Using high-resolution LiDAR-derived canopy structure and topography to characterise hibernaculum locations of the hazel dormouse.

The hazel dormouse is predominantly an arboreal species that moves down to the ground to hibernate in the autumn in temperate parts of its distributional ranges at locations not yet well understood. The main objective of this study is to test whether environmental characteristics surrounding hazel dormouse hibernacula can be identified using high-resolution remote sensing and data collected in situ. To achieve this, remotely sensed variables, including canopy height and cover, topographic slope, sky view, solar radiation and cold air drainage, were modelled around 83 dormouse hibernacula in England (n = 62) and the Netherlands (n = 21), and environmental characteristics that may be favoured by pre-hibernating dormice were identified. Data on leaf litter depth, temperature, canopy cover and distance to the nearest tree were collected in situ and analysed at hibernaculum locations in England. The findings indicated that remotely sensed data were effective in identifying attributes surrounding the locations of dormouse hibernacula and when compared to in situ information, provided more conclusive results. This study suggests that remotely sensed topographic slope, canopy height and sky view have an influence on hazel dormice choosing suitable locations to hibernate; whilst in situ data suggested that average daily mean temperature at the hibernaculum may also have an effect. Remote sensing proved capable of identifying localised environmental characteristics in the wider landscape that may be important for hibernating dormice. This study proposes that this method can provide a novel progression from habitat modelling to conservation management for the hazel dormouse, as well as other species using habitats where topography and vegetation structure influence fine-resolution favourability.

Soft-Tissue Masses: A Visual Guide to the Good, the Bad, and the Ugly.

Benign soft-tissue masses drastically outnumber malignant tumors. Both benign and malignant soft-tissue masses can present in the same manner, as a painless growing soft-tissue lump or bump. The implications of misdiagnosing a soft-tissue sarcoma can be devastating. The most common mistake occurs when all masses are assumed to be lipomas. A careful history, physical examination, and appropriate imaging can determine the benign or malignant nature of a tumor. A mass that is large (>5 cm), deep (in relation to investing fascia), and firmer than the surrounding muscle should raise suspicion for a malignancy. Small, superficial masses are more likely to be benign, but up to 32% of soft-tissue sarcomas can present in this manner. The orthopaedic surgeon should be able to recognize common imaging findings for benign and malignant entities.

[M@Sn14-xSbx]q- (M = La, Ce, or U; x = 6-8; q = 3, 4): Interaction of 4f or 5f Metal Ions with 5p Metal Atoms in Intermetalloid Clusters.

The impact of 4f metal ions Ln3+ (Ln = La or Ce) versus 5f metal ions Un+ (n = 3 or 4) on the compositions and distribution of 5p metal atoms in the cluster shells of endohedral species [M@Sn14-xSbx]q- (M = La, Ce, or U; x = 6-8; q = 3, 4) was studied by means of combined experimental and quantum chemical investigations. While all known f-block metal ion-centered endohedral clusters possessed combinations of larger main group metal atoms so far (Sn/Bi or Pb/Bi), resulting in mixtures of 13- and 14-atom cages, the 14-atom cages reported herein comprise exclusively Sn and Sb atoms and therefore are challenged in accommodating the large 4f and 5f ions. We show that the clusters form in reactions of (Sn2Sb2)2- anions with [Ln(C5Me4H)3] or [U(C5Me4H)3Cl], and that salts of [La@Sn6Sb8]3-, [La@Sn7Sb7]4-, [U@Sn8Sb6]4-, and [U@Sn7Sb7]3- can be isolated from them. The assignment of Sn versus Sb in the encapsulating cage follows a simple rule. Different central atoms cause only slight differences in this regard and with respect to distortions of the cluster shells. The reactions also yielded the salt of the new binary anion (Sn4Sb4)2- that was recently predicted by quantum chemical studies.

Between Elemental Match and Mismatch: From K12 Ge3.5 Sb6 to Salts of (Ge2 Sb2 )2- , (Ge4 Sb12 )4- , and (Ge4 Sb14 )4.

