Aortic pseudocoarctation is a rare congenital aortic anomaly that causes elongation, stenosis and kinking of the aorta at the isthmus level. Although aortic coarctation and pseudocoarctation share a similar clinical spectrum, pseudocoarctation rarely results in a significant gradient in descending aorta and haemodynamic consequence. Therefore, it's critical to differentiate in coarctation. All imaging modalities but especially cardiac CT angiography and catheterization are very important in the differential diagnosis. Our case highlighted to differences between aortic pseudocoarctation and coarctation, with other cardiac anomalies accompanying pseudocoarctation. And also the importance of cardiac imaging in the differential diagnosis of pseudocoarctation was emphasized.

Ricinodendron heudelotii, Vitex doniana and Cleome gynandra are three indigenous species whose seeds contain oil that can provide interesting alternatives to conventional seed oil species. This review focused on the physicochemical characteristics of their seeds and the nutritional properties of the extracted oils. Scientific articles and reports were collected and needed information was extracted and synthesized. Ricinodendron seed oil is higher (51.83 mg/100 g) than that of Vitex (28.55 mg/100 g) and Cleome (27.35 mg/100 g). The three seed oils are polyunsaturated oils. Ricinodendron seed oil is composed mainly of linoleic acid (28.3-51.1%). Cleome seeds oil is mainly composed of linoleic acid (56.3% -61.1%) and oleic acid (19.6-23.9%). Ricinodendron seed oil can be used for the preparation of fast drying binder and resins. Vitex seed oil can be used for the production of resin, paint and skin cream production. No application of Cleome seed oil has been stated.

We are reporting a COVID-19 positive patient who developed diplopia and was found to have an isolated abducens palsy. We reviewed the available English literature of cranial mononeuropathy as a possible manifestation of COVID-19 infection.It is a rare presentation of COVID-19.

Background: Combined treatment with probiotic and peanut oral immunotherapy (PPOIT) was shown to induce sustained unresponsiveness (SU) in a proof-of-concept randomized trial. Additional data on safety and long-term outcomes are needed. This study aimed to evaluate the safety and long-term effects of PPOIT in children with peanut allergy. Methods: Open-label study of 20 children aged 1-12 years with challenge-confirmed peanut allergy; all children received 18-months of PPOIT. Efficacy endpoints were desensitization, 8-week SU, and persistence of 8-week SU at 3-years post-treatment, assessed by double-blind placebo-controlled food challenge (cumulative 4950mg peanut protein). Treatment emergent adverse events and relationship to study treatment were recorded. Immunologic measures and health related quality of life (HRQL) were evaluated at screening, end-of-treatment and 3-years post-treatment. Results: Sixteen children (75%) completed treatment. By intention-to-treat analysis, 75% (15/20) achieved desensitization and 60% (12/20) achieved 8-week SU. Ten of 12 participants with SU at end-of-treatment consented to the 3-year SU challenge; 6 (60%) had persistence of SU. PPOIT was associated with significantly reduced peanut skin prick test wheal size and serum peanut specific-IgE levels at end-of-treatment, 12-months and 3-years post-treatment. There were no serious adverse events. HRQL scores improved (exceeding the Minimal Clinically Important Difference of 0.45) at 12-months post-treatment with benefit sustained at 3-years post-treatment. Conclusions: Eighteen months of PPOIT induced high rates of desensitization and SU, and SU persisted to 3-years post-treatment in a majority of initial responders. PPOIT led to long-lasting suppression of peanut sIgE and long-lasting clinically important improvement in HRQL.

G-protein-coupled receptors (GPCRs) are the largest family of human membrane proteins and represent the primary targets of about one third of currently marketed drugs. Despite the critical importance, experimental structures have been determined for only a limited portion of GPCRs and functional mechanisms of GPCRs remain poorly understood. Here, we have constructed novel sequence coevolutionary models of the A and B classes of GPCRs and compared them with residue contact frequency maps generated with available experimental structures. Significant portions of structural residue contacts were successfully detected in the sequence-based covariational models. “Exception” residue contacts predicted from sequence coevolutionary models but not available structures added missing links that were important for GPCR activation and allosteric modulation. Moreover, we identified distinct residue contacts involving different sets of functional motifs for GPCR activation, such as the Na+ pocket, CWxP, DRY, PIF and NPxxY motifs in the class A and the HETx and PxxG motifs in the class B. Finally, we systematically uncovered critical residue contacts tuned by allosteric modulation in the two classes of GPCRs, including those from the activation motifs and particularly the extracellular and intracellular loops in class A GPCRs. These findings provide a promising framework for rational design of ligands to regulate GPCR activation and allosteric modulation.

