The Impact of Cardiovascular Risk Factors on the Incidence, Severity, and Prognosis of Sudden Sensorineural Hearing Loss (SSHL): A Systematic Review.

Sudden sensorineural hearing loss (SSHL) is believed to be mainly idiopathic since the cause is not usually identified. Several recent studies have examined the role of cardiovascular risk factors in this disease. The aim of this systematic literature review is to investigate the possible association between acquired and inherited cardiovascular risk factors and the incidence, severity, and prognosis of SSHL. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A search of the PubMed database for the period between February 2010 and January 2023 was performed in order to retrieve eligible articles. The analytic cohort included 24 studies. Overall, this systematic review includes a total of 61,060 patients that were encompassed in these studies. According to most studies, the prevalence of dyslipidaemia, diabetes, and ultrasound indices of atherosclerosis was significantly higher in SSHL patients compared to controls. On the other hand, obesity, hypertension, and smoking did not seem to influence the risk of SSHL. Most studies suggest the presence of a correlation between a high cardiovascular risk profile and the risk of developing SSHL. The theory of microvascular impairment in the development of SSHL is indirectly supported by the findings of this review.

Managing fluid balance and nutritional status in a short bowel syndrome patient awaiting intestinal transplant: a case report.

BACKGROUND: Despite being a long-term therapy for patients with short bowel syndrome (SBS), subcutaneous injections of teduglutide promote the regeneration of the gastrointestinal tract. Such cases are particularly concerning for patients with residual small bowel. METHODS: In this report, we present a case of an SBS patient with only 5 cm of remaining small bowel and a high-output duodenal stoma, who was treated with teduglutide. RESULTS: The initiation of teduglutide injections in our patient resulted in a reduction of stoma output, improvement in the patient's nutritional status, regulation of fluid balance, and stabilization of their clinical condition. CONCLUSIONS: This case suggests that subcutaneous injections of teduglutide, when combined with appropriate nutritional care, can effectively treat high-output stomas, even in cases where the small bowel is nearly absent.

Skeletal defects and bone metabolism in Noonan, Costello and cardio-facio-cutaneous syndromes.

Noonan, Costello and Cardio-facio-cutaneous syndromes belong to a group of disorders named RASopathies due to their common pathogenetic origin that lies on the Ras/MAPK signaling pathway. Genetics has eased, at least in part, the distinction of these entities as they are presented with overlapping clinical features which, sometimes, become more pronounced with age. Distinctive face, cardiac and skeletal defects are among the primary abnormalities seen in these patients. Skeletal dysmorphisms range from mild to severe and may include anterior chest wall anomalies, scoliosis, kyphosis, short stature, hand anomalies, muscle weakness, osteopenia or/and osteoporosis. Patients usually have increased serum concentrations of bone resorption markers, while markers of bone formation are within normal range. The causative molecular defects encompass the members of the Ras/MAPK/ERK pathway and the adjacent cascades, important for the maintenance of normal bone homeostasis. It has been suggested that modulation of the expression of specific molecules involved in the processes of bone remodeling may affect the osteogenic fate decision, potentially, bringing out new pharmaceutical targets. Currently, the laboratory imprint of bone metabolism on the clinical picture of the affected individuals is not clear, maybe due to the rarity of these syndromes, the small number of the recruited patients and the methods used for the description of their clinical and biochemical profiles.

Anatomical Variations of the Sinonasal Area and Their Clinical Impact on Sinus Pathology: A Systematic Review

Abstract Introduction Anatomical variations of the nasal cavity and of the paranasal sinuses are frequently encountered and play an important role in dysfunctional drainage of sinuses. However, it is not clear in the literature whether they predispose to sinus pathology. Objectives The aim of the present review is to summarize the understanding of the association between anatomical variations of the sinonasal area and sinus pathology. Data Synthesis The present review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We performedathorough research on PubMed from October2004 until May 2020 byusing the search terms paranasal sinus anatomical variations and sinus disease, sinusitis, and mucosal disease. Thirty studies were eligible and were included in the analysis. Overall, the studies encompassed a total of 6,999 patients included in the present review. In many studies, it has been statistically established that certain anatomical variations increase the risk of sinus disease. On the other hand, the rest of the collected studies failed to show any statistically significant correlation between anatomical variants and sinus pathology. Conclusion The present study highlights the possible correlation between some anatomical variations of the sinonasal area and pathologies of the paranasal sinuses. Careful assessment and computed tomography (CT) in patients with chronic rhinosinusitis is needed, especially in those undergoing endoscopic surgery, to identify and treat anatomical variations in the paranasal sinuses that may be correlated with rhinosinusitis. Due to contradictory results in the literature, further research is needed to elucidate the effects of anatomical variants of the sinonasal area.

