Incretins-Based Therapies and Their Cardiovascular Effects: New Game-Changers for the Management of Patients with Diabetes and Cardiovascular Disease.

Atherosclerosis is the leading cause of death worldwide, especially in patients with type 2 diabetes mellitus (T2D). GLP-1 receptor agonists and DPP-4 inhibitors were demonstrated to play a markedly protective role for the cardiovascular system beyond their glycemic control. Several cardiovascular outcome trials (CVOT) reported the association between using these agents and a significant reduction in cardiovascular events in patients with T2D and a high cardiovascular risk profile. Moreover, recent evidence highlights a favorable benefit/risk profile in myocardial infarction and percutaneous coronary revascularization settings. These clinical effects result from their actions on multiple molecular mechanisms involving the immune system, platelets, and endothelial and vascular smooth muscle cells. This comprehensive review specifically concentrates on these cellular and molecular processes mediating the cardiovascular effects of incretins-like molecules, aiming to improve clinicians' knowledge and stimulate a more extensive use of these drugs in clinical practice as helpful cardiovascular preventive strategies.

A reassessment of the distinctiveness of dryopithecine genera from the Iberian Miocene based on enamel-dentine junction geometric morphometric analyses.

A vast diversity of catarrhines primates has been uncovered in the Middle to Late Miocene (12.5-9.6 Ma) of the Vallès-Penedès Basin (northeastern Spain), including several hominid species (Pierolapithecus catalaunicus, Anoiapithecus brevirostris, Dryopithecus fontani, Hispanopithecus laietanus, and Hispanopithecus crusafonti) plus some remains attributed to 'Sivapithecus' occidentalis (of uncertain taxonomic validity). However, Pierolapithecus and Anoiapithecus have also been considered junior synonyms of Dryopithecus by some authors, which entail a lower generic diversity and an inflated intrageneric variation of the latter genus. Since the distinction of these taxa partly relies on dental features, the detailed and quantitative analysis of tooth shape might help disentangling the taxonomic diversity of these Miocene hominids. Using diffeomorphic surface matching and three-dimensional geometric morphometrics, we investigate the enamel-dentine junction shape (which is a reliable taxonomic proxy) of these Miocene hominids, with the aim of investigating their degree of intra- and intergeneric variation compared with that of extant great ape genera. We conducted statistical analyses, including between-group principal component analyses, canonical variate analyses, and permutation tests, to investigate whether the individual and combined (i.e., Dryopithecus s.l.) variation of the extinct genera exceeds that of the extant great apes. Our results indicate that Pierolapithecus, Anoiapithecus, Dryopithecus, and Hispanopithecus show morphological differences of enamel-dentine junction shape relative to the extant great apes that are consistent with their attribution to different genera. Specifically, the variation displayed by the Middle Miocene taxa combined exceeds that of extant great ape genera, thus undermining the single-genus hypothesis. 'Sivapithecus' occidentalis specimens fall close to Dryopithecus but in the absence of well-preserved comparable teeth for Pierolapithecus and Anoiapithecus, their taxonomic attribution remains uncertain. Among the Hispanopithecus sample, IPS1802 from Can Llobateres stands out and might either be an outlier in terms of morphology, or represent another dryopithecine taxon.

Morphologies in-between: The impact of the first steps on the human talus.

OBJECTIVE: The development of bipedalism is a very complex activity that contributes to shaping the anatomy of the foot. The talus, which starts ossifying in utero, may account for the developing stages from the late gestational phase onwards. Here, we explore the early development of the talus in both its internal and external morphology to broaden the knowledge of the anatomical changes that occur during early development. MATERIALS AND METHODS: The sample consists of high-resolution microCT scans of 28 modern juvenile tali (from 36 prenatal weeks to 2 years), from a broad chronological range from the Late Roman period to the 20th century. We applied geometric morphometric and whole-bone trabecular analysis to investigate the early talar morphological changes. RESULTS: In the youngest group (<6 postnatal months), the immature external shell is accompanied by an isotropic internal structure, with thin and densely packed trabeculae. After the initial attempts of locomotion, bone volume fraction decreases, while anisotropy and trabecular thickness increase. These internal changes correspond to the maturation of the external shell, which is now more defined and shows the development of the articular surfaces. DISCUSSION: The internal and external morphology of the human talus reflects the diverse load on the foot during the initial phases of the bipedal locomotion, with the youngest group potentially reflecting the lack of readiness of the human talus to bear forces and perform bipedal walking. These results highlight the link between mechanical loading and bone development in the human talus during the acquisition of bipedalism, providing new insight into the early phases of talar development.

