Homo sapiens reached the higher latitudes of Europe by 45,000 years ago.

The Middle to Upper Palaeolithic transition in Europe is associated with the regional disappearance of Neanderthals and the spread of Homo sapiens. Late Neanderthals persisted in western Europe several millennia after the occurrence of H. sapiens in eastern Europe1. Local hybridization between the two groups occurred2, but not on all occasions3. Archaeological evidence also indicates the presence of several technocomplexes during this transition, complicating our understanding and the association of behavioural adaptations with specific hominin groups4. One such technocomplex for which the makers are unknown is the Lincombian-Ranisian-Jerzmanowician (LRJ), which has been described in northwestern and central Europe5-8. Here we present the morphological and proteomic taxonomic identification, mitochondrial DNA analysis and direct radiocarbon dating of human remains directly associated with an LRJ assemblage at the site Ilsenhöhle in Ranis (Germany). These human remains are among the earliest directly dated Upper Palaeolithic H. sapiens remains in Eurasia. We show that early H. sapiens associated with the LRJ were present in central and northwestern Europe long before the extinction of late Neanderthals in southwestern Europe. Our results strengthen the notion of a patchwork of distinct human populations and technocomplexes present in Europe during this transitional period.

Initial Upper Palaeolithic humans in Europe had recent Neanderthal ancestry.

Modern humans appeared in Europe by at least 45,000 years ago1-5, but the extent of their interactions with Neanderthals, who disappeared by about 40,000 years ago6, and their relationship to the broader expansion of modern humans outside Africa are poorly understood. Here we present genome-wide data from three individuals dated to between 45,930 and 42,580 years ago from Bacho Kiro Cave, Bulgaria1,2. They are the earliest Late Pleistocene modern humans known to have been recovered in Europe so far, and were found in association with an Initial Upper Palaeolithic artefact assemblage. Unlike two previously studied individuals of similar ages from Romania7 and Siberia8 who did not contribute detectably to later populations, these individuals are more closely related to present-day and ancient populations in East Asia and the Americas than to later west Eurasian populations. This indicates that they belonged to a modern human migration into Europe that was not previously known from the genetic record, and provides evidence that there was at least some continuity between the earliest modern humans in Europe and later people in Eurasia. Moreover, we find that all three individuals had Neanderthal ancestors a few generations back in their family history, confirming that the first European modern humans mixed with Neanderthals and suggesting that such mixing could have been common.

Initial Upper Palaeolithic Homo sapiens from Bacho Kiro Cave, Bulgaria.

The Middle to Upper Palaeolithic transition in Europe witnessed the replacement and partial absorption of local Neanderthal populations by Homo sapiens populations of African origin1. However, this process probably varied across regions and its details remain largely unknown. In particular, the duration of chronological overlap between the two groups is much debated, as are the implications of this overlap for the nature of the biological and cultural interactions between Neanderthals and H. sapiens. Here we report the discovery and direct dating of human remains found in association with Initial Upper Palaeolithic artefacts2, from excavations at Bacho Kiro Cave (Bulgaria). Morphological analysis of a tooth and mitochondrial DNA from several hominin bone fragments, identified through proteomic screening, assign these finds to H. sapiens and link the expansion of Initial Upper Palaeolithic technologies with the spread of H. sapiens into the mid-latitudes of Eurasia before 45 thousand years ago3. The excavations yielded a wealth of bone artefacts, including pendants manufactured from cave bear teeth that are reminiscent of those later produced by the last Neanderthals of western Europe4-6. These finds are consistent with models based on the arrival of multiple waves of H. sapiens into Europe coming into contact with declining Neanderthal populations7,8.

A Neandertal dietary conundrum: Insights provided by tooth enamel Zn isotopes from Gabasa, Spain.