Anatomical Variations of the Sinonasal Area and Their Clinical Impact on Sinus Pathology: A Systematic Review.

Introduction Anatomical variations of the nasal cavity and of the paranasal sinuses are frequently encountered and play an important role in dysfunctional drainage of sinuses. However, it is not clear in the literature whether they predispose to sinus pathology. Objectives The aim of the present review is to summarize the understanding of the association between anatomical variations of the sinonasal area and sinus pathology. Data Synthesis The present review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We performed a thorough research on PubMed from October 2004 until May 2020 by using the search terms paranasal sinus anatomical variations and sinus disease , sinusitis , and mucosal disease . Thirty studies were eligible and were included in the analysis. Overall, the studies encompassed a total of 6,999 patients included in the present review. In many studies, it has been statistically established that certain anatomical variations increase the risk of sinus disease. On the other hand, the rest of the collected studies failed to show any statistically significant correlation between anatomical variants and sinus pathology. Conclusion The present study highlights the possible correlation between some anatomical variations of the sinonasal area and pathologies of the paranasal sinuses. Careful assessment and computed tomography (CT) in patients with chronic rhinosinusitis is needed, especially in those undergoing endoscopic surgery, to identify and treat anatomical variations in the paranasal sinuses that may be correlated with rhinosinusitis. Due to contradictory results in the literature, further research is needed to elucidate the effects of anatomical variants of the sinonasal area.

Molecular and clinical profile of patients referred as Noonan or Noonan-like syndrome in Greece: a cohort of 86 patients.

Noonan syndrome (NS) is an autosomal dominant disorder characterized by clinical and genetic heterogeneity. It belongs to a wider group of pathologies, known as Rasopathies, due to the implication of genes encoding components of the Ras/MAPK signalling pathway. Recording the genetic alterations across populations helps assessing specific features to specific genes which is essential for better disease's recognition, prognosis and monitoring. Herein, we report the clinical and molecular data of a Greek cohort comprising of 86 NS or NS-like patients admitted at a single tertiary Centre in Athens, Greece. The analysis was performed using Sanger and next-generation sequencing, comprising 14 different genes. The mutational rates of the confirmed NS-associated genes in the Greek NS population are as follows: PTPN11 32.5%; RIT1 5.8%; SOS1 4.7%; BRAF 1.2%; CBL 1.2%; KRAS 1.2%; MAP2K1 1.2%; RAF1 1.2%; SHOC2 1.2%, corresponding to 50% of positivity in total NS population. The genotype-phenotype analysis showed statistically significant differences in craniofacial dysmorphisms (p = 0.005) and pulmonary valve stenosis (PS) (p < 0.001) frequencies between patients harbouring a pathogenic variant and patients without pathogenic variant in any of the tested genes. Patients with at least a pathogenic variant had 6.71 times greater odds to develop PS compared to pathogenic variant-negative patients (OR = 6.71, 95%; CI = (2.61, 17.27)). PTPN11 positive patients showed higher frequency of epicanthal folds (p = 0.004), ptosis (p = 0.001) and coarseness (p = 0.001) and lower frequency of neurological findings (p = 0.006), compared to patients carrying pathogenic variants in other genes. CONCLUSION: Craniofacial dysmorphism and PS prevail among pathogenic variant positive compared to pathogenic variant negative NS and NS-like patients while neurological defects are less common in PTPN11-affected NS patients compared to patients harbouring pathogenic variants in other genes. The significant prevalence of the Ras/MAPK pathogenic variants (17.4%), other than PTPN11, in Greek NS patients, highlights the necessity of a wider spectrum of molecular diagnosis. WHAT IS KNOWN: • Noonan syndrome (NS) has been associated with pathogenic variants in molecules-components of the Ras/MAPK pathway. • Clinical and genetic description of NS patients worldwide helps establishing personalized monitoring. WHAT IS NEW: • NS and NS-like mutational rate in Greece reaches 50% with pathogenic variants identified mostly in PTPN11 (32.5%), RIT1 (6%) and SOS1 (4.7%) genes. • The risk for pulmonary stenosis increases 6.71-fold in NS patients with a pathogenic variant compared to patients without genetic alterations.

