The Foot of \u3cem\u3eHomo naledi\u3c/em\u3e

Modern humans are characterized by a highly specialized foot that reflects our obligate bipedalism. Our understanding of hominin foot evolution is, although, hindered by a paucity of well-associated remains. Here we describe the foot of Homo naledi from Dinaledi Chamber, South Africa, using 107 pedal elements, including one nearly-complete adult foot. The H. naledi foot is predominantly modern human-like in morphology and inferred function, with an adducted hallux, an elongated tarsus, and derived ankle and calcaneocuboid joints. In combination, these features indicate a foot well adapted for striding bipedalism. However, the H. naledi foot differs from modern humans in having more curved proximal pedal phalanges, and features suggestive of a reduced medial longitudinal arch. Within the context of primitive features found elsewhere in the skeleton, these findings suggest a unique locomotor repertoire for H. naledi, thus providing further evidence of locomotor diversity within both the hominin clade and the genus Homo

A pilot study of a nurse-led integrated care review (the INCLUDE review) for people with inflammatory rheumatological conditions in primary care: feasibility study findings.

BACKGROUND: People with inflammatory rheumatological conditions such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polymyalgia rheumatica and giant cell arteritis are at an increased risk of common comorbidities including cardiovascular disease, osteoporosis and mood problems, leading to increased morbidity and mortality. Identifying and treating these problems could lead to improved patient quality of life and outcomes. Despite these risks being well-established, patients currently are not systematically targeted for management interventions for these morbidities. This study aimed to assess the feasibility of conducting a randomised controlled trial (RCT) of a nurse-led integrated care review in primary care to identify and manage these morbidities. METHODS: A pilot cluster RCT was delivered across four UK general practices. Patients with a diagnostic Read code for one of the inflammatory rheumatological conditions of interest were recruited by post. In intervention practices (n = 2), eligible patients were invited to attend the INCLUDE review. Outcome measures included health-related quality of life (EQ-5D-5L), patient activation, self-efficacy and treatment burden. A sample (n = 24) of INCLUDE review consultations were audio-recorded and assessed against a fidelity checklist. RESULTS: 453/789 (57%) patients responded to the invitation, although 114/453 (25%) were excluded as they either did not fulfil eligibility criteria or failed to provide full written consent. In the intervention practices, uptake of the INCLUDE review was high at 72%. Retention at 3 and 6?months both reached pre-specified success criteria. Participants in intervention practices had more primary care contacts than controls (mean 29 vs 22) over the 12?months, with higher prescribing of all relevant medication classes in participants in intervention practices, particularly so for osteoporosis medication (baseline 29% vs 12?month 46%). The intervention was delivered with fidelity, although potential areas for improvement were identified. CONCLUSIONS: The findings of this pilot study suggest it is feasible to deliver an RCT of the nurse-led integrated care (INCLUDE) review in primary care. A significant morbidity burden was identified. Early results suggest the INCLUDE review was associated with changes in practice. Lessons have been learnt around Read codes for patient identification and refining the nurse training. TRIAL REGISTRATION: ISRCTN, ISRCTN12765345

Leaf photosynthesis and associations with grain yield, biomass and nitrogen-use efficiency in landraces, synthetic-derived lines and cultivars in wheat

