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Primary questions regarding the foraging behaviour of the first hunter–gatherers who colonized the New World are how they found, procured and utilized high‐quality raw materials for manufacturing stone tools. In this paper, we present evidence from the late Pleistocene site of Cueva Bautista in the highlands of south‐western Bolivia, which demonstrates that a substantial portion of the recovered stone tool assemblage originated in Cerro Kaskio, a recently discovered obsidian source located 15 km south‐west of the site. In addition to describing the geological and geochronological setting, we provide the first geochemical characterization of the Cerro Kaskio source by means of instrumental neutron activation analysis and energy‐dispersive X‐ray fluorescence. Supported on the technological analysis and archaeometric sourcing of the obsidian lithics found in Cueva Bautista, we discuss the nature of the procurement strategies practised by the earliest mobile hunter–gatherers who explored and colonized the Andean highlands. We conclude that opportunistic lithic resource procurement was probably an important component of the first foraging societies that explored the highland Andes. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 ( NF1) has long been considered a well-defined, recognizable monogenic disorder, with neurofibromas constituting a pathognomonic sign. This dogma has been challenged by recent descriptions of patients with enlarged nerves or paraspinal tumors, suggesting that neurogenic tumors and hypertrophic neuropathy may be a complication of Noonan syndrome with multiple lentigines (NSML) or RASopathy phenotype. We describe a 15-year-old boy, whose mother previously received clinical diagnosis of NF1 due to presence of bilateral cervical and lumbar spinal lesions resembling plexiform neurofibromas and features suggestive of NS. NF1 molecular analysis was negative in the mother. The boy presented with Noonan features, multiple lentigines and pectus excavatum. Next-generation sequencing analysis of all RASopathy genes identified p. Ser548Arg missense mutation in SOS1 in the boy, confirmed in his mother. Brain and spinal magnetic resonance imaging scans were negative in the boy. No heart involvement or deafness was observed in proband or mother. This is the first report of a SOS1 mutation associated with hypertrophic neuropathy resembling plexiform neurofibromas, a rare complication in Noonan phenotypes with mutations in RASopathy genes. Our results highlight the overlap between RASopathies, suggesting that NF1 diagnostic criteria need rethinking. Genetic analysis of RASopathy genes should be considered when diagnosis is uncertain. [ABSTRACT FROM AUTHOR]

The article discusses a cohort study conducted to better understand the comorbidity and multimorbidity patterns in older patients with haemophilia, in order to avoid multiple medications that may increase bleeding. According to the author, haemophiliacs had more comorbidities than normal people but had less cardiovascular risk factors including hypertension, hypercholesterolaemia and overweight.

Objectives We assessed whether changes in community viral load ( CVL) over time were associated with the rate of new HIV diagnoses ( NDs). Methods HIV-1-positive individuals referred to our institute and permanently residing in our province were considered for inclusion in the study. A total of 861 HIV-infected adults with at least one HIV RNA measurement (12 530 measurements in total) between 2008 and 2014 were included. Viraemia copy-years were calculated from all HIV RNA values for each patient using the trapezoidal rule; multiple CVL indicators were considered. Total NDs and recent infections (< 1 year) were analysed separately. The association between NDs and CVL was tested by means of mixed Poisson models, with CVL as a fixed effect and year as a random effect. Results The incidence of NDs was 2.28 per 100 000 residents in 2008 and 2.52 per 100 000 residents in 2014. Total numbers of NDs and recent infections did not vary significantly over time ( P for trend 0.879 and 0.39, respectively). Mean HIV RNA decreased from 31 095.8 HIV-1 RNA copies/mL in 2008 to 21 231.5 copies/mL in 2014 ( P < 0.001); a downward trend was always observed regardless of the CVL indicator considered. Depending on the indicator, there were some differences in CVL by patient characteristics. The most substantial contributors to CVL appeared to be male individuals, men who have sex with men ( MSM), non-Italians, and untreated subjects (all P < 0.05). The relative risk of ND increased among Italians and MSM with an increasing proportion of subjects having an undetectable HIV RNA, and decreased in the same population with increasing levels of CVL. Conclusions In our setting, CVL represented a good marker of access to care and treatment; however, reduced CVL did not coincide with a reduction in the rate of NDs. [ABSTRACT FROM AUTHOR]

This paper presents the findings arising from neutron activation analysis (NAA) of northern Chilean domestic ceramic samples from Caleta Vitor (n = 38) and clay samples (n = 15) from nearby valley, coast and highland contexts. This study presents the first NAA data set of ceramics spanning a temporal period of 1500 years (c.2000 to c.476 bp) from the Vitor Valley as well as the first attempt to use NAA to characterize potential clay sources in the region. On the basis of this study, we argue that the majority of domestic ceramics from Caleta Vitor share compositional similarities with clay samples collected from nearby valleys, allowing us to infer that the Caleta Vitor populations primarily procured their clay for domestic ceramics from local sources throughout a 1500-year period. Thus, despite the fact that there were inter-regional interactions during this period that included the influence of powerful Andean polities, it would appear that domestic ceramics continued to be produced locally, and by implication it can be argued that such interactions did not substantially affect this sphere of material culture production. Further, the apparent continuities in domestic ceramic production allow us to reflect on local decision-making processes throughout the cultural phases considered in this research. [ABSTRACT FROM AUTHOR]