New insights into the neural network of the nongravid uterus.

The human uterus is exposed to epigenetic factors during maturation, which might influence its neural network. The mesh muscle is formed from the circular muscle during development and maturation, and it coordinates the longitudinal and circular muscle function. The uterus has an autonomous neural network with contractility and propagation patterns that determine its reproductive potential and health during pregnancy and delivery. Emerging knowledge on the uterine neural network and mesh muscle ultrastructure contributes to new ideas and solutions on the role of intrauterine pressure and distending fluid intravasation during hysteroscopy, and even allows for improving the operative techniques of myomectomy, adenoma cytoreductive surgery and metroplasty. Good health and well-being start from the in utero stage of life. Prenatal and antenatal care are of paramount importance to minimize the risks of malnutrition and pollutants, and foster a healthy uterus. Research regarding the neural network, function and contractility of the nongravid uterus is a new chapter in gynecology that provides significant information for a better understanding and early diagnosis and treatment of uterine pathologies and early pregnancy support.

Methylprednisolone stimulated gene expression (GILZ, MCL-1) and basal cortisol levels in multiple sclerosis patients in relapse are associated with clinical response.

Glucocorticoids (GCs) are the main treatment of relapse in multiple sclerosis (MS). Decreased sensitivity to GCs in MS patients has been associated with lack of the suppressive effect of GCs on inflammatory molecules as well as increased resistance to apoptosis. We investigated GC-sensitivity by measuring the effect of intravenous methylprednisolone (IVMP) treatment on transactivation of anti-inflammatory and apoptotic genes (GILZ, MCL-1 and NOXA respectively), in accordance to clinical outcome. Thirty nine MS patients were studied: 15 with clinically isolated syndrome (CIS), 12 with relapsing remitting (RRMS) and 12 with secondary progressive (SPMS) under relapse. Patients underwent treatment with IVMP for 5 days. Blood was drawn before IVMP treatment on day 1 and 1 h after IVMP treatment on days 1 and 5. GIlZ, MCL-1 and NOXA were determined by qPCR. The Expanded Disability Status was evaluated and patients were divided according to their clinical response to IVMP. GILZ and MCL-1 gene expression were significantly higher following first IVMP treatment in responders, compared to non-responders. Furthermore, serum basal cortisol and 1,25-OH Vitamin D levels were significantly higher in clinical-responders as compared to non-clinical responders. Our findings suggest that the differential GILZ and MCL-1 gene expression between clinical-responders and non-clinical responders may implicate the importance of GILZ and MCL-1 as possible markers for predicting glucocorticoid sensitivity and response to GC-therapy in MS patients following first IVMP injection.

Study of Xbal and Pvull polymorphisms of estrogen receptor alpha (ERα) gene in girls with precocious/early puberty.

PURPOSE: Studies examining association of estrogen receptor alpha (ERα) polymorphisms with early puberty are scarce and results are controversial; data in Caucasian girls are lacking. Main objective was to determine association of Xbal and Pvull polymorphisms of ERα gene in Greek girls with precocious/early puberty METHODS: We studied 107 girls with idiopathic precocious/early puberty and 81 young women with pubertal maturation within normal age (controls). Pubertal stage, height SDS (HSDS), and BMI z-score were determined in patients. In controls, height was measured and menarcheal age was self-reported. All participants in the study were genotyped for XbaI and PvuII polymorphisms of the ERα gene. RESULTS: There was no significant difference in XbaI and PvuII polymorphisms between patients and controls. Homozygous, xx and pp, girls had an earlier onset of puberty, although non-significant, than heterozygous or with no polymorphisms p = 0.9; in girls with pubertal onset <7 years, the association tended to become significant, p = 0.09. Girls with xxpp genotype were significantly taller, HSDS 1.63, p = 0.014. In controls, homozygosity for Xbal (xx) and PvuII (pp) was associated with significantly earlier menarche than in women with no polymorphism, p = 0.013 and p = 0.026, respectively, and xxpp genotype was associated with taller adult height, p = 0.017. CONCLUSION: XbaI and PvuII polymorphisms are not related to idiopathic precocious/early puberty. Early pubertal girls homozygous for both polymorphisms presented earlier onset of puberty, although statistically non-significant, and taller height than girls heterozygous or without these polymorphisms. Homozygosity for both polymorphisms is associated with earlier menarche and taller adult height.