Glycaemic Control in Patients Undergoing Percutaneous Coronary Intervention: What Is the Role for the Novel Antidiabetic Agents? A Comprehensive Review of Basic Science and Clinical Data.

Coronary artery disease (CAD) remains one of the most important causes of morbidity and mortality worldwide, and revascularization through percutaneous coronary interventions (PCI) significantly improves survival. In this setting, poor glycaemic control, regardless of diabetes, has been associated with increased incidence of peri-procedural and long-term complications and worse prognosis. Novel antidiabetic agents have represented a paradigm shift in managing patients with diabetes and cardiovascular diseases. However, limited data are reported so far in patients undergoing coronary stenting. This review intends to provide an overview of the biological mechanisms underlying hyperglycaemia-induced vascular damage and the contrasting actions of new antidiabetic drugs. We summarize existing evidence on the effects of these drugs in the setting of PCI, addressing pre-clinical and clinical studies and drug-drug interactions with antiplatelet agents, thus highlighting new opportunities for optimal long-term management of these patients.

Prevalence and Clinical Implications of COVID-19 Myocarditis.

The clinical manifestations of COVID-19 are widely variable and may involve several districts. Although the clinical course is mostly characterized by respiratory involvement, up to 30% of hospitalized patients have evidence of myocardial injury due to acute coronary syndrome, cardiac arrhythmias, myocarditis, and cardiogenic shock. In particular, myocarditis is a well-recognized severe complication of COVID-19 and is associated with fulminant cardiogenic shock and sudden cardiac death. In this article, the authors aim to present a comprehensive review about COVID-19-related myocarditis, including clinical characteristics, diagnostic workup, and management.

A proposed strategy for anticoagulation therapy in noncompaction cardiomyopathy.

Noncompaction cardiomyopathy (NCCM) is a rare condition characterized by prominent trabeculae, deep intertrabecular recesses, and a left ventricular myocardium with a two-layered structure, characterized by a spongy endocardial layer and a thinner and compacted epicardial one. NCCM can be isolated or associated with other congenital heart diseases and complex syndromes involving neuromuscular disorders and facial dysmorphisms. To date, more than 40 genes coding for sarcomeric, cytoskeletal, ion channels, and desmosomal proteins have been identified. Clinical presentation is also highly variable, ranging from no symptoms to end-stage heart failure (HF), lethal arrhythmias, sudden cardiac death, or thromboembolic events. In particular, the prevalence of thromboembolism in NCCM patients appears to be higher than that of a similar, age-matched population without NCCM. Thromboembolism has a multifactorial aetiology, which is linked to genetic, as well as traditional cardiovascular risk factors. In previous studies, atrial fibrillation (AF) was observed in approximately 25-30% of adult NCCM patients and embolism had a cardiac source in ~63-69% of cases; therefore, AF represents a strong predictor of adverse events, especially if associated to HF and neuromuscular disorders. Left ventricular dysfunction is another risk factor for thromboembolism, as a result of blood stagnation and local myocardial injury. Moreover, it is not completely clarified if the presence of deep intertrabecular recesses causing stagnant blood flow can constitute per se a thrombogenic substrate even in absence of ventricular dysfunction. For the clinical management of NCCM patients, an appropriate stratification of the thromboembolic risk is of utmost importance for a timely initiation of anticoagulant therapy. The aim of the present study is to review the available literature on NCCM with particular attention on thromboembolic risk stratification and prevention and the current evidence for oral anticoagulation therapy. The use of direct oral anticoagulants vs. vitamin K antagonists is also discussed with important implications for patient treatment and prognosis.

Growth of Neanderthal infants from Krapina (120-130 ka), Croatia.