The solid mixture "K2 GeSb" was shown to comprise single-crystalline K12 Ge3.5 Sb6 (1), a double salt of K5 [GeSb3 ] with carbonate-like [GeSb3 ]5- anions, and the metallic Zintl phase K2 Ge1.5 . Extraction of 1 with ethane-1,2-diamine in the presence of crypt-222 afforded [K(crypt-222)]+ salts of several novel binary Zintl anions: (Ge2 Sb2 )2- (in 2), (Ge4 Sb12 )4- (in 3), and in the presence of [AuMePPh3 ] also (Ge4 Sb14 )4- (in 4). The anion in 2 represents a predicted, yet heretofore missing pseudo-tetrahedral anion. 4 comprises a cluster analogous to (Ge4 Bi14 )4- and (Ga2 Bi16 )4- , and thus one of the most Sb-rich binary p-block anions. The unprecedented cluster topology in 3 can be viewed as a defect-version of the one in 4 upon following a "dead end" of cluster growth. The findings indicate that Ge and Sb atoms are at the border of a well-matching and a mismatch elemental combination. We discuss the syntheses, the geometric structures, and the electronic structures of the new compounds.

Climate-driven variation in biotic interactions provides a narrow and variable window of opportunity for an insect herbivore at its ecological margin.

Climate-driven geographic range shifts have been associated with transitions between dietary specialism and generalism at range margins. The mechanisms underpinning these often transient niche breadth modifications are poorly known, but utilization of novel resources likely depends on phenological synchrony between the consumer and resource. We use a climate-driven range and host shift by the butterfly Aricia agestis to test how climate-driven changes in host phenology and condition affect phenological synchrony, and consider implications for host use. Our data suggest that the perennial plant that was the primary host before range expansion is a more reliable resource than the annual Geraniaceae upon which the butterfly has become specialized in newly colonized parts of its range. In particular, climate-driven phenological variation in the novel host Geranium dissectum generates a narrow and variable 'window of opportunity' for larval productivity in summer. Therefore, although climatic change may allow species to shift hosts and colonise novel environments, specialization on phenologically limited hosts may not persist at ecological margins as climate change continues. We highlight the potential role for phenological (a)synchrony in determining lability of consumer-resource associations at range margins and the importance of considering causes of synchrony in biotic interactions when predicting range shifts. This article is part of the theme issue 'Species' ranges in the face of changing environments (Part II)'.

Synthesis and Evaluation of Novel Tetrahydronaphthyridine CXCR4 Antagonists with Improved Drug-like Profiles.

Our first-generation CXCR4 antagonist TIQ15 was rationally modified to improve drug-like properties. Introducing a nitrogen atom into the aromatic portion of the tetrahydroisoquinoline ring led to several heterocyclic variants including the 5,6,7,8-tetrahydro-1,6-naphthyridine series, greatly reducing the inhibition of the CYP 2D6 enzyme. Compound 12a demonstrated the best overall properties after profiling a series of isomeric tetrahydronaphthyridine analogues in a battery of biochemical assays including CXCR4 antagonism, CYP 2D6 inhibition, metabolic stability, and permeability. The butyl amine side chain of 12a was substituted with various lipophilic groups to improve the permeability. These efforts culminated in the discovery of compound 30 as a potent CXCR4 antagonist (IC50 = 24 nM) with diminished CYP 2D6 activity, improved PAMPA permeability (309 nm/s), potent inhibition of human immunodeficiency virus entry (IC50 = 7 nM), a cleaner off-target in vitro safety profile, lower human ether a-go-go-related gene channel activity, and higher oral bioavailability in mice (% FPO = 27) compared to AMD11070 and TIQ15.

Multicenter, retrospective comparison of implant survival, complications and cost between plate and screw and intramedullary nail fixation for metastatic lesions of the diaphyseal humerus.