Parietal aplasia and hypophosphatasia in a child harboring a novel mutation in RUNX2 and a likely pathogenic variant in TNSALP.

Cleidocranial dysplasia is a dominantly inherited skeletal dysplasia resulting from inherited or spontaneous mutations of Runt-related transcription factor 2 gene (RUNX2). It represents a clinical continuum typically characterized by wide calvarial sutures, clavicular hypoplasia and dental abnormalities. CDD has been rarely associated with skeletal and biochemical features that mimic hypophosphatasia. We report clinical, biochemical and molecular profile of a 3-year-old female with CCD, presented in utero with large cranial defects. She displayed severe parietal dysplasia, wide cranial sutures, clavicular abnormalities and biochemical features of hypophospatasia (HHP). She was preliminary diagnosed with benign perinatal HHP, harboring a likely pathogenic heterozygous TNSALP variant (p.Ser181Leu) inherited by the mother, who also displayed low levels of ALP. Asfotase alfa was introduced for a six-month-period with rather positive impact on cranial ossification. Nevertheless, focal skeletal disease (cranium and clavicles) and absence of clinical symptoms in the mother, carrier of the same genetic variant, posed diagnosis into question and further genetic analysis detected the novel spontaneous frameshift mutation c.1191delC (p.Phe398Leufs*86) in RUNX2 gene, establishing the CCD diagnosis. Although genotype-phenotype correlations are difficult, p.Phe398Leufs*86 appears to be associated with a severe cranial phenotype and absence of parietal bones, similarly to other adjacent frameshift/splicing mutations. The TNSALP variant (p.Ser181Leu) may contributed to patient's final phenotype, as well as to maternal low ALP levels. However, since low ALP levels have been also reported in few CCD patients with no alterations in TNSALP gene, studies to elucidate RUNX2 and TNSALP interactions could shed more light on differential diagnosis between CCD and HHP, CCD appropriate therapy and genetic counselling. ACCESSION NUMBER: (SUB8185506).

Anatomical Variations of the Nasal Cavities and Paranasal Sinuses: A Systematic Review.

The anatomy of the nasal cavities and paranasal sinuses is one of the most varied in the human body. The aim of this study is to review the prevalence of anatomical variations in the sinonasal area. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We performed on PubMed a literature search from October 2004 until May 2020. The search strategy included the following keywords: ('paranasal sinus' OR 'frontal sinus' OR 'maxillary sinus' AND ('anatomical variants' OR 'anomalies')). Fifty studies were eligible and included in the analysis. Overall, the studies encompassed a total of 18,118 patients included in this review. Most common anatomical variations include agger nasi cells, nasal septum deviation and concha bullosa. Other variations seen in this region are uncinate process variations, paradoxical middle turbinate, Haller, Onodi and supraorbital ethmoid cells, accessory ostia of maxillary sinus. Less common variations include any sinus aplasia, crista galli pneumatization and dehiscence of the optic or maxillary nerve, internal carotid artery and lamina papyracea. Anatomical variations of this region also differ among ethnic groups. This study highlights the amount, variability and significance of most anatomical variants reported in the literature in the last years. It is essential for the sinus surgeon to have a broad spectrum of knowledge not only of "the typical" anatomy but also all the possible anatomical variations. With modern imaging modalities, anatomical variations can be detected, and uneventful pitfalls might be prevented.

ß-Amyloid and mitochondrial-derived peptide-c are additive predictors of adverse outcome to high-on-treatment platelet reactivity in type 2 diabetics with revascularized coronary artery disease.