Environmental DNA (eDNA) analysis is a promising tool for non-disruptive and cost-efficient estimation of species abundance. However, its practical applicability in natural environments is limited owing to a potential gap between eDNA concentration and species abundance in the field. Although the importance of accounting for eDNA dynamics, such as transport and degradation, has been discussed, the influence of eDNA characteristics, including production source and cellular/molecular state, on the accuracy of eDNA-based abundance estimation was entirely overlooked. We conducted meta-analyses using 44 of previous eDNA studies and investigated the relationships between the accuracy (R2) of eDNA-based abundance estimation and eDNA characteristics. First, we found that estimated R2 values were significantly lower for crustaceans and mussels than fish. This finding suggests that less frequent eDNA production of these taxa owing to their external morphology and physiology may impede accurate estimation of their abundance via eDNA. Moreover, linear mixed modeling showed that, despite high variances, R2 values were positively correlated with filter pore size, indicating that selective collection of larger-sized eDNA, which is typically fresher, could improve the estimation accuracy of species abundance. Although our collected dataset was somewhat biased to the studies targeting specific taxa, our findings shed a new light on the importance of what characteristics of eDNA should be targeted for more accurate estimation of species abundance. Further empirical studies are required to validate our findings and fully elucidate the relationship between eDNA characteristics and eDNA-based abundance estimation.

Animal seed dispersers may influence plant genetic diversity, though there are few examples linking disperser behavior to population genomic diversity. We hypothesized that breeding colonies of the frugivorous White-Crowned Pigeon (Patagioenas leucocephala) would increase population diversity and decrease population differentiation in fruit trees at nesting sites due to increased seed dispersal from foraging trips. We measured the density and extent of colonies at Parque Nacional Jaragua (Dominican Republic) and used nuclear and plastid SNPs from ddRADseq to examine the spatial genetic structure of two common species: poisonwood (Metopium toxiferum), a key fruit resource during the breeding season, and gumbo limbo (Bursera simaruba). We found that pigeon nesting aggregations in and around Parque Nacional Jaragua occupy areas between 3 and 5 Km2, with an estimated number of active nests for 2016 extrapolated to 3 km2 of 159,144  21,484 s.e., making this one of the largest breeding aggregations for the species across its range. However, colony locations did not determine tree genetic diversity and differentiation. Gumbo limbo (consumed by a diverse community) showed less isolation by distance than poisonwood. Saplings and plastid markers, expected to be more strongly influenced by seed dispersal, did not display geographic structure associated with colony sites, suggesting that patterns were not primarily due to pigeon foraging. Our results highlight the diversity of population genomic patterns among co-occurring species with similar ecological niches and demonstrate the limitations for frugivores to influence genetic differences among plant species.

In this paper, we establish existence of infinitely many weak solutions for a class of quasilinear stationary Kirchhoff type equations, which involves a general variable exponent elliptic operator with critical growth. Precisely, we study the following nonlocal problem \begin{equation*} \begin{cases} -\displaystyle{M}(\mathscr{A}(u))\operatorname{div}\Bigl(a(|\nabla u|^{p(x)})|\nabla u|^{p(x)-2}\nabla u\Bigl) = \lambda f(x,u)+ |u|^{s(x)-2}u \text{ in }\Omega, \\ u = 0 \text{ on } \partial \Omega, \end{cases} \end{equation*} where $\Omega$ is a bounded smooth domain of $\mathbb{R}^N,$ with homogeneous Dirichlet boundary conditions on $\partial \Omega,$ the nonlinearity $f:\overline{\Omega}\times \mathbb{R}\to \mathbb{R}$ is a continuous function, $a:\mathbb{R}^{+}\to\mathbb{R}^{+}$ is a function of the class $C^{1},$ $M:\mathbb{R}^{+}_{0}\to\mathbb{R}^{+}$ is a continuous function, whose properties will be introduced later, $\lambda$ is a positive parameter and $p,s\in C(\overline{\Omega})$. We assume that $\mathscr{C}=\{x\in \Omega: s(x)=\gamma^{*}(x)\}\neq \emptyset,$ where $\gamma^{*}(x)=N\gamma(x)/(N-\gamma(x))$ is the critical Sobolev exponent. We will prove that the problem has infinitely many solutions and also we obtain the asymptotic behavior of the solution as $\lambda\to 0^{+}$. Furthermore, we emphasize that a difference with previous researches is that the conditions on $a(\cdot)$ are general overall enough to incorporate some interesting differential operators. Our work covers a feature of the Kirchhoff’s problems, that is, the fact that the Kirchhoff’s function $M$ in zero is different from zero, it also covers a wide class of nonlocal problems for $p(x)>1,$ for all $x\in \overline{\Omega}.$ The main tool to find critical points of the Euler Lagrange functional associated with this problem is through a suitable truncation argument, concentration-compactness principle for variable exponent found in \cite{bonder}, and the genus theory introduced by Krasnoselskii.