Primary autosomal recessive microcephaly ( MCPH) is a developmental disorder characterized by prenatal onset of abnormal brain growth. MCPH occurs both alone and as part of a broad range of neurodevelopmental syndromes with or without cortical malformations and growth retardation. Here we report a consanguineous Moroccan family with two siblings affected by severe primary microcephaly, failure to thrive, congenital dermatitis and severe developmental delay. Brain magnetic resonance imaging showed lissencephaly of frontal lobes and periventricular heterotopia of the gray matter. We performed both Comparative Genomic Hybridization array and whole exome sequencing ( WES) analyses of the kindred. No quantitative defects were detected. However, WES identified a new homozygous missense variation in the penultimate nucleotide of exon 23 of RTTN gene (c. 2953A>G; pArg985Gly). cDNA sequencing revealed two abnormal spliced products, one lacking only exon 23 and the other lacking exons 22 and 23 (out-of-frame). RTTN is a protein involved in cilia structure and function. Homozygous mutations in RTTN gene have been described in bilateral diffuse isolated polymicrogyria and, more recently, in microcephalic primordial dwarfism ( PD). We found a novel homozygous mutation in RTTN associated with microcephalic PD as well as complex brain malformations and congenital dermatitis, thus expanding the phenotypic spectrum of both RTTN-associated diseases and ciliary dysfunction. [ABSTRACT FROM AUTHOR]

Bleeding phenotype in factor XI (FXI)-deficient patients is variable, and not related to baseline FXI:Act. Aims of our study were to describe the characteristics and the management of surgery and deliveries in FXI-deficient patients, and to investigate the relationship between the haemorrhagic phenotype and the baseline FXI:Act. Ninety-five patients were diagnosed and followed in our centre for a median follow-up of 0.9 years (0.1-36.2); median FXI:Act of all patients: 38% (0.5-69%). Fifty-six patients (59%) experienced bleeding episodes not surgery-related. Prior to diagnosis, 64 patients underwent 132 surgeries, and after diagnosis, 23 patients underwent 36 surgeries. Globally 26 of 168 surgeries were prophylactically treated, whereas 142 of 168 were not. As regard as surgeries performed without prophylaxis, 30 bleeding events (21%) occurred in 21 patients. At diagnosis, the median FXI:Act of bleeding and non-bleeding patients was 28% and 37%, respectively, without statistically significant difference between the two groups ( P = 0.26). As regard as surgeries performed under prophylactic treatment just 1 bleeding event occurred. Prior to diagnosis, 31 spontaneous deliveries (SD) and eight caesarian sections (CS) were performed without prophylaxis: 4 postpartum haemorrhages (10.5%) occurred (patients FXI:Act: 2%, 6%, 27%, 52.3% respectively). After diagnosis, four SD and five CS were performed with prophylaxis: no postpartum haemorrhages occurred. We confirm the wide bleeding phenotype variability in FXI-deficient patients, not related to the baseline FXI:Act levels. We highlight the importance of performing a correct diagnosis and follow-up, because a good management of prophylactic treatment, dramatically reduces the bleeding rate in case of surgery or deliveries. [ABSTRACT FROM AUTHOR]

Only very few pharmacokinetic (PK) studies comparing plasma derived FVIII (pd-FVIII) against recombinant FVIII ( rFVIII) concentrates are available. The studies have been generally conducted to demonstrate the bioequivalence of a new product with an old one. The switch from a plasma-derived FVIII (pd-FVIII) to a rFVIII concentrate is a good moment to enrol the patients in a comparative PK study. To achieve information on the PK characteristics of two different classes of FVIII concentrates, according to two different designs: a 10 FVIII concentration/time point design and a reduced 4-point design. A single dose PK comparing pd- and rFVIII concentrates has been performed in four Haemophilia Centres of Italy. Seventeen haemophilia A patients underwent two subsequent single dose PK studies at the moment of switching. Two-compartment- and Non-compartment-analysis did not show significant differences between the outcomes of PK of pd-FVIII and rFVIII, due to inter-patient variability. In vivo recovery (IVR) of rFVIII was slightly higher than that of pd-FVIII and rFVIII/pd-FVIII AUC ratio was 1.37 in 11/17 patients. The difference is only due to the initial distribution phase because after the first 10 h from the end of the infusion, the two decay curves are overlapping. The elimination half-life of the concentrates was very similar even though a complete bioequivalence was not demonstrated because of a higher AUC of rFVIII concentrates, limited to the distribution phase. The higher Cmax and IVR of rFVIII may be due to the presence of heterodimers activated forms of the recombinant molecules. [ABSTRACT FROM AUTHOR]