BACKGROUND AND AIMS: Increased ß-amyloid and decreased mitochondrial-derived peptide (MOTS-c), are reported in diabetes. We investigated their additive value to high on-clopidogrel platelet reactivity (HPR) for adverse outcome in type 2 diabetics after recent revascularization. PATIENTS AND METHODS: In 121 type II diabetics, treated with clopidogrel and aspirin, (93 males, mean age 67.2 years) we measured: (a) maximum platelet aggregation to adenosine diphosphate (ADP) by light transmission aggregometry (LTAmax), (b) malondialdehyde (MDA), as oxidative stress marker, (c) MOTS-c, (d) ß-amyloid blood levels. Cardiac death and acute coronary syndromes (MACE) were recorded during 2 years of follow-up. RESULTS: Out of 121 patients, 32 showed HPR (LTAmax > 48%,). At baseline, HPR was associated with ß-amyloid > 51 pg/ml (p = 0.006) after adjusting clinical variables, HbA1c, MOTS-c, MDA and medication. During follow-up, 22 patients suffered a MACE. HPR, ß-amyloid > 51 pg/ml and MOTS-c < 167 ng/ml were predictors of MACE (relative risk 3.1, 3.5 and 3.8 respectively, p < 0.05) after adjusting for confounders and medication. There was significant interaction between HPR and ß-amyloid or MOTS-c for the prediction of MACE (p < 0.05). Patients with HPR and ß-amyloid > 51 mg/dl or HPR and MOTS-c concentration < 167 ng/ml had a fourfold higher risk for MACE than patients without these predictors (relative risk 4.694 and 4.447 respectively p < 0.01). The above results were confirmed in an external validation cohort of 90 patients with diabetes and CAD. CONCLUSIONS: Increased ß-amyloid or low MOTS-c are additive predictors to high on-clopidogrel platelet reactivity for adverse outcome in diabetics with CAD during 2-years follow-up. Clinical Trial Registration-URL: https://www.clinicaltrials.gov. Unique identifier: NCT04027712.

Screening for TSC1 and TSC2 mutations using NGS in Greek children with tuberous sclerosis syndrome.

Tuberous Sclerosis Complex (TSC) is a rare neurocutaneous syndrome inherited by an autosomal dominant manner. The disorder is commonly manifested by the presence of multiple benign tumors located in numerous tissues, including the brain, heart, skin and kidneys. Seizures, autism, developmental and behavioral delay, as well as non-neurological phenotypic findings, are suggestive of TSC. The identification of one pathogenic mutation in either the TSC1 or TSC2 genes is considered to be an independent diagnostic criterion. In our study, seventeen Greek patients, 2yo on average, were analyzed for the presence of pathogenic germline mutations in the aforementioned loci by Next-Generation Sequencing. A TSC1/2 gene panel was designed for the molecular diagnosis of the disease. Patients underwent initial diagnosis based on their clinical symptoms, most frequently involving the presence of skin lesions and/or epilepsy. Only one case was familial. Sixteen different genetic alterations were identified in TSC1 and TSC2 genes in fifteen patients, giving a 88% detection rate by employing NGS technology. Overall, most pathogenic mutations (11/15) identified were located in the TSC2 gene with exon 41 being the most frequent. With respect to genotype-phenotype association, no patient TSC1 (+) developed SEGA or renal cysts. No significant differences were observed between different types of TSC2 mutations and any clinical feature. Sequencing also revealed 18 different SNPs across the TSC1 and 20 across the TSC2 genes. This is the first registry of the genetic profile of TSC patients in Greece using a custom-made gene panel as molecular diagnostic tool.

Wiskott-Aldrich Syndrome Misdiagnosed as Immune Thrombocytopenic Purpura: A Case Report.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency characterized by various clinical phenotypes. We report the case of a 3-year-old immigrant boy presenting with persistent infant-onset thrombocytopenia treated for refractory immune thrombocytopenic purpura. Sequence analysis confirmed the diagnosis of WAS. The patient responded neither to IV infusions of immunoglobulin (Ig) nor a thrombopoietin receptor agonist and is currently planned for stem cell transplantation. Raised awareness is thus vital of this potentially misdiagnosed and lethal disorder. The diagnosis of WAS should be considered in all males with infant-onset immune thrombocytopenic purpura-like features, especially, if mean platelet volume is decreased (<7 fL) and good increment to platelet transfusions are evident.

MTP Gene Variants and Response to Lomitapide in Patients with Homozygous Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder, which leads to premature cardiovascular diseases. Microsomal triglyceride transport protein (MTP) inhibitors, such as lomitapide, offer a new therapeutic approach for treating these patients. We evaluated the lipid lowering (LL) efficacy of lomitapide according to several gene variants in MTP. Four clinically and/or molecularly defined HoFH patients were treated with lomitapide in addition to conventional high intensity LL therapy and regular lipoprotein apheresis. Two patients responded to the therapy, with a significant reduction of LDL cholesterol (LDL-C＞50%, hyper-responders). Sequencing of all exonic and intronic flanking regions of the MTP gene in all patients revealed 36 different variants. The hyper-responders to lomitapide shared six common variants: rs17533489, rs79194015, rs745075, rs41275715, rs1491246, and rs17533517, which were not seen in hypo-responders (reduction in LDL-C＜50%). We suggest that in HoFH variants in the MTP gene may impact on the therapeutic response to lomitapide, but this requires further investigation.