The case was a male neonate born by emergent cesarean section due to non-reassuring fetal status at 30 weeks of gestation. His manifestations were consistent with those of Rodriguez syndrome. Molecular analysis revealed an SF3B4 mutation.

Background and Purpose Orally administered ketoconazole rarely induces liver injury and adrenal dysfunction. In cellulo studies showed that a metabolite formed by arylacetamide deacetylase (AADAC)-mediated hydrolysis is relevant to ketoconazole-induced cytotoxicity. This study tried to examine the significance of AADAC in ketoconazole-induced toxicity in vivo using Aadac knockout mice. Experimental Approach Wild-type and Aadac knockout mice orally received 150 or 300 mg/kg/day ketoconazole, and plasma parameters, the concentrations of ketoconazole and N-deacetylketoconazole in plasma and tissues, and hepatic mRNA levels of immune- and inflammatory-related factors were measured. The effects of pretreatment with corticosterone (40 mg/kg, s.c.) on ketoconazole-induced liver injury were also examined. Key Results In a study of a single oral administration of 150 mg/kg ketoconazole, the area under the plasma concentration curve values of ketoconazole and N-deacetylketoconazole in Aadac knockout mice were significantly higher and lower than those in wild-type mice, respectively. With the administration of ketoconazole (300 mg/kg/day) for 7 days, Aadac knockout mice showed higher mortality (100%) than wild-type mice (42.9%), with significantly higher plasma alanine transaminase and lower corticosterone levels, representing liver injury and adrenal dysfunction, respectively. In Aadac knockout mice, hepatic mRNA levels of immune- and inflammatory-related factors were increased by the administration of ketoconazole, and the increase was restored by the replenishment of corticosterone, which shows anti-inflammatory effects. Conclusion and Implications Aadac defects exacerbated ketoconazole-induced liver injury by inhibiting glucocorticoid synthesis and enhancing the inflammatory response. This in vivo study revealed that the hydrolysis of ketoconazole by AADAC can mitigate ketoconazole-induced toxicities.

IIntroduction Isolated tricuspid valve prolapse (TVP) is a rare finding on transthoracic echocardiography. Right atrial enlargement or prominent ” v ” waves as a consequence of hemodynamic changes in severe tricuspid regurgitation (TR) are rarely seen with isolated TVP. Here is a case of isolated prolapse of anterior tricuspid leaflet presenting with giant C-V waves also known as Lancisi’s sign. Case Report A 66-year-old male presented with increasing exercise limitation and leg edema in recent months and was complaining about the persistent pulsation at his neck and elevated jugular venous pulse with prominent systolic pulsation that represents giant C-V waves, also known as ‘Lancisi’s sign’ consequence of severe TR due to isolated prolapse of the anterior leaflet.The patients’ symptoms resolved completely after tricuspid valve replacement. Discussion TVP is best defined at parasternal short axis view with more than 2 mm atrial displacement (AD) of leaflet/leaflets. TVP can also be detected from four chamber view with more than 2 mm AD or in right ventricular inflow view with more than 4 mm AD. As a consequence of TVP, the physiological jugular venous waveform alters due to severe TR.During severe TR; retrograde blood flow through right atrium during ventricular systole restrains x descent and produces a fusion of c and v waves that appears as a large pulsation in physical examination called as ‘Lancisi’s sign’ Conclusion ‘Lancisi’s sign’ is defined as a large visible systolic neck pulsation as a consequence of the c-v waves fusion by preventing x descent during severe TR.