Background: The humerus is a common site of metastatic disease that can be fixated with either plate and screw or intramedullary nail (IMN) constructs. A multicenter retrospective comparison study was undertaken to compare implant survival, complication rate and cost between the two constructs. No prior studies have included a cost comparison. Methods: Databases of two academic practices were queried retrospectively to identify patients with metastases of the humerus. Inclusion criteria were a lesion in the proximal metaphysis to distal diaphysis and amenable to both implant options with available cost data. Follow-up was at least 6 months barring death or discharge to hospice sooner. Demographic, clinical and outcome data was recorded. Costs were estimated based on contract pricing. Operating room (OR) costs were estimated using per minute OR costs proposed by other investigators. Results: One hundred and one humeri in 96 patients were included (72 plates and 29 nails). The most common malignancies were renal cell, myeloma and lung. Half presented with a displaced fracture. Demographics were similar in both groups. Lesions were larger in the plate group. Surgical times were longer in the plate group, 146 vs. 75 min, P<0.001. Estimated blood loss (EBL) was higher in the plate group, 510 vs. 221 mL, P<0.001. A trend toward increased failure was seen in the plate group, 12.5% vs. 0% (P=0.056). The most common complications in the plate group were pain, stiffness and swelling compared to pain, refracture and PE in the nail group. Local disease progression was equivalent. Implant costs were higher in the IMN group ($2,753 vs. $1,553, P<0.001), while OR costs were lower ($2,349 vs. $4,395, P<0.001). Overall cost of implantation was lower in the IMN group ($5,102 vs. $5,949, P=0.005). Conclusions: IMN of metastases of the humerus offers a faster, potentially more durable construct with lower blood loss, faster OR times and decreased cost of implantation.

Amino-Heterocycle Tetrahydroisoquinoline CXCR4 Antagonists with Improved ADME Profiles via Late-Stage Buchwald Couplings.

This work surveys a variety of diamino-heterocycles as an isosteric replacement for the piperazine substructure of our previously disclosed piperarinyl-tetrahydroisoquinoline containing CXCR4 antagonists. A late-stage Buchwald coupling route was developed for rapid access to final compounds from commercial building blocks. Among 13 analogs in this study, compound 31 embodying an aza-piperazine linkage was found to have the best overall profile with potent CXCR4 inhibitory activity and favorable in vitro absorption, distribution, metabolism, and excretion (ADME) properties. An analysis of the calculated physiochemical parameters (ROF, cLogD) and the experimental ADME attributes of the analogs lead to the selection of 31 for pharmacokinetic studies in mice. Compared with the clinical compound AMD11070, compound 31 has no CYP450 3A4 or 2D6 inhibition, higher metabolic stability and PAMPA permeability, greatly improved physiochemical parameters, and superior oral bioavailability (%F = 24). A binding rationale for 31 within CXCR4 was elucidated from docking and molecular simulation studies.

Microclimate and resource quality determine resource use in a range-expanding herbivore.

The consequences of climate change for biogeographic range dynamics depend on the spatial scales at which climate influences focal species directly and indirectly via biotic interactions. An overlooked question concerns the extent to which microclimates modify specialist biotic interactions, with emergent properties for communities and range dynamics. Here, we use an in-field experiment to assess egg-laying behaviour of a range-expanding herbivore across a range of natural microclimatic conditions. We show that variation in microclimate, resource condition and individual fecundity can generate differences in egg-laying rates of almost two orders of magnitude in an exemplar species, the brown argus butterfly (Aricia agestis). This within-site variation in fecundity dwarfs variation resulting from differences in average ambient temperatures among populations. Although higher temperatures did not reduce female selection for host plants in good condition, the thermal sensitivities of egg-laying behaviours have the potential to accelerate climate-driven range expansion by increasing egg-laying encounters with novel hosts in increasingly suitable microclimates. Understanding the sensitivity of specialist biotic interactions to microclimatic variation is, therefore, critical to predict the outcomes of climate change across species' geographical ranges, and the resilience of ecological communities.

A Case of Tumor-Induced Osteomalacia: Finding the Culprit Acetabular Tumor and Successful Resection with a Novel Hip Joint-Preserving Surgery.