The characterization of Neandertals' diets has mostly relied on nitrogen isotope analyses of bone and tooth collagen. However, few nitrogen isotope data have been recovered from bones or teeth from Iberia due to poor collagen preservation at Paleolithic sites in the region. Zinc isotopes have been shown to be a reliable method for reconstructing trophic levels in the absence of organic matter preservation. Here, we present the results of zinc (Zn), strontium (Sr), carbon (C), and oxygen (O) isotope and trace element ratio analysis measured in dental enamel on a Pleistocene food web in Gabasa, Spain, to characterize the diet and ecology of a Middle Paleolithic Neandertal individual. Based on the extremely low δ66Zn value observed in the Neandertal's tooth enamel, our results support the interpretation of Neandertals as carnivores as already suggested by δ15N isotope values of specimens from other regions. Further work could help identify if such isotopic peculiarities (lowest δ66Zn and highest δ15N of the food web) are due to a metabolic and/or dietary specificity of the Neandertals.

Initial Upper Paleolithic bone technology and personal ornaments at Bacho Kiro Cave (Bulgaria).

The expansion of Homo sapiens and our interaction with local environments, including the replacement or absorption of local populations, is a key component in understanding the evolution of our species. Of special interest are artifacts made from hard animal tissues from layers at Bacho Kiro Cave (Bulgaria) that have been attributed to the Initial Upper Paleolithic. The Initial Upper Paleolithic is characterized by Levallois-like blade technologies that can co-occur with bone tools and ornaments and likely represents the dispersal of H. sapiens into several regions throughout Eurasia starting by 45 ka or possibly earlier. Osseous artifacts from the Initial Upper Paleolithic are important components of this record and have the potential to contribute to our understanding of group interactions and population movements. Here, we present a zooarchaeological, technological, and functional analysis of the diverse and sizable osseous artifact collection from Bacho Kiro Cave. Animal raw material sources are consistent with taxa found within the faunal assemblage including cervids, large bovids, and cave bears. A variety of bone tool morphologies, both formal and informal, indicate a diverse technological approach for conducting various on-site activities, many of which were focused on the processing of animal skins, likely for cold weather clothing. Technological flexibility is also evident in the manufacture of personal ornaments, which were made primarily from carnivore teeth, especially cave bear, though herbivore teeth and small beads are also represented. The osseous artifacts from Bacho Kiro Cave provide a series of insights into the bone technology and indirectly on the social aspects of these humans in southeast Europe, and when placed within the broader Initial Upper Paleolithic context, both regional and shared behaviors are evidently indicating widespread innovation and complexity. This is especially significant given the location and chronology of the site in the context of H. sapiens dispersals.

Subsistence behavior during the Initial Upper Paleolithic in Europe: Site use, dietary practice, and carnivore exploitation at Bacho Kiro Cave (Bulgaria).

The behavioral dynamics underlying the expansion of Homo sapiens into Europe remains a crucial topic in human evolution. Owing to poor bone preservation, past studies have strongly focused on the Initial Upper Paleolithic (IUP) stone tool record. Recent excavations and extensive radiocarbon dating at Bacho Kiro Cave (Bulgaria) pushed back the arrival of IUP H. sapiens into Europe to ca. 45,000 years ago. This site has exceptional bone preservation, and we present the study of 7431 faunal remains from across two IUP layers (I and J) and one Middle Paleolithic layer (K). We identified a shift in site use and occupation intensity through time, marked by increased find density and human modifications in Layer I. Alongside a decrease in carnivore presence and seasonality data demonstrating human presence in all seasons, this indicates a more frequent or prolonged occupation of the site by IUP groups. Contrarily, the dietary focus across the IUP and Middle Paleolithic layers is similar, centered on the exploitation of species from a range of habitats including Bos/Bison, Cervidae, Equidae, and Caprinae. While body parts of large herbivores were selectively transported into the site, the bear remains suggest that these animals died in the cave itself. A distinct aspect of the IUP occupation is an increase in carnivore remains with human modifications, including these cave bears but also smaller taxa (e.g., Canis lupus, Vulpes vulpes). This can be correlated with their exploitation for pendants, and potentially for skins and furs. At a broader scale, we identified similarities in subsistence behavior across IUP sites in Europe and western Asia. It appears that the first IUP occupations were less intense with find densities and human modifications increasing in succeeding IUP layers. Moreover, the exploitation of small game appears to be limited across IUP sites, while carnivore exploitation seems a recurrent strategy.