The recent progress in RSV vaccine technology.

The most effective way to control RSV infection would be the development of an expedient and safe vaccine. Subunit vaccines, live attenuated RSV vaccines, plasmid DNA vaccines have been tested either in human or in mouse models without reaching the ultimate goal of efficacy and safety, at least in humans. Viruses such as adenovirus, sendai virus, measles virus were also used as vectors for the generation of RSV vaccines with promising results in animal models. Recent patents describe new techniques for the generation of candidate vaccines. These patents include virus like particles as vaccine platforms, recombinant RSVs or modified RSV F protein as component of the vaccine. Despite the number of the candidate vaccines, the new RSV vaccines should overcome many obstacles before being established as effective vaccines for the control of RSV infections especially for the young infants who are more susceptible to the virus.

Therapeutic approach to Gradenigo's syndrome: a case report.

INTRODUCTION: Traditional management of Gradenigo's syndrome requires aggressive and radical surgery without any attempt to preserve hearing. Recent reports, however, describe a successful outcome after conservative surgical intervention without labyrinthectomy. A similar outcome has also been reported in patients who were only prescribed with antibiotics and did not undergo myringotomy. CASE PRESENTATION: We report the case of a 24-year-old Caucasian Greek woman with Gradenigo's syndrome who was treated by draining her petrous apex via an infralabyrithine approach between her posterior semicircular canal and the jugular bulb. Her inner ear was not sacrificed during the procedure. She presented pre-operatively with ipsilateral conductive hearing loss, which recovered completely four weeks after the surgery. CONCLUSIONS: Patients with Gradenigo's syndrome may be successfully treated with a combination of long-term permanent drainage and ventilation of the apical cells with corresponding hearing preservation. This can be achieved via a combination of transmastoid, infralabyrinthine and suprajugular approaches, if such would be allowed by the anatomy of the region or if there is enough space between the posterior semicircular canal and the jugular bulb.

Assessment of bone mineral density and markers of bone turnover in children under long-term oral anticoagulant therapy.

Oral anticoagulants antagonize vitamin K action and potentially impair the carboxylation of osteocalcin, a protein essential for normal bone matrix formation. In the present study, bone mineral density (BMD) and bone turnover markers were evaluated in 23 children under long-term oral anticoagulant therapy. BMD of the lumbar spine was assessed (Dual Energy x-ray Absorptiometry) and reported as z score. Osteoblast [bone alkaline phosphatase, osteocalcin (Gla-Oc), amino-terminal procollagen 1 extension peptide] and osteoclast (urinary calcium and deoxypyridinoline, serum cross-linked C telopeptide) activity markers were measured. Vitamin D {[25(OH) D], parathormone, calcium, phosphorus, magnesium} and vitamin K status [factors II, VII, IX, X, protein C, protein S, undercarboxylated osteocalcin (Glu-Oc)] were determined. The above parameters were also evaluated in 25 healthy controls. Patients presented with higher levels in Glu-Oc, parathormone, and bone resorption markers, lower levels in bone formation markers and 25(OH) D, whereas 52% of them showed signs of osteopenia (-1>BMD z score>-2.5). Statistical analysis demonstrated that anticoagulant therapy was an independent predictor of alterations in Glu-Oc, Gla-Oc, bone alkaline phosphatase, amino-terminal procollagen 1 extension peptide, and serum cross-linked C telopeptide levels. It seems that long-term use of coumarin derivatives may cause osteopenia in children with the risk of developing osteoporosis later in life.

A comprehensive phylogeny of beetles reveals the evolutionary origins of a superradiation.

Beetles represent almost one-fourth of all described species, and knowledge about their relationships and evolution adds to our understanding of biodiversity. We performed a comprehensive phylogenetic analysis of Coleoptera inferred from three genes and nearly 1900 species, representing more than 80% of the world's recognized beetle families. We defined basal relationships in the Polyphaga supergroup, which contains over 300,000 species, and established five families as the earliest branching lineages. By dating the phylogeny, we found that the success of beetles is explained neither by exceptional net diversification rates nor by a predominant role of herbivory and the Cretaceous rise of angiosperms. Instead, the pre-Cretaceous origin of more than 100 present-day lineages suggests that beetle species richness is due to high survival of lineages and sustained diversification in a variety of niches.