Future genetic progress in wheat grain yield will depend on increasing above-ground biomass and this must be achieved without commensurate increases in N fertilizer inputs to minimise environmental impacts. Our objective was to quantify variation in grain yield, above-ground biomass and N-use efficiency (NUE) and associated traits in a panel of diverse hexaploid wheat germplasm comprising: (i) landraces from the AE Watkins collection, (ii) synthetic-derived hexaploid lines in a cv. Paragon spring wheat background and (iii) UK modern cultivars including cv. Paragon under low N and high N conditions. A field experiment was carried out in two seasons examining 15 genotypes (five landraces, five synthetic-derived (SD) hexaploid lines and five UK modern cultivars) under low N and high N conditions at Nottingham University farm, UK. Machine-harvested grain yield, above-ground biomass and NUE were measured. Physiological traits were assessed including flag-leaf light-saturated photosynthetic rate (Amax) and relative chlorophyll content (SPAD) under HN conditions; and flag-leaf senescence duration and rate and Normalized Difference Vegetative Index (NDVI) under LN and HN conditions. Under HN conditions, the modern cultivars overall produced higher grain yield than the SD lines (+9.7%) and the landraces (+60.4%); and the modern cultivars and SD lines also produced higher biomass than the landraces (30.3% and 28.4%, respectively). Under LN conditions, reduction in grain yield and biomass compared to HN conditions was least for the landraces (−1% and −8.6%, respectively), intermediate for the SD lines (−7.4 and −10.2%, respectively) and highest for the modern cultivars (−9.3 and −24.6%, respectively). As a result, the SD lines had higher biomass (+17%) than the modern cultivars under LN conditions. Under HN conditions the synthetic derivatives (23.8 μmol m−2 s−1) and modern cultivars (241.1 μmol m−2 s−1) had higher pre-anthesis Amax than the landraces (19.7 μmol m−2 s−1) (P < 0.001). Pre-anthesis Amax was strongly positively linearly associated with above-ground biomass (R2 = 0.63, P < 0.001) and grain yield (R2 = 0.75, P < 0.001) amongst the 15 genotypes. Flag-leaf Amax was also positively linearly associated with flag-leaf relative chlorophyll content at anthesis (R2 = 0.74; P < 0.001). Comparing the SD lines to the recurrent parent Paragon, under HN conditions one line (SD 22) had higher pre-anthesis flag-leaf Amax than Paragon (P < 0.05). Under LN conditions one line (SD 24, +27%) had higher yield than Paragon (P < 0.05) and two lines (SD 24 and SD 38, +32% and +31%, respectively) had more biomass than Paragon (P < 0.05). Our results indicated that introgressing traits from synthetic-derived wheat and landraces into UK modern wheat germplasm offers scope to raise above-ground biomass and grain yield in moderate-to-low N availability environments

Stiffness of the human foot and evolution of the transverse arch

The stiff human foot enables an efficient push-off when walking or running, and was critical for the evolution of bipedalism(1-6). The uniquely arched morphology of the human midfoot is thought to stiffen it(5-9), whereas other primates have flat feet that bend severely in the midfoot(7,10,11). However, the relationship between midfoot geometry and stiffness remains debated in foot biomechanics(12,13), podiatry(14,15) and palaeontology(4-6). These debates centre on the medial longitudinal arch(5,6) and have not considered whether stiffness is affected by the second, transverse tarsal arch of the human foot(16). Here we show that the transverse tarsal arch, acting through the inter-metatarsal tissues, is responsible for more than 40% of the longitudinal stiffness of the foot. The underlying principle resembles a floppy currency note that stiffens considerably when it curls transversally. We derive a dimensionless curvature parameter that governs the stiffness contribution of the transverse tarsal arch, demonstrate its predictive power using mechanical models of the foot and find its skeletal correlate in hominin feet. In the foot, the material properties of the inter-metatarsal tissues and the mobility of the metatarsals may additionally influence the longitudinal stiffness of the foot and thus the curvature-stiffness relationship of the transverse tarsal arch. By analysing fossils, we track the evolution of the curvature parameter among extinct hominins and show that a human-like transverse arch was a key step in the evolution of human bipedalism that predates the genus Homo by at least 1.5 million years. This renewed understanding of the foot may improve the clinical treatment of flatfoot disorders, the design of robotic feet and the study of foot function in locomotion

Footprint evidence of early hominin locomotor diversity at Laetoli, Tanzania

Bipedal trackways discovered in 1978 at Laetoli site G, Tanzania and dated to 3.66 million years ago are widely accepted as the oldest unequivocal evidence of obligate bipedalism in the human lineage1-3. Another trackway discovered two years earlier at nearby site A was partially excavated and attributed to a hominin, but curious affinities with bears (ursids) marginalized its importance to the paleoanthropological community, and the location of these footprints fell into obscurity3-5. In 2019, we located, excavated and cleaned the site A trackway, producing a digital archive using 3D photogrammetry and laser scanning. Here we compare the footprints at this site with those of American black bears, chimpanzees and humans, and we show that they resemble those of hominins more than ursids. In fact, the narrow step width corroborates the original interpretation of a small, cross-stepping bipedal hominin. However, the inferred foot proportions, gait parameters and 3D morphologies of footprints at site A are readily distinguished from those at site G, indicating that a minimum of two hominin taxa with different feet and gaits coexisted at Laetoli

Abstract B094: Novel method for patient stratification in breast carcinoma based upon spatial analysis of tumor microenvironment