INTRODUCTION: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic disorder caused by tumors that produce fibroblast growth factor 23 (FGF23) resulting in phosphate wasting and inadequate bone mineralization. Complete resection of the tumor can be curative. However, these tumors are typically difficult to find anatomically due to small size and location. CASE REPORT: We present the case of a patient who presented for evaluation of recurrent fractures and hypophosphatemia in the setting of elevated FGF23 suggestive of TIO. 68Gallium-DOTATATE revealed multiple somatostatin avid lesions in several ribs, left acetabulum, sacrum, right tibia, and feet, some of which appeared with fracture on computed tomography scan, initially concerning for metastatic disease. However, the lesion in acetabulum was considered the culprit tumor given its remarkably higher maximum standard uptake values. Complete surgical removal of the FGF23-secreting tumor led to cure of this disease. CONCLUSION: This case report highlights the challenges with functional imaging differentiating fractures from the culprit lesion and reports on a novel surgical technique that allowed for surgical cure while preserving the hip joint.

Definitive Local Therapy Is Associated with Improved Survival in Metastatic Soft Tissue Sarcomas.

Background: Definitive local therapy is often utilized in patients with metastatic soft tissue sarcomas (STS) to reduce morbidity associated with local tumor progression. We hypothesize that it is associated with improved overall survival (OS). Methods: Patients with newly diagnosed metastatic STS treated with chemotherapy were identified from the National Cancer Database and dichotomized into cohorts: 1. definitive local therapy (defined as either definitive dose radiotherapy, definitive surgery, or surgery with perioperative radiotherapy) or 2. conservative therapy (defined as systemic therapy with or without palliative therapy). The association between definitive local therapy and OS, and factors associated with the receipt of definitive local therapy were assessed. Results: Total of 4180 patients were identified. Compared with the conservative therapy, receipt of any definitive local therapy was associated with improved OS (median 17.9 vs. 10.1 months). The survival benefit remained on multivariate analyses and propensity-score matched analyses, with a stepwise improvement with surgery and combined modality local therapy, specifically radiotherapy (HR: 0.77; p < 0.001), surgery (HR: 0.67; p < 0.001), and combined surgery and radiotherapy (HR: 0.42; p < 0.001). Conclusions: Analysis of a large national cancer registry of patients with metastatic STS suggests that chemotherapy plus definitive local therapy is associated with a significant survival benefit compared to the standard chemotherapy alone.

Radiotherapy Remains Underused in the Treatment of Soft-Tissue Sarcomas: Disparities in Practice Patterns in the United States.

BACKGROUND: Practice patterns of radiation therapy (RT) use for soft-tissue sarcoma (STS) remain quite variable, despite clinical practice guidelines recommending the addition of RT to surgery for patients with high-grade STS, particularly for larger tumors. Using the National Cancer Database (NCDB), we assessed patterns of overall RT use, neoadjuvant versus adjuvant treatment, and specific RT modalities in this population. PATIENTS AND METHODS: Patients aged ≥18 years with stage II/III STS in 2004 through 2015 were identified from the NCDB. Patterns of care were assessed using multivariable logistic regression analysis. RESULTS: Of 27,426 total patients, 11,654 (42%) were treated with surgery alone versus 15,772 (58%) with RT in addition to surgery, with no overall increase in RT use over the study period. Notable clinical predictors of receipt of RT included tumor size (>5 cm), grade III, and tumors arising in the extremities. Conversely, female sex, older age (≥70 years), Black race, noncommercial insurance coverage, farther distance to treatment, and poor performance status were negative predictors of RT use. Of those receiving RT, 27% were treated with neoadjuvant RT and 73% with adjuvant RT. The proportion of those receiving neoadjuvant RT increased over time. Relevant factors associated with neoadjuvant RT included treatment at academic centers, larger tumor size, and extremity tumors. Of those who received RT with a modality specified as either intensity-modulated RT (IMRT) or 3D conformal RT (3DCRT), 61% were treated with IMRT and 39% with 3DCRT. The proportion of patients treated with IMRT increased over time. Relevant factors associated with IMRT use included treatment at academic centers, commercial insurance coverage, and larger and nonextremity tumors. CONCLUSIONS: Although use of neoadjuvant RT and IMRT has increased over time, a significant number of patients with STS are not receiving adjuvant or neoadjuvant RT. Our findings also note potential sociodemographic disparities and highlight the concern that not all patients with STS are being equally considered for RT.

Intra- and interspecific variation in the responses of insect phenology to climate.