An evaluation of SecondBite® 's FoodMate® , a nutrition education and skill-building program aimed at reducing food insecurity.

ISSUE ADDRESSED: Enhancing food skills and nutrition knowledge may help promote healthy eating among people who are food insecure. FoodMate® by SecondBite® , an 8-week nutrition education and food hamper program, focuses on developing food skills and independence among Australians at risk of/experiencing food insecurity. This study aimed to explore participants' perceptions of and experiences with FoodMate® over a long-term (up to 2 years) follow-up. METHODS: For evaluation purposes, SecondBite® previously collected data from participants prior to (T1) and following completion (T2) of FoodMate® . This paper reports results from semi-structured telephone interviews conducted in a follow-up study (2016/2017, T3) among 19 adults enrolled in FoodMate® programs delivered in Victoria and New South Wales within the previous two years. Data were analysed using inductive thematic analysis of responses to T3 open-ended questions, and descriptive analysis of closed-ended question responses (T1 vs T2 vs T3). RESULTS: Major qualitative themes included program enjoyment; perceived positive long-term program impact on participants' eating and related attitudes and skills; barriers to cooking; suggested program modifications; and impact on others. In descriptive quantitative analyses, participants' diet; confidence to cook using basic ingredients, follow simple recipes and try new foods; cooking and food-related skills; social engagement and life satisfaction all improved between T1 and T3. CONCLUSIONS: Overall, FoodMate® was well-received and associated with long-term positive changes in a range of outcomes. Wider implementation among vulnerable groups should be considered. SO WHAT?: Future health promotion initiatives could adopt FoodMate® to increase food skills and knowledge among adults experiencing food insecurity.

Subsistence strategies throughout the African Middle Pleistocene: Faunal evidence for behavioral change and continuity across the Earlier to Middle Stone Age transition.

The African Middle Pleistocene (781-126 ka) is a key period for human evolution, witnessing both the origin of the modern human lineage and the lithic turnover from Earlier Stone Age (ESA) Acheulean bifacial tools to Middle Stone Age (MSA) prepared core and point technologies. This ESA/MSA transition is interpreted as representing changing landscape use with greater foraging distances and more active hunting strategies. So far, these behavioral inferences are mainly based on the extensive stone tool record, with only a minor role for site-based and regional faunal studies. To provide additional insights into these behavioral changes, this paper details a pan-African metastudy of 63 Middle Pleistocene faunal assemblages from 40 sites. A hierarchical classification system identified 26 well-contextualized assemblages with quantitative paleontological and/or zooarcheological data available for detailed comparative analyses and generalized linear mixed modeling. Modeling of ungulate body size classes structured around three dimensions (context, antiquity and technology) illustrates no one-to-one correlation between changes in lithic technology (Acheulean vs. MSA) and changes in prey representation. All assessed faunal assemblages are dominated by medium-sized bovids, and variations between smaller and larger body size classes are linked to site context (cave vs. open-air), with an increase in cave sites during the Middle Pleistocene. Current data do not signal a broadening of the hominin dietary niche during the Middle Pleistocene; no meaningful variation was visible in the exploitation of smaller-sized bovids or dangerous game, with coastal resources exploited when available. Proportions of anthropogenic bone surface modifications, and hence carcass processing intensity, do increase over time although more zooarcheological data is crucial before making behavioral inferences. Overall, this paper illustrates the potential of broad scale comparative faunal analyses to provide additional insights into processes of human behavioral evolution and the mechanisms underlying patterns of technological, chronological and contextual change.

Foreclosures and weight gain: Differential associations by longer neighborhood exposure.