Modern humans have a slow and extended period of childhood growth, but to what extent this ontogenetic pathway was present in Neanderthals is debated. Dental development, linked to the duration of somatic growth across modern primates, is the main source for information about growth and development in a variety of fossil primates, including humans. Studies of Neanderthal permanent teeth report a pace of development either similar to recent humans or relatively accelerated. Neanderthal milk teeth, which form and emerge before permanent teeth, provide an opportunity to determine which pattern was present at birth. Here we present a comparative study of the prenatal and early postnatal growth of five milk teeth from three Neanderthals (120 000-130 000 years ago) using virtual histology. Results reveal regions of their milk teeth formed quickly before birth and over a relatively short period of time after birth. Tooth emergence commenced towards the earliest end of the eruption schedules displayed by extant human children. Advanced dental development is consistent with expectations for Neanderthal infant feeding.

Early Alpine occupation backdates westward human migration in Late Glacial Europe.

Before the end of the Last Glacial Maximum (LGM, ∼16.5 ka ago)1 set in motion major shifts in human culture and population structure,2 a consistent change in lithic technology, material culture, settlement pattern, and adaptive strategies is recorded in Southern Europe at ∼18-17 ka ago. In this time frame, the landscape of Northeastern Italy changed considerably, and the retreat of glaciers allowed hunter-gatherers to gradually recolonize the Alps.3-6 Change within this renewed cultural frame (i.e., during the Late Epigravettian phase) is currently associated with migrations favored by warmer climate linked to the Bølling-Allerød onset (14.7 ka ago),7-11 which replaced earlier genetic lineages with ancestry found in an individual who lived ∼14 ka ago at Riparo Villabruna, Italy, and shared among different contexts (Villabruna Cluster).9 Nevertheless, these dynamics and their chronology are still far from being disentangled due to fragmentary evidence for long-distance interactions across Europe.12 Here, we generate new genomic data from a human mandible uncovered at Riparo Tagliente (Veneto, Italy), which we directly dated to 16,980-16,510 cal BP (2σ). This individual, affected by focal osseous dysplasia, is genetically affine to the Villabruna Cluster. Our results therefore backdate by at least 3 ka the diffusion in Southern Europe of a genetic component linked to Balkan/Anatolian refugia, previously believed to have spread during the later Bølling/Allerød event. In light of the new genetic evidence, this population replacement chronologically coincides with the very emergence of major cultural transitions in Southern and Western Europe.

Ranolazine Improves Glycemic Variability and Endothelial Function in Patients with Diabetes and Chronic Coronary Syndromes: Results from an Experimental Study.

BACKGROUND: Ranolazine is a second-line drug for the management of chronic coronary syndromes (CCS). Glucose-lowering and endothelial effects have also been reported with this agent. However, whether ranolazine may improve short-term glycemic variability (GV), strictly related to the prognosis of patients with type 2 diabetes (T2D), is unknown. Thus, we aimed to explore the effects of adding ranolazine to standard anti-ischemic and glucose-lowering therapy on long- and short-term GV as well as on endothelial function and oxidative stress in patients with T2D and CCS. METHODS: Patients starting ranolazine (n = 16) were evaluated for short-term GV, haemoglobin 1Ac (Hb1Ac) levels, endothelial-dependent flow-mediated vasodilation (FMD), and oxidative stress levels at enrolment and after 3-month follow-up. The same measurements were collected from 16 patients with CCS and T2D that did not receive ranolazine, matched for age, gender, and body mass index. RESULTS: A significant decline in Hb1Ac levels was reported after 3-month ranolazine treatment (mean change -0.60%; 2-way ANOVA p = 0.025). Moreover, among patients receiving ranolazine, short-term GV indexes were significantly improved over time compared with baseline (p = 0.001 for time in range; 2-way ANOVA p = 0.010). Conversely, no significant changes were reported in patients without ranolazine. Finally, greater FMD and lower oxidative stress levels were observed in patients on ranolazine at 3 months. CONCLUSIONS: Ranolazine added to standard anti-ischemic and glucose-lowering therapy demonstrated benefit in improving the glycemic status of patients with T2D and CCS. How this improvement contributes to the overall myocardial benefit of ranolazine requires further studies.

Skull osteology of Vipera walser (Squamata, Viperidae): Description, variability, ontogeny, and diagnostic characters in comparison to other Italian vipers.