Phenological change is the most widely documented biological impact of climate change, but shows marked variation in magnitude among populations and species. Thus, quantifying the environmental factors and organismal differences driving this intra- and interspecific variability in phenology is vital to understand and forecast the ecological consequences of climate change. Here, we test intra- and interspecific differences for a set of butterfly species in the organismal sensitivity of flight phenology and its dependence on environmental factors, using as our model system an elevation gradient in a Mediterranean mountain range where temperature and relative humidity vary substantially over space and time. We use field-collected meteorological data, and butterfly counts for 20 univoltine species over 14 years, to test the relative effects on phenology of temperature and relative humidity, the sensitivity of phenology to spatial and temporal variation in temperature and whether ecological traits account for inter-specific variation in sensitivity. For all species, temperature in the months immediately preceding adult emergence had the strongest relationship with phenology. All species appeared earlier in warmer years, with those flying earlier in the season showing the greatest sensitivity to annual (temporal) variation in temperature. However, only a minority of species showed evidence of plastic, space-for-time responses to temperature. Instead, most species showed strong evidence that phenology was more sensitive to temporal than spatial variation in temperature. Our results support the dominant influence of temperature on phenology, even in Mediterranean environments suffering summer drought. They also suggest that accurate forecasts of species' phenological shifts could require the isolation of spatial from temporal components of temperature variation, because the sensitivity of populations and species may differ across these two dimensions. The factors driving synchronisation of phenology over space merit particular research in the context of climate change, given their potential to expose populations simultaneously to environmental extremes.

Substantial π-aromaticity in the anionic heavy-metal cluster [Th@Bi12]4.

The concept of aromaticity was originally defined as a property of unsaturated, cyclic planar organic molecules like benzene, which gain stability by the inherent delocalization of 4n + 2 π-electrons over the ring atoms. Since then, π-aromaticity has been observed for a large variety of organic and inorganic non-metal compounds, yet, for molecules consisting only of metal atoms, it has remained restricted to systems with three to five atoms. Here, we present the straightforward synthesis of a metal 12-ring that exhibits 2π-aromaticity and has a ring current much stronger than that of benzene (6π) and equivalent to that of porphine (26π), despite these organic molecules having (much) larger numbers of π-electrons. Highly reducing reaction conditions allowed access to the heterometallic anion [Th@Bi12]4-, with interstitial Th4+ stabilizing a Bi128- moiety. Our results show that it is possible to design and generate substantial π-aromaticity in large metal rings, and we hope that such π-aromatic heavy-metal cycles will eventually find use in cluster-based reactions.

Consistent population declines but idiosyncratic range shifts in Alpine orchids under global change.

Mountains are plant biodiversity hotspots considered particularly vulnerable to multiple environmental changes. Here, we quantify population changes and range-shift dynamics along elevational gradients over the last three decades for c. two-thirds of the orchid species of the European Alps. Local extinctions were more likely for small populations, after habitat alteration, and predominated at the rear edge of species' ranges. Except for the most thermophilic species and wetland specialists, population density decreased over time. Declines were more pronounced for rear-edge populations, possibly due to multiple pressures such as climate warming, habitat alteration, and mismatched ecological interactions. Besides these demographic trends, different species exhibited idiosyncratic range shifts with more than 50% of the species lagging behind climate warming. Our study highlights the importance of long-term monitoring of populations and range distributions at fine spatial resolution to be able to fully understand the consequences of global change for orchids.

Flow Homogenization Enables a Massively Parallel Fluidic Design for High-throughput and Multiplexed Cell Isolation.

Microfluidic devices are widely used for applications such as cell isolation. Currently, the most common method to improve throughput for microfluidic devices involves fabrication of multiple, identical channels in parallel. However, this 'numbering up' only occurs in one dimension, thereby limiting gains in volumetric throughput. In contrast, macro-fluidic devices permit high volumetric flow-rates but lack the finer control of microfluidics. Here, we demonstrate how a micro-pore array design enables flow homogenization across a magnetic cell capture device, thus creating a massively parallel series of micro-scale flow channels with consistent fluidic and magnetic properties, regardless of spatial location. This design enables scaling in 2-dimensions, allowing flow-rates exceeding 100 mL/hr while maintaining >90% capture efficiencies of spiked lung cancer cells from blood in a simulated circulating tumor cell system. Additionally, this design facilitates modularity in operation, which we demonstrate by combining two different devices in tandem for multiplexed cell separation in a single pass with no additional cell losses from processing.