While home foreclosure can lead to mental and physical health declines in persons experiencing the foreclosure, whether neighborhood foreclosures can affect the health of other residents is debatable. Using a racially/ethnically diverse sample of Chicago metropolitan area residents linked to foreclosure data from 2008 to 2014, we assessed whether exposure to neighborhood foreclosure fillings was associated with changes in objectively measured body mass index (BMI) over time. Using a retrospective longitudinal design, we employed fixed-effects regression models that controlled for individual- and neighborhood-level covariates to test the association of neighborhood foreclosures and BMI in >60,000 individuals and for individuals who did not move during the follow-up period. We also adjusted for the non-linear association of age and BMI and comorbidities and employed a series of sensitivity analysis to test for robustness. In fully adjusted models, a standard-deviation increase in neighborhood foreclosure filings within 500 m was associated with increases in BMI for individuals who did not move (nonmovers) (mean = 0.03 BMI units, 95% confidence interval: 0.01, 0.06). Neighborhood foreclosure rates were not associated with changes in BMI for the full sample. Given the potential deleterious effects of neighborhood foreclosure on individuals with longer exposure to the local vicinity, clarifying the potential health effects of neighborhood foreclosures would help policymakers when planning actions to prevent home losses, predatory home loans, and that aim to more efficiently return foreclosure properties to productive uses.

Effect of Arginine on the Aggregation of Protein in Freeze-Dried Formulations Containing Sugars and Polyol: II. BSA Reconstitution and Aggregation.

The current paper continues our study on the ability of L-arginine to prevent/reduce the aggregation of proteins that results from the various stresses during the lyophilisation and/or storage of lyophilized protein-based products. The first part of our study, i.e. formulation development, was devoted to the rational design and optimization of an L-arginine containing lyophilized formulation which can resist the natural tendency of L-arginine to absorb atmosphere moisture. Mannitol and trehalose were chosen among other excipients to be included in the protein-based formulation, as mannitol in a combination with L-arginine has been shown to reduce moisture sorption while trehalose provides a degree of lyoprotection. In the present study, a number of formulations, which comprised bovine serum albumin (BSA) with and without L-arginine, and with five different ratios of trehalose-to-mannitol (from 30:70 to 80:20) were lyophilised and assessed. The internal structures and the moisture sorption/retention of the lyophilized formulations were characterised. To study the effect of L-arginine on BSA solid-phase stability, the lyophilized powder was exposed to accelerated storage conditions (high moisture (75% RH) and temperature (22 or 45 °C)) for up to 24 h. The lyophilized BSA formulations were then reconstituted and solution-state protein aggregation assessed by turbidimetry at 360 nm and fluorescence spectroscopy using the thioflavin T assay. It was demonstrated that L-arginine can be used in protein-based freeze-dried formulations to significantly reduce the aggregation of protein during the manufacturing, storage and subsequent reconstitution. The results also revealed the importance of a sufficient amount of mannitol in the arginine-containing formulations.

Effect of Arginine on the Aggregation of Protein in Freeze-Dried Formulations Containing Sugars and Polyol: 1-Formulation Development.

L-arginine was introduced into protein-based freeze-dried formulations to study the ability of arginine to reduce/prevent from protein aggregation during manufacturing, storage and reconstitution of lyophilized protein-based pharmaceuticals. As L-arginine is known to be very hygroscopic, additional excipients which could provide a moisture buffering capacity need to be introduced into the formulation. In the first part of our study-excipient formulation development-the screening of a number of sugars/polyols has been done in order to select the best combination of excipients that, in a complex with L-arginine, can (i) produce freeze-dried cakes with elegant appearance, adequate mechanical properties and reconstitution times, and (ii) resist/minimise the moisture sorption. Various freeze-dried cakes containing L-arginine in combination with mannitol, trehalose, lactose and sucrose were produced and analysed by TGA, DSC, texture analysis, moisture sorption, cake shrinkage, TVIM and SEM. The non-linear dependencies of the physicochemical properties of the freeze-dried cakes on the sugar-to-mannitol ratios were found. The best combinations of excipients (L-arginine, mannitol and trehalose) were selected to be used in the second part of this work, in which the impact of each selected formulation will be studied in relation to the aggregation of a protein.