No abstract as per author guidelines for submission of this format

Biochar application is currently considered to be an effective soil organic carbon (SOC) management to prevent land degradation by enhancing SOC stock. However, quantitative information on the impact of biochar application on carbon dioxide (CO2) flux and associated microbial responses is still scarce, especially in degraded tropical agroecosystems. Here, we evaluated the impact of land management (control (C), biochar (B; 8.2 Mg C ha−1), farmyard manure (FYM) (M; 1.1 Mg C ha−1 yr−1), and a mixture of both (BM; 8.2 Mg biochar-C ha−1 and 1.1 Mg FYM-C ha−1 yr−1)) on CO2 flux, SOC stock, microbial biomass C (MBC), and metabolic quotient (qCO2) in degraded tropical alkaline cropland of southern India, based on a 27-month field experiment. Cumulative CO2 flux over the experiment was 2.4, 2.7, 4.0, and 3.7 Mg C ha−1 in the C, B, M, and BM treatments, respectively. Biochar application increased soil moisture and SOC stock, though did not affect CO2 flux, MBC, and qCO2, indicating the limited response of microbes to increased soil moisture because of small amount of SOC. Combined application of biochar and FYM did not increase CO2 flux compared with FYM alone, due to little difference of microbial responses between the M and BM treatments. Additionally, SOC increment (8.9 Mg C ha−1) and the rate of C-input retention in soil (0.78) was most significant in the BM treatment. Hence, the combined application of biochar and FYM could be sustainable land management by efficient increase of SOC stock in the tropical degraded cropland.

Objectives. Neuroblastoma is the most common extracranial tumour in children, and prognosis for refractory and relapsed disease is still poor. Early Phase clinical trials play a pivotal role in the development of novel drugs. Ensuring adequate recruitment is crucial. The primary aim was to determine the rate of participation trials for children with refractory/relapsed neuroblastoma in two of the largest Drug Development European institutions. Methods. Data from patients diagnosed with refractory/relapsed neuroblastoma between January 2012 and December 2018 at the two institutions were collected and analysed. Results. Overall, 48 patients were included. A total of 31 (65%) refractory/relapsed cases were enrolled in early Phase trials. The main reasons for not participating in clinical trials included: not fulfilling eligibility criteria prior to consent (12/17, 70%) and screening failure (2/17, 12%). Median time on trial was 4.3 months (range 0.6-13.4). Most common cause for trial discontinuation was disease progression (67.7%). Median overall survival was longer in refractory (28 months, 95% CI, 20.9-40.2) than in relapsed patients (14 months, 95% CI, 8.1-20.1)) [p=0,034]. Conclusions. Although two thirds of children with refractory/relapsed neuroblastoma were enrolled in early Phase trials, recruitment rates can still be improved. The main cause for not participating on trials was not fulfilling eligibility criteria prior to consent, mainly due to performance status and short life expectancy. This study highlights the hurdles to access to innovative therapies for children with relapsed/refractory neuroblastomas and identifies key areas of development to improve recruitment to early phase trials.

Allergen immunotherapy (AIT) has gained a permanent place in the therapeutic arsenal for the patient with allergy. Particularly, substantial evidence has been established for the efficacy of AIT in allergic rhinitis. A hallmark of AIT is it disease modifying effect resulting in persistent benefit after the treatment has been terminated. Both the subcutaneous and sublingual mode of administration appear to be safe. It is, however, a matter of debate whether AIT can be implemented for patients with asthma. EAACI and GINA guidelines recommend sublingual AIT in house dust mite driven asthma. The question however remains whether the different available forms of AIT should be used for allergic asthma in general.