Vipera walser is the most recently recognized European viper. This rare species is endemic to a small area in the Piedmont Alps of Italy, but its closest relatives are found among the Caucasian viper species. In order to provide a starting point for a phylogenetic and biogeographic investigation based on osteology, and including fossils remains, we analyzed four specimens of V. walser and compared them with specimens of the four other Italian viper species. Based on these specimens, we improved the diagnosis of V. walser and provided a first evaluation of intraspecific variability and ontogenetic variation. The skull of V. walser is subject to significant variation, most likely related to ontogeny in some cases (i.e., development of the parietal crest, development of the basioccipital process, shape of the posterior margin of the parabasisphenoid, shape of the quadrate). Based on the studied material, it is possible to distinguish V. walser from the other Italian vipers by the shape of the occipital crest of the supraoccipital, which is posteriorly directed, whereas it is laterally directed in the other species. The osteological diagnosibility provides further support for the validity of V. walser as a distinct species from Vipera berus.

Exploring late Paleolithic and Mesolithic diet in the Eastern Alpine region of Italy through multiple proxies.

OBJECTIVES: The analysis of prehistoric human dietary habits is key for understanding the effects of paleoenvironmental changes on the evolution of cultural and social human behaviors. In this study, we compare results from zooarchaeological, stable isotope and dental calculus analyses as well as lower second molar macrowear patterns to gain a broader understanding of the diet of three individuals who lived between the end of the Late Pleistocene and the Early Holocene (ca., 17-8 ky cal BP) in the Eastern Alpine region of Italy. MATERIALS AND METHODS: We analyze individuals buried at the sites of Riparo Tagliente (Verona), Riparo Villabruna, and Mondeval de Sora (Belluno). The three burials provide a unique dataset for diachronically exploring the influence of climatic changes on human subsistence strategies. RESULTS: Isotopic results indicate that all individuals likely relied on both terrestrial and freshwater animal proteins. Even though dental calculus analysis was, in part, hindered by the amount of mineral deposit available on the teeth, tooth macrowear study suggests that the dietary habits of the individuals included plant foods. Moreover, differences in macrowear patterns of lower second molars have been documented between Neanderthals and modern humans in the present sample, due to a prevalence of Buccal wear among the former as opposed to higher values of Lingual wear in modern human teeth. DISCUSSION: Isotopic analyses have emphasized the contribution of animal proteins in the diet of the three foragers from the Eastern Alpine region. The possible intake of carbohydrate-rich plant foods, suggested by the retrieval of plant remains in dental calculus, is supported by the signal of macrowear analysis. Moreover, the latter method indicates that the distribution of macrowear in lower second molars (M2 s) allows us to discriminate between Neanderthals and modern humans within the present reference sample. Overall, our results show these three prehistoric hunter-gatherers were well adapted to the environment in which they lived exploiting many natural resources.

Early life of Neanderthals.

The early onset of weaning in modern humans has been linked to the high nutritional demand of brain development that is intimately connected with infant physiology and growth rate. In Neanderthals, ontogenetic patterns in early life are still debated, with some studies suggesting an accelerated development and others indicating only subtle differences vs. modern humans. Here we report the onset of weaning and rates of enamel growth using an unprecedented sample set of three late (∼70 to 50 ka) Neanderthals and one Upper Paleolithic modern human from northeastern Italy via spatially resolved chemical/isotopic analyses and histomorphometry of deciduous teeth. Our results reveal that the modern human nursing strategy, with onset of weaning at 5 to 6 mo, was present among these Neanderthals. This evidence, combined with dental development akin to modern humans, highlights their similar metabolic constraints during early life and excludes late weaning as a factor contributing to Neanderthals' demise.

The first evidence for Late Pleistocene dogs in Italy.