The impact of the context and recruitment materials on nondonors' willingness to donate blood.

BACKGROUND: Anxiety is a frequently cited barrier to blood donor recruitment. Although the mere presence of donation paraphernalia can heighten anxiety for some individuals, such stimuli are a necessary and unavoidable part of donation. Drawing on France and colleagues' research on tailored donor education and coping materials, the current study assessed whether modifying recruitment materials could improve donor recruitment in a context where anxiety is heightened. STUDY DESIGN AND METHODS: A field study comprising a 2 (presence or absence of a mobile blood collection unit [MCU]) × 2 (recruitment brochure: standard, coping) between-subjects design was conducted with 922 nondonors who believed themselves eligible to donate blood. In either the presence or absence of the MCU, participants received a standard or modified recruitment brochure modeled on France and colleagues' education and coping materials. Donation anxiety, attitude, subjective norm, self-efficacy, and intention were assessed, and donation behavior was tracked for 30 days. RESULTS: Participants who were assessed in the presence of the MCU reported heightened anxiety, and female participants reported decreased self-efficacy. The coping brochure improved self-efficacy, heightened the intention to donate in the presence of the MCU, and promoted blood donation behavior relative to the standard brochure. Path analyses supported a model in which, in the presence of the MCU, the coping brochure boosted self-efficacy and led to increased donation intention and behavior. CONCLUSIONS: In a context in which donation-related anxiety is heightened, provision of materials that address prospective donor concerns and suggest coping strategies can bolster self-efficacy and promote recruitment.

Proximity of the axillary nerve during bicortical drilling for biceps tenodesis.

PURPOSE: Pathology of the biceps tendon can contribute to significant shoulder pain and dysfunction for which biceps tenodesis may be indicated. A variety of techniques tenodesing the biceps tendon have been described. Recently, tenodesis using a uni- or bicortical button has been advocated. This cadaveric study investigates the proximity of the axillary nerve to the position of bicortical drill passages during biceps tenodesis. METHODS: Twelve cadaveric shoulder specimens were used. The axillary nerve was marked during a preparatory dissection using wire. Drills were passed through the humerus at the proximal and distal ends of the bicipital groove, and at the superior insertion point of pectoralis major (PM). These were left in situ. The distances between these drills and the axillary nerves were measured using computed tomography imaging. RESULTS: The drill bits placed at the superior insertion of PM were in closest proximity to the axillary nerve (3D distance mean 10.7 mm, 95 % confidence interval 7.2-14.2 mm). A drill placed at the distal end of the bicipital groove was a mean distance of 18.2 mm from the nerve. CONCLUSIONS: This study highlights the need for caution when drilling the posterior humeral cortex during biceps tenodesis, particularly during drilling at the superior insertion of PM as this is the location that poses the highest risk to the axillary nerve. To our knowledge, this is the first cadaveric study to radiologically assess the proximity of the axillary nerve to the positions of biceps tenodesis. Surgeons should therefore be cautious when performing bicortical drilling for biceps tenodesis, and a supero-lateral drill trajectory would pose a smaller risk to the axillary nerve.

Neanderthal megafaunal exploitation in Western Europe and its dietary implications: a contextual reassessment of La Cotte de St Brelade (Jersey).