Objective: To evaluate the cost-effectiveness of insertable cardiac monitors (ICMs) compared to standard of care (SoC) for detecting atrial fibrillation (AF) in patients at high risk of stroke (CHADS2 >2), in the US. Background: ICMs are a clinically effective means of detecting AF in high-risk patients, prompting the initiation of non-vitamin K oral anticoagulants (NOACs). Their cost-effectiveness from a US clinical payer perspective is not yet known. Methods: Using patient data from the REVEAL AF trial (n= 446, average CHADS2 score= 2.9), a Markov model estimated the lifetime costs and benefits of detecting AF with an ICM or with SoC (namely, intermittent use of electrocardiograms [ECGs] and 24-hour Holter monitors). Ischemic and hemorrhagic strokes, intra- and extra-cranial hemorrhages, and minor bleeds were modelled. Diagnostic and device costs were included, plus costs of treating stroke and bleeding events and of NOACs. Costs and health outcomes, measured as quality-adjusted life years (QALYs), were discounted at 3% per annum. One-way deterministic and probabilistic sensitivity analyses (PSA) were undertaken. Results: Lifetime per-patient cost for ICM was $58,132 vs. $52,019 for SoC. ICMs generated a total 7.75 QALYs vs. 7.59 for SoC, with 34 fewer strokes projected per 1,000 patients. The incremental cost-effectiveness ratio (ICER) was $35,452 per QALY gained. ICMs were cost-effective in 72% of PSA simulations, using a $50,000 per QALY threshold. Conclusions: The use of ICMs to identify AF in a high-risk population is likely to be cost-effective in the US healthcare setting.

A differential diagnosis of sudden abdominal pain with scoliosis indicates uterine torsion, a rare condition in clinical practice.

Evolutionary theory predicts that the process of range expansion will lead to differences between core and edge population in life history and dispersal traits. Selection and genetic drift can influence reproductive ability while spatial sorting by dispersal ability can increase dispersal at the edge. However, the context of individuals (e.g., population density and mating status) also impacts dispersal behavior. We evaluated theoretical predictions for evolution of reproductive life history and dispersal traits using the range expansion of a biological control agent, Diorhabda carinulata, or northern tamarisk beetle. We found divergence of fecundity, age at first reproduction, and female body size between core and edge populations. We also show that density and mating status influence dispersal and that dispersal increases at the edge of the range. We demonstrate that theory of evolution during range expansions applies to the range expansion of a biocontrol agent, especially when the ecological context is considered.

Prosthetic valve endocarditis is a complication of bacteremia which can cause damage to the prosthetic valve or the tissue to which it was sewn. Extensive tissue damage can result in a loss of anchoring and allow for abnormal valvular motion. Dehiscence can lead to excessive motion of the valve which is termed rocking. Through advances in imaging technology, live 3-dimentional (3-D) transesophageal echocardiography can allow for precise identification of the location of, and amount of dehiscence. We present a 37-year old male with a rocking prosthetic valve demonstrated on 3-D echocardiography and correlated to surgical manipulation.

We described eleven patients positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The younger age and female gender seem to contribute to poor outcomes possibly. Furthermore, the left ventricle ejection fraction and pro-BNP improvement within the first week of treatment might indicate a good prognosis.

The problem of soil heavy metals (HMs) accumulation from protected cultivation (PC) needs an urgent solution. 132 soil samples from typically high-density PC areas were analyzed for accumulation, risk, and sources of 8 HMs in 16 cities of 8 provinces, China. The soil HMs accumulation characteristics were prominent; Cu, Zn, Pb, Cd, As over-standard (GB 15618-2016) rates reached 15.2, 4.5, 3.0, 27.3, and 2.3%, respectively. The single-factor pollution index indicates that Cd reached slightly contaminated levels in the whole area, while Cu was at a slightly contaminated level only in Yunnan Province. The Nemeiro comprehensive pollution index and the comprehensive quality index suggested that HMs accumulation were at the slightly contaminated levels, with Yunnan province being the most affected and Henan followed. Cu and Zn accumulations are mainly related to frequent input of organic fertilizer, especially livestock manure’s direct return to the field. Therefore, Cu and Zn showed a strong correlation (P＜0.01) with soil organic material (SOM), and their available amounts linearly correlated with the extension of planting years in PC. On the contrary, Pb and Cd amounts are only related (P＜0.01) to soil texture, and their main sources are related to the parent material of soil formation. Moreover, their available amounts did not correlate with the planting years. Our results suggest that long-term and unreasonable PC may lead to soil HMs accumulation. Therefore, appropriate agricultural materials, planting systems, and fertilization methods must be used to effectively avoid the risk of excessive HMs accumulation in the PC soils.