Limb Salvage and Reconstruction Options in Osteosarcoma.

Advances in chemotherapy, sophisticated imaging, and surgical techniques over the last few decades have allowed limb-salvage surgery (LSS) to become the preferred surgical treatment for bone sarcomas of the extremities. The goal of LLS is to maximize limb functionality to allow for the maintenance of quality of life without compromising overall survival and tumor local recurrence rates. Today, limb-salvage procedures are performed on 80-95% of patients with extremity osteosarcoma, and the 5-year survival rate in extremity osteosarcoma patients is now 60-75%.This chapter will focus on LSS for extremity osteosarcoma. Common types of surgical reconstruction techniques including endoprostheses, intercalary or osteoarticular allografts, vascularized fibular autografts, and allograft prosthetic composites (APC), and their complications such as infection, local recurrence, graft fracture, implant failure, and nonunion will be discussed in detail. Anatomic locations of lesions discussed include the proximal femur, distal femur, proximal tibia, distal tibia, proximal humerus, distal humerus, and forearm bones.

The Arachno-Zintl Ion (Sn5 Sb3 )3- and the Effects of Element Composition on the Structures of Isoelectronic Clusters: Another Facet of the Pseudo-Element Concept.

The pseudo-element concept, in its most general formulation, states that isoelectronic atoms form equal numbers of bonds. Hence, clusters such as Zintl ions usually retain their structure upon isoelectronic replacement of some or all atoms. Here, a deviation from this common observation is presented, namely the formation of (Sn5 Sb3 )3- (1), a rare example of an eight-vertex Zintl ion, and an unprecedented example of a Zintl ion synthesized by solution means that has an arachno-type structure according to the Wade-Mingos rules. Three structure-types of interest for (Sn5 Sb3 )3- were identified by DFT calculations: one that matched the X-ray diffraction data, and two that that were reminiscent of fragments of known clusters. A study on the isoelectronic series of clusters, (Snx Sb8-x )2-x (x=0-8), showed that the relative energies of these three isomers vary significantly with composition (independent of electron count) and that each is the global minimum at least once within the series.

Accelerated Discovery of Potent Fusion Inhibitors for Respiratory Syncytial Virus.

A series of five benzimidazole-based compounds were identified using a machine learning algorithm as potential inhibitors of the respiratory syncytial virus (RSV) fusion protein. These compounds were synthesized, and compound 2 in particular exhibited excellent in vitro potency with an EC50 value of 5 nM. This new scaffold was then further refined leading to the identification of compound 44, which exhibited a 10-fold improvement in activity with an EC50 value of 0.5 nM.

Butterfly phenology in Mediterranean mountains using space-for-time substitution.

Inferring species' responses to climate change in the absence of long-term time series data is a challenge, but can be achieved by substituting space for time. For example, thermal elevational gradients represent suitable proxies to study phenological responses to warming. We used butterfly data from two Mediterranean mountain areas to test whether mean dates of appearance of communities and individual species show a delay with increasing altitude, and an accompanying shortening in the duration of flight periods. We found a 14-day delay in the mean date of appearance per kilometer increase in altitude for butterfly communities overall, and an average 23-day shift for 26 selected species, alongside average summer temperature lapse rates of 3°C per km. At higher elevations, there was a shortening of the flight period for the community of 3 days/km, with an 8.8-day average decline per km for individual species. Rates of phenological delay differed significantly between the two mountain ranges, although this did not seem to result from the respective temperature lapse rates. These results suggest that climate warming could lead to advanced and lengthened flight periods for Mediterranean mountain butterfly communities. However, although multivoltine species showed the expected response of delayed and shortened flight periods at higher elevations, univoltine species showed more pronounced delays in terms of species appearance. Hence, while projections of overall community responses to climate change may benefit from space-for-time substitutions, understanding species-specific responses to local features of habitat and climate may be needed to accurately predict the effects of climate change on phenology.