerically but not significantly different across groups for community-acquired pneumonia (concordance: ID physicians, 75%; hospitalists, 60%; other internists, 56%; P = .0914), for non–catheter-associated asymptomatic bacteriuria (concordance: ID physicians, 65%; hospitalists, 55%; other internists, 40%; P = .322), and for catheter-associated asymptomatic bacteriuria (concordance: ID physicians, 27% concordant; hospitalists, 8% discordant; other internists 13% discordant; P = .12).
Conclusions:
Significant differences in performance regarding management of cellulitis and low overall performance regarding asymptomatic bacteriuria point to these conditions as being potentially high-yield targets for stewardship interventions.
l-Citrulline may improve non-invasive vascular function and cardiometabolic risk markers through increases in l-arginine bioavailability and nitric oxide synthesis. A meta-analysis of randomised controlled trials (RCT) was performed to examine longer-term and postprandial effects of l-citrulline supplementation and watermelon consumption on these markers for CVD in adults. Summary estimates of weighted mean differences in vascular function and cardiometabolic risk markers with accompanying 95 % CI were calculated using random or fixed-effect meta-analyses. Seventeen RCT were included involving an l-citrulline intervention, of which six studied postprandial and twelve longer-term effects. Five studies investigated longer-term effects of watermelon consumption and five assessed effects during the postprandial phase. Longer-term l-citrulline supplementation improved brachial artery flow-mediated vasodilation (FMD) by 0·9 %-point (95 % CI 0·7, 1·1, P < 0·001). Longer-term watermelon consumption improved pulse wave velocity by 0·9 m/s (95 % CI 0·1, 1·5, P < 0·001), while effects on FMD were not studied. No postprandial effects on vascular function markers were found. Postprandial glucose concentrations decreased by 0·6 mmol/l (95 % CI 0·4, 0·7, P < 0·001) following watermelon consumption, but no other longer-term or postprandial effects were observed on cardiometabolic risk markers. To conclude, longer-term l-citrulline supplementation and watermelon consumption may improve vascular function, suggesting a potential mechanism by which increased l-citrulline intake beneficially affects cardiovascular health outcomes in adults. No effects on postprandial vascular function markers were found, while more research is needed to investigate the effects of l-citrulline and watermelon on risk markers related to cardiometabolic health.
The numerous new excavations and archaeozoological analyses of Pre-Pottery Neolithic (PPN) sites in the Levant during the last 15 years shed new light on the domestication and early husbandry of animals. This chapter provides a synthetic update of the dates and locations of the early domestication of dog, cat, pig, sheep, goat and cattle, and of their utilisation by PPN societies. It also briefly discusses patterns and processes, with special attention to the commensalism and controlled hunting. Based on the data presented, the authors discuss different mechanisms and possible reasons behind early animal domestications in the Levant, as well as the role of animal domestication in the Neolithic transition.
The incorporation of the region north of the Alpine divide and its foreland into the Imperium Romanum initiated major changes in economic and social structure and in everyday life in the newly-founded province of Raetia. Controversy exists, however, about the continuity of local La Tène traditions into early Roman times, since the archaeological evidence recorded to date tends to give the impression that the northern Alpine foreland was largely unpopulated at the time of the Roman conquest in 15 bc. However, ongoing excavations in this region are gradually enhancing the archaeological visibility of this transitional phase. Compared to early Roman provincial populations settled along the Via Claudia Augusta and its hinterland, a culturally unique community stands out: the Heimstetten group. This group is located in the eastern Raetian hinterlands and dates to around 30–60 ad. Its building tradition, settlement structure, and burial customs show close affinities with the La Tène culture, thus suggesting continuity in autochthonous culture at the time of the early Roman occupation. Since faunal remains can potentially act as cultural markers, additional insights can be gained from a spatial-temporal analysis of livestock composition and breeding practices. The results presented here clearly show that, during the Iron Age, marked regional differences in species composition are visible, implying the possibility of distinct developments during early Romanization. In addition to evaluating faunal developments in the study area between c. 100 bc–100 ad, the issue of cattle breeding—traditionally the mainstay of livestock economies in many regions and especially in the Munich Gravel Plain at least since the Bronze Age—is addressed in greater detail.
The article presents new results of stable isotope analyses made on animal and human bones from the Mesolithic–early Neolithic sites of Lepenski Vir and Vlasac in the Danube Gorges of the Balkans. It reconstructs the food web for the region during these periods on the basis of stable isotope analyses of mammal and fish species found at Vlasac. These results are compared to measurements made on human burials from the two sites. In the light of these new results, the article also discusses interpretations provided by previous isotopic studies of this material. It concludes that great care is required in the interpretation of stable isotope results due to inherent methodological complexities of this type of analysis, and suggests that it is also necessary to integrate stable isotope results with information based on the examination of faunal remains and the archaeological context of analysed burials when making inferences about palaeodietary patterns.