The recurrent presence at Middle Palaeolithic sites of megafaunal remains, such as mammoth, elephant and rhinoceros, together with isotope analyses signalling meat as a prominent protein source, have been used to argue that these species played a central role in Neanderthal diet. Key to this model are the bone heap horizons from La Cotte de St Brelade (Jersey), which were previously interpreted as game drive debris resulting from systematic Neanderthal hunting. However, this hypothesis has never been rigorously tested, neither at a site-scale, incorporating taphonomic and contextual data, nor at a wider European scale. First, this paper provides a contextual reassessment of the faunal remains from La Cotte to fully understand Neanderthal behaviour at the site. Second, a comparative database of 30 well-published Middle Palaeolithic sites with megafauna permits a data-driven, broader spatial (European) and diachronic assessment of the role of megafauna in Neanderthal subsistence behaviour. Results suggest initial Neanderthal occupation at La Cotte was intensive although through time site visits became more infrequent, as highlighted by a reduction in cultural debris concurrent with a rise in carnivore presence. While mammoths, just as other large mammals and occasionally carnivores, were clearly butchered at this locality, their acquisition and role in Neanderthal diet remains ambiguous. Broader comparisons across Western Europe indicate a main focus on a range of large herbivores, with only a minor, opportunistic, role for megafauna. Whilst stable isotope analysis suggests that Neanderthal diet was meat-oriented, zooarchaeological data do not support the inference that megafauna were the major contributor of meat.

Effect of acidic and basic pH on Thioflavin T absorbance and fluorescence.

Thioflavin T (ThT) is a fluorescent dye able to enhance significantly its fluorescence quantum yield upon binding to protein amyloids. ThT assay is widely used to detect and quantify amyloids in a variety of conditions, including solutions with different pH levels. In the present work, the effect of acidic and basic pH on the conformation of the ThT molecule and its absorption and fluorescence properties was studied. The results show that both acidic and basic pH decrease significantly the intensity of ThT absorption in the visible region and fluorescence emission intensity. Low pHs induce an immediate "all-or-nothing" decrease in the ThT signal, while in alkaline solutions the ThT signal decreases gradually over time. pH-induced signal quenching is less in the presence of glycerol or protein aggregates. Two different mechanisms are responsible for the ThT signal quenching-the ThT hydroxylation at basic pH and protonation of the nitrogen atom of the dimethylamino group at acidic pH. ThT assays should be carefully carried out at basic or acidic pH as strong pH dependence of ThT could be responsible for misinterpretation and false positive/negative experimental results. The potential unsuitability of ThT as a probe in solutions with high pH (>9) has been shown.

How to survive in research: advice for the novice investigator.

OBJECTIVES: This paper, written by the RANZCP Committee for Research, provides an outline for how to survive in research, considering the ingredients likely to contribute to success, the role of supportive structures and the expected challenges. Learning how to survive in research is relevant for both trainees and for Fellows undertaking research at any stage of their career. CONCLUSIONS: Intellectual curiosity, perseverance, frustration tolerance, patience and humility are key for success as a researcher. Selection of the right supervisor is important, as is development and maintenance of a good working supervisor/supervisee relationship. The personal benefits of undertaking research include flexibility in work hours, and improved skills in writing, oral presentations, objectivity, critical thinking, problem solving and project management.

A guide to clinical research supervision for psychiatrists: a mentoring approach.

OBJECTIVES: To provide a guide for clinically-based psychiatrist supervisors of research projects for early career researchers. METHODS: This paper will describe a mentoring framework for supervision, for psychiatrist clinical research supervisors and early career researchers. RESULTS: The domains discussed include, across various aspects of a study: the role of the supervisor, project management, and where and when to seek advice. CONCLUSIONS: Supervision of clinical research can be a professionally rewarding experience for psychiatrists, as well as early career researcher supervisees.

Getting started in research: research questions, supervisors and literature reviews.

OBJECTIVES: Research can seem daunting, especially for trainees and early career researchers. This paper focuses on how to formulate and begin a research project such as the RANZCP Scholarly Project. METHODS: We outline an approach to framing a research question, developing theses and hypotheses, choosing a supervisor and conducting a literature review. CONCLUSIONS: Through systematic planning early career researchers and other clinicians can plan and conduct research suitable for the Scholarly Project or other research activity.