The identification of the earliest dogs is challenging because of the absence and/or mosaic pattern of morphological diagnostic features in the initial phases of the domestication process. Furthermore, the natural occurrence of some of these characters in Late Pleistocene wolf populations and the time it took from the onset of traits related to domestication to their prevalence remain indefinite. For these reasons, the spatiotemporal context of the early domestication of dogs is hotly debated. Our combined molecular and morphological analyses of fossil canid remains from the sites of Grotta Paglicci and Grotta Romanelli, in southern Italy, attest of the presence of dogs at least 14,000 calibrated years before present. This unambiguously documents one of the earliest occurrence of domesticates in the Upper Palaeolithic of Europe and in the Mediterranean. The genetic affinity between the Palaeolithic dogs from southern Italy and contemporaneous ones found in Germany also suggest that these animals were an important common adjunct during the Late Glacial, when strong cultural diversification occurred between the Mediterranean world and European areas north of the Alps. Additionally, aDNA analyses indicate that this Upper Palaeolithic dog lineage from Italy may have contributed to the genetic diversity of living dogs.

First nearly complete skull of Gallotia auaritae (lower-middle Pleistocene, Squamata, Gallotiinae) and a morphological phylogenetic analysis of the genus Gallotia.

The Canary Islands are an Atlantic archipelago known for its high number of endemic species. Among the most known endemic vertebrate species are the giant lizards of the genus Gallotia. We describe the cranial osteology of the first almost complete and articulated fossil skull of the taxon Gallotia auaritae, recovered from the lower-middle Pleistocene of the La Palma island. In this work, X-ray computed microtomography images were used to perform an exhaustive phylogenetic analysis where most of the extant and fossil species of the genus Gallotia were included for first time. This analysis recovered a monophyletic Gallotia clade with similar topology to that of molecular analyses. The newly described specimen shares some characters with the group formed by G. bravoana, G. intermedia and G. simonyi, G. auaritae, and its position is compatible with a referral to the latter. Our study adds new important data to the poorly known cranial morphology of G. auaritae, and the phylogenetic analysis reveals an unexpected power of resolution to obtain a morphology-based phylogeny for the genus Gallotia, for inferring the phylogenetic position of extinct species and for helping in the identification of fossil specimens.

X-ray computed microtomography of Megachirella wachtleri.

Understanding the origin and early evolution of squamates has been a considerable challenge given the extremely scarce fossil record of early squamates and their poor degree of preservation. In order to overcome those limitations, we conducted high-resolution X-ray computed tomography (CT) studies on the fossil reptile Megachirella wachtleri (Middle Triassic, northern Italy), which revealed an important set of features indicating this is the oldest known fossil squamate in the world, predating the previous oldest record by ca. 75 million years. We also compiled a new phylogenetic data set comprising a large sample of diapsid reptiles (including morphological and molecular data) to investigate the phylogenetic relationships of early squamates and other reptile groups along with the divergence time of those lineages. The re-description of Megachirella and a new phylogenetic hypothesis of diapsid relationships are presented in a separate study. Here we present the data descriptors for the tomographic scans of Megachirella, which holds fundamental information to our understanding on the early evolution of one of the largest vertebrate groups on Earth today.

Oldest skeleton of a fossil flying squirrel casts new light on the phylogeny of the group.

Flying squirrels are the only group of gliding mammals with a remarkable diversity and wide geographical range. However, their evolutionary story is not well known. Thus far, identification of extinct flying squirrels has been exclusively based on dental features, which, contrary to certain postcranial characters, are not unique to them. Therefore, fossils attributed to this clade may indeed belong to other squirrel groups. Here we report the oldest fossil skeleton of a flying squirrel (11.6 Ma) that displays the gliding-related diagnostic features shared by extant forms and allows for a recalibration of the divergence time between tree and flying squirrels. Our phylogenetic analyses combining morphological and molecular data generally support older dates than previous molecular estimates (~23 Ma), being congruent with the inclusion of some of the earliest fossils (~36 Ma) into this clade. They also show that flying squirrels experienced little morphological change for almost 12 million years.

The Middle Pleistocene (MIS 12) human dental remains from Fontana Ranuccio (Latium) and Visogliano (Friuli-Venezia Giulia), Italy. A comparative high resolution endostructural assessment.