Breast cancer consists of several intrinsic molecular subtypes, providing the basis for clinical treatment decisions. Lately, it is becoming increasingly recognized that factors other than the intrinsic cancer characteristics, such as immune components’ activity in the tumor microenvironment, have important effects on treatment choices and efficacy. bioSyntagma has developed a method, the Molecular Fingerprint (mPrint®), that enables multiplexed analysis of spatially defined regions in formalin-fixed, paraffin-embedded (FFPE) tumor samples allowing for analysis of the gene signatures unique to the tumor microenvironment. This method was applied to molecularly defined sets of breast cancers and used to evaluate four different tumor regions of interest (ROIs): 1) viable carcinoma proper (>90% cancer cells), 2) fibrotic tumor center (sparse cellularity), 3) interface between viable tumor and inflammatory component (tumor and inflammatory microenvironment) and 4) tissue away from the tumor (normal breast tissue). This was compared to the whole tissue scrapes from each patient block. Each ROI and tissue scrape was analyzed by high throughput qPCR for a panel of 248 genes using SmartChip technology (Takara Bio, USA). Sequential tissue slices from each patient were also analyzed using immunohistochemistry (IHC) for three targets and investigated for correlation with qPCR results for validation of the method. Overall, reasonable concordance was observed in general expression trends between selected IHC and RNA expression. qPCR data were further analyzed using hierarchical clustering analysis and showed that morphologically defined ROI’s cluster completely differently than traditional clustering of entire tissue scrapes. Notably, patient clustering based on morphological regions was independent of the intrinsic cancer subtype, as determined by molecular profiling of whole tissue scrapes, as well as independent of trends in Tumor Mutational Burden (TMB) and Microsatellite Instability (MSI). These findings suggest that current methods of patient stratification based on whole tumor molecular subtyping may be inferior to stratification based on molecular characteristics of the tumor microenvironment.bioSyntagma, LLC, PHOENIX, AZ; Takara Bio USA, Inc., Mountain View, CA

Assay‐agnostic spatial profiling detects tumor microenvironment signatures: new diagnostic insights for triple‐negative breast cancer

The role of the tumor microenvironment (TME) in immuno‐oncology has driven demand for technologies that deliver in situ, or spatial, molecular information. Compartmentalized heterogeneity that traditional methods miss is becoming key to predicting both acquired drug resistance to targeted therapies and patient response to immunotherapy. Here, we describe a novel method for assay‐agnostic spatial profiling and demonstrate its ability to detect immune microenvironment signatures in breast cancer patients that are unresolved by the immunohistochemical (IHC) assessment of programmed cell death ligand‐1 (PD‐L1) on immune cells, which represents the only FDA microenvironment‐based companion diagnostic test that has been approved for triple‐negative breast cancer (TNBC). Two distinct physiological states were found that are uncorrelated to tumor mutational burden (TMB), microsatellite instability (MSI), PD‐L1 expression, and intrinsic cancer subtypes

How safe is primary care? A systematic review.

IMPORTANCE: Improving patient safety is at the forefront of policy and practice. While considerable progress has been made in understanding the frequency, causes and consequences of error in hospitals, less is known about the safety of primary care. OBJECTIVE: We investigated how often patient safety incidents occur in primary care and how often these were associated with patient harm. EVIDENCE REVIEW: We searched 18 databases and contacted international experts to identify published and unpublished studies available between 1 January 1980 and 31 July 2014. Patient safety incidents of any type were eligible. Eligible studies were critically appraised using validated instruments and data were descriptively and narratively synthesised. FINDINGS: Nine systematic reviews and 100 primary studies were included. Studies reported between <1 and 24 patient safety incidents per 100 consultations. The median from population-based record review studies was 2-3 incidents for every 100 consultations/records reviewed. It was estimated that around 4% of these incidents may be associated with severe harm, defined as significantly impacting on a patient's well-being, including long-term physical or psychological issues or death (range <1% to 44% of incidents). Incidents relating to diagnosis and prescribing were most likely to result in severe harm. CONCLUSIONS AND RELEVANCE: Millions of people throughout the world use primary care services on any given day. This review suggests that safety incidents are relatively common, but most do not result in serious harm that reaches the patient. Diagnostic and prescribing incidents are the most likely to result in avoidable harm. SYSTEMATIC REVIEW REGISTRATION: This systematic review is registered with the International Prospective Register of Systematic Reviews (PROSPERO CRD42012002304)