Abstract Objective: We investigated the effect of morphological diversity of the tricuspid valve with multiple posterior leaflets on the technical outcomes of tricuspid valve repair. Methods: From April 2016 to November 2020, 141 patients were diagnosed with secondary tricuspid regurgitation associated with left heart disease and underwent tricuspid valve repair. We retrospectively analyzed the clinical and echocardiographic data of patients who underwent both preoperative and postoperative transthoracic echocardiography. We divided the patients into two groups according to the surgical technique used to treat tricuspid regurgitation: ring annuloplasty alone (Group 1, n=109) or additional approximation of leaflet edges (edge-to-edge repair) with ring annuloplasty (Group 2, n=32). We measured the morphological diversity of the tricuspid valve during the operation in all patients. Results: The preoperative tricuspid regurgitation score was higher in Group 2 than in Group 1 (2.1±0.78 vs. 1.6±0.7, respectively; p=0.0046), and Group 2 contained more patients with two posterior leaflets than Group 1 [20 (63%) vs. 36 (33%), respectively; p=0.003]. The univariate and multivariate logistic regression analyses showed that the presence of two posterior leaflets was an independent risk factor for additional procedures during tricuspid valve repair (odds ratio, 2.6; 95% confidence interval, 1.1–6.1; p=0.033). Conclusions: Additional procedures to reduce tricuspid regurgitation were required more frequently in patients with two posterior leaflets of the tricuspid valve. The morphological diversity of two posterior leaflets is a potential risk factor for a more complicated tricuspid repair.

Purpose Pediatric patients with metastatic solid tumors historically have a poor overall survival. Some pediatric patients may still be potentially curable with aggressive local therapy to metastatic disease. The purpose of this study is to report results of the use of SBRT in the treatment of pediatric metastatic disease. Materials and Methods Pediatric patients who received SBRT between the years 2000-2020. Study endpoints included local control (LC), progression free survival (PFS), overall survival (OS), cumulative incidence (CI) of death or local failure and toxicity. The endpoints with respect to survival and LC were calculated using the Kaplan-Meier estimate. The cumulative incidence of local failure was calculated using death as a competing risk. Results 16 patients with 36 lesions irradiated met inclusion criteria. The median OS and PFS was 17 months and 15.7 months, respectively. The 1-year OS was 75%. The 6- and 12-month LC was 85% and 78%, respectively. There were no local failures in lesions receving a BED10≥100 Gy. Patients who had ≤5 metastatic lesions at first recurrence had a superior 1-year OS of 100% versus 50% with >5 lesions. One patient (6.3%) experienced a grade 3 CNS toxicity. Conclusions LC was excellent with SBRT delivered to metastatic disease, particularly for lesions receiving a BED10≥100 Gy. High-grade toxicity was rare in our patient population. Patients with ≤5 metastatic sites have a significantly better OS compared to >5 sites. Future prospective trials with multi-institutional collaboration will be necessary to evaluate appropriate patient selection and the optimal radiation dose regimen.

Knowing the abundance of a population is a crucial component to assess its conservation status and develop effective conservation plans. For most cetaceans, abundance estimation is difficult given their cryptic and mobile nature, especially when the population is small and has a transnational distribution. In the Baltic Sea, the number of harbour porpoises (Phocoena phocoena) has collapsed since the mid-20th century and the Baltic Proper harbour porpoise is listed as Critically Endangered by the IUCN; however, its abundance remains unknown. Here, one of the largest ever passive acoustic monitoring studies was carried out by eight Baltic Sea nations to estimate the abundance of the Baltic Proper harbour porpoise for the first time. By logging porpoise echolocation signals at 298 stations during May 2011-April 2013, calibrating the loggers’ spatial detection performance at sea, and measuring the click rate of tagged individuals, we estimated an abundance of 66-1,143 individuals (95% CI, point estimate 490) during May-October within the population’s proposed management border. The small abundance estimate strongly supports that the Baltic Proper harbour porpoise is facing an extremely high risk of extinction, and highlights the need for immediate and efficient conservation actions through international cooperation. It also provides a starting point in monitoring the trend of the population abundance to evaluate the effectiveness of management measures and determine its interactions with the larger neighbouring Belt Sea population. Further, we offer evidence that design-based passive acoustic monitoring can generate reliable estimates of the abundance of rare and cryptic animal populations across large spatial scales.