Charcoal was sampled in four soil profiles at the Mayumbe forest boundary (DRC). Five fire events were recorded and 44 charcoal types were identified. One stratified profile yielded charcoal assemblages around 530 cal yr BP and > 43.5 cal ka BP in age. The oldest assemblage precedes the period of recorded anthropogenic burning, illustrating occasional long-term absence of fire but also natural wildfire occurrences within tropical rainforest. No other charcoal assemblages older than 2500 cal yr BP were recorded, perhaps due to bioturbation and colluvial reworking. The recorded paleofires were possibly associated with short-lived climate anomalies. Progressively dry climatic conditions since ca. 4000 cal yr BP onward did not promote paleofire occurrence until increasing seasonality affected vegetation at the end of the third millennium BP, as illustrated by a fire occurring in mature rainforest that persisted until around 2050 cal yr BP. During a drought episode coinciding with the "Medieval Climate Anomaly", mature rainforest was locally replaced by woodland savanna. Charcoal remains from pioneer forest indicate that fire hampered forest regeneration after climatic drought episodes. The presence of pottery shards and oil-palm endocarps associated with two relatively recent paleofires suggests that the effects of climate variability were amplified by human activities.
Mass-loss in cool supergiants remains poorly understood, but is one of the key elements in their evolution towards exploding as supernovae. Some show evidence of asymmetric mass loss, discrete mass-ejections and outbursts, with seemingly little to distinguish them from more quiescent cases. To explore the prevalence of discrete ejections and companions we have conducted a high-constrast survey using near-infrared imaging and optical polarimetric imaging of nearby southern and equatorial red supergiants, using the extreme adaptive optics instrument SPHERE, which was designed to image planets around nearby stars. We present the initial results of this survey, including the detection of large (500 nm) dust grains in the ejecta of VY CMa and a candidate dusty torus aligned with the maser ring of VX Sgr. We briefly speculate on the consequences for our understanding of mass loss in these extreme stars.
Two methods are especially suited for tomographic imaging with histological detail of macroscopic samples that consist of multiple tissue types (bone, muscle, nerve or fat): Light sheet (based) fluorescence microscopy (LSFM) and micro-computed tomography (micro-CT). Micro-CT requires staining with heavy chemical elements (and thus fixation and sometimes dehydration) in order to make soft tissue imageable when measured alongside denser structures. LSMF requires fixation, decalcification, dehydration, clearing and staining with a fluorescent dye. The specimen preparation of both imaging methods is prone to shrinkage, which is often not mentioned, let alone quantified. In this paper the presence and degree of shrinkage are quantitatively identified for the selected preparation methods/stains. LSFM delivers a volume shrinkage of 17% for bone, 56% for muscle and 62% for brain tissue. The three most popular micro-CT stains (phosphotungstic acid, iodine with potassium iodide, and iodine in absolute ethanol) deliver a volume shrinkage ranging from 10 to 56% for muscle and 27–66% for brain, while bone does not shrink in micro-CT preparation.
It has been postulated that aging is the consequence of an accelerated accumulation of somatic DNA mutations and that subsequent errors in the primary structure of proteins ultimately reach levels sufficient to affect organismal functions. The technical limitations of detecting somatic changes and the lack of insight about the minimum level of erroneous proteins to cause an error catastrophe hampered any firm conclusions on these theories. In this study, we sequenced the whole genome of DNA in whole blood of two pairs of monozygotic (MZ) twins, 40 and 100 years old, by two independent next-generation sequencing (NGS) platforms (Illumina and Complete Genomics). Potentially discordant single-base substitutions supported by both platforms were validated extensively by Sanger, Roche 454, and Ion Torrent sequencing. We demonstrate that the genomes of the two twin pairs are germ-line identical between co-twins, and that the genomes of the 100-year-old MZ twins are discerned by eight confirmed somatic single-base substitutions, five of which are within introns. Putative somatic variation between the 40-year-old twins was not confirmed in the validation phase. We conclude from this systematic effort that by using two independent NGS platforms, somatic single nucleotide substitutions can be detected, and that a century of life did not result in a large number of detectable somatic mutations in blood. The low number of somatic variants observed by using two NGS platforms might provide a framework for detecting disease-related somatic variants in phenotypically discordant MZ twins.
This chapter summarizes the current state of the literature relating to each of the disaster phases across a wide range of variables, including sociocultural factors and environment and community resources. Social networks among racial/ethnic minority cultures can be a significant protective factor against adverse mental health consequences, and the emphasis on social networks among many racial/ethnic minority cultures appears to also influence evacuation efforts. Differences in risk perception between minority and majority populations contribute to differences in disaster exposure. A variety of cultural beliefs appear to affect individuals in pre- and peridisaster phases. Several factors have an impact on marginalized populations' postdisaster mental health outcomes. Environmental and community resources suggest that limited or lack of resources appears to significantly impact disaster-response in marginalized populations. The chapter further discusses the implications for research, disaster-response efforts, and practice.
There are few prospective studies on risk factors for health problems
after disasters in which actual pre-disaster health data are
available.
Aims
To examine whether survivors' personal characteristics, and pre-disaster
psychological problems, and disaster-related variables, are related to
their post-disaster health.
Method
Two studies were combined: a longitudinal survey using the electronic
medical records of survivors' general practitioners (GPs), from 1 year
before to 1 year after the disaster, and a survey in which questionnaires
were filled in by survivors, 3 weeks and 18 months after the disaster.
Data from both surveys and the electronic medical records were available
for 994 survivors.
Results
After adjustment for demographic and disaster-related variables,
pre-existing psychological problems were significantly associated with
post-disaster self-reported health problems and post-disaster problems
presented to the GP. This association was found for both psychological
and physical post-disaster problems.
Conclusions
In trying to prevent long-term health consequences after disaster, early
attention to survivors with pre-existing psychological problems, and to
those survivors who are forced to relocate or are exposed to many
stressors during the disaster, appears appropriate.
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