The penecontemporaneous Middle Pleistocene sites of Fontana Ranuccio (Latium) and Visogliano (Friuli-Venezia Giulia), set c. 450 km apart in central and northeastern Italy, respectively, have yielded some among the oldest human fossil remains testifying to a peopling phase of the Italian Peninsula broadly during the glacial MIS 12, a stage associated with one among the harshest climatic conditions in the Northern hemisphere during the entire Quaternary period. Together with the large samples from Atapuerca Sima de los Huesos, Spain, and Caune de l'Arago at Tautavel, France, the remains from Fontana Ranuccio and Visogliano are among the few mid-Middle Pleistocene dental assemblages from Western Europe available for investigating the presence of an early Neanderthal signature in their inner structure. We applied two- three-dimensional techniques of virtual imaging and geometric morphometrics to the high-resolution X-ray microtomography record of the dental remains from these two Italian sites and compared the results to the evidence from a selected number of Pleistocene and extant human specimens/samples from Europe and North Africa. Depending on their preservation quality and on the degree of occlusal wear, we comparatively assessed: (i) the crown enamel and radicular dentine thickness topographic variation of a uniquely represented lower incisor; (ii) the lateral crown tissue proportions of premolars and molars; (iii) the enamel-dentine junction, and (iv) the pulp cavity morphology of all available specimens. Our analyses reveal in both samples a Neanderthal-like inner structural signal, for some aspects also resembling the condition shown by the contemporary assemblage from Atapuerca SH, and clearly distinct from the recent human figures. This study provides additional evidence indicating that an overall Neanderthal morphological dental template was preconfigured in Western Europe at least 430 to 450 ka ago.

The origin of squamates revealed by a Middle Triassic lizard from the Italian Alps.

Modern squamates (lizards, snakes and amphisbaenians) are the world's most diverse group of tetrapods along with birds 1 and have a long evolutionary history, with the oldest known fossils dating from the Middle Jurassic period-168 million years ago2-4. The evolutionary origin of squamates is contentious because of several issues: (1) a fossil gap of approximately 70 million years exists between the oldest known fossils and their estimated origin5-7; (2) limited sampling of squamates in reptile phylogenies; and (3) conflicts between morphological and molecular hypotheses regarding the origin of crown squamates6,8,9. Here we shed light on these problems by using high-resolution microfocus X-ray computed tomography data from the articulated fossil reptile Megachirella wachtleri (Middle Triassic period, Italian Alps 10 ). We also present a phylogenetic dataset, combining fossils and extant taxa, and morphological and molecular data. We analysed this dataset under different optimality criteria to assess diapsid reptile relationships and the origins of squamates. Our results re-shape the diapsid phylogeny and present evidence that M. wachtleri is the oldest known stem squamate. Megachirella is 75 million years older than the previously known oldest squamate fossils, partially filling the fossil gap in the origin of lizards, and indicates a more gradual acquisition of squamatan features in diapsid evolution than previously thought. For the first time, to our knowledge, morphological and molecular data are in agreement regarding early squamate evolution, with geckoes-and not iguanians-as the earliest crown clade squamates. Divergence time estimates using relaxed combined morphological and molecular clocks show that lepidosaurs and most other diapsids originated before the Permian/Triassic extinction event, indicating that the Triassic was a period of radiation, not origin, for several diapsid lineages.

Discovery of ancient Roman "highway" reveals geomorphic changes in karst environments during historic times.

Sinkholes are a well-known geologic hazard but their past occurrence, useful for subsidence risk prediction, is difficult to define, especially for ancient historic times. Consequently, our knowledge about Holocene carbonate landscapes is often limited. A multidisciplinary study of Trieste Karst (Italy), close to early Roman military fortifications, led to the identification of possible ancient road tracks, cut by at least one sinkhole. Electrical Resistivity Tomography through the sinkhole has suggested the presence of a cave below its bottom, possibly responsible of the sinkhole formation, while Ground Penetrating Radar has detected no tectonic disturbances underneath the tracks. Additionally, archaeological surveys led to the discovery of over 200 Roman shoe hobnails within or close to the investigated route. According to these data, the tracks are interpreted as the remains of a main Roman road, whose itinerary has been reconstructed for more than 4 km together with other elements of ancient landscape. Our results provide the first known evidence of a Roman main road swallowed by sinkholes and suggest that Holocene karst landscapes could be much different from what previously believed. In fact, sinkholes visible nowadays in the investigated region could have been flat areas filled by sediments up to the Roman time.