Summary. In patients with confirmed or suspected type 1 von Willebrand disease (VWD), adenotonsillectomy has been reported to be associated with a rate of peri-operative hemorrhage between 8 and 23%. Desmopressin acetate (DDAVP, 1-deamino 8-D arginine- vasopressin) is the treatment of choice for type 1 patients with baseline von Willebrand factor levels of 10 IU/dL or greater. DDAVP is generally well tolerated; however, severe hyponatremia and seizures have been reported in young children less than 2 years of age, limiting its use in this age group. Antifibrinolytic therapy plays an important adjunctive role in the effective treatment of mucocutaneous bleeding, particularly in the oropharynx where the salivary concentration of fibrinolytic enzymes is high. During the past 10 years, we treated 6 pediatric patients with mild/moderate type 1 VWD undergoing an adenotonsillar procedure at our institution with the same hemostatic regimen consisting of one single dose of DDAVP and an extended use of EACA. In this small case series, the above mentioned prophylactic treatment regimen was both well tolerated and efficacious in controlling hemorrhage. Furthermore, DDAVP-related complications were avoided in a pediatric population with a higher risk of developing them. [ABSTRACT FROM AUTHOR]

Summary. Severe factor XI (sFXI) deficiency is a rare bleeding disorder (RBD). FXI replacement is most often required for surgical hemostasis. Plasma, the sole US treatment option, is often complicated by life-threatening allergic reactions. In such circumstances, the FDA offers a mechanism for institution-industry collaboration to facilitate limited use of replacement products licensed abroad. A 58 years old man with sFXI deficiency, required hip replacement. In the past, he received prophylactic plasma for thyroidectomy and experienced a severe allergic reaction. A single use institutional IND FDA application was initiated in collaboration with LFB (Les Ulis, France) to access Hemoleven®, a plasma-derived FXI concentrate. The application required an investigator-initiated IRB-approved protocol for treatment and safety/efficacy monitoring that included: preoperative thrombophilia, FXI inhibitor and pharmacokinetic (PK) evaluations; peri- postoperative administration of ≤ 4 doses of 10-15 U/kg Hemoleven®; DIC monitoring; postoperative thromboprophylaxis; observation for product efficacy and potential complications. PK study demonstrated the expected 1.8% FXI recovery per U/kg with half-life of 62 hours. Mild D-Dimer elevation was noted 6-9 hours post-infusion. The initial dose (15U/kg) was administered 15 hours before surgery; subsequently, 3 doses (10U/kg) were infused every 72 hours. Hemostasis was excellent. No complications were observed. Collaboration allowed for successful patient access to Hemoleven® with excellent PK, safety, and efficacy. This case underscores the need for additional efforts to ensure safe and effective licensed replacement therapies for RBD patients. [ABSTRACT FROM AUTHOR]

Platelet transfusions, main therapy of Glanzmann Thromboasthenia (GT), can induce an allo-immunization against human leucocyte antigen and integrin αIIbβ3. We have investigated in our GT patients the rate of allo-immunization and of refractoriness to platelet transfusions. From 1975 until December 2005, we have followed 17 GT patients: 14 type 1, 3 variant type; nine females, eight males; median age at diagnosis 9.8 years (range 1–44.5); median age at the time of the study 35.5 years (range 23.6–68.5). In our patients, 121 bleeding episodes occurred (24 severe, 37 moderate, and 60 mild). Ten major and 22 minor surgical procedures have been performed. Two spontaneous deliveries and three caesarian sections with five live births were performed; moreover, one late foetal loss occurred, and one voluntary abortion was performed. Sixteen of 17 patients have been transfused at least once in life with platelets and/or red blood cells (RBC). All transfused patients have been investigated for the presence of anti-HLA and anti-integrin αIIbβ3 allo-antibodies. The positiveness of allo-antibodies has been demonstrated in 4/16 transfused patients (25%): isolated for anti-HLA in two; isolated for anti-integrin αIIbβ3 in one; and combined in one. In spite of the presence of allo-antibodies, platelet transfusions have always been effective and the haemostasis was not compromised. [ABSTRACT FROM AUTHOR]

Inhibitor development, because of its impact on patients’ morbidity and quality of life, is presently the most serious complication of haemophilia A treatment. The identification of several genetic and non-genetic risk factors may be used for the stratification of inhibitor risk and the definition of prevention strategies, particularly for patients with a high-risk genetic profile. The most extensively studied genetic factor is the type of F8 mutation, i.e. large deletions, nonsense mutations and inversions, which are associated with a higher risk of inhibitor development. This is the basis for the increased risk in patients with inhibitor family history; however, concordance family studies showed that factors other than F8 mutations are involved. An emerging role is investigated for polymorphisms of immune-regulatory genes that may increase (IL-10 and TNF-α) or reduce (CTLA-4) inhibitor risk and whose heterogeneous ethnic distribution may correlate to the higher inhibitor risk in non-caucasian patients. A role for FVIII haplotypes, particularly in black haemophiliacs, has been recently proposed. Recent studies report an increased inhibitor risk for initial intensive treatments (surgery or severe bleeds requiring high-dose and/or prolonged treatment, presence of danger signals), whereas regular prophylaxis (absence of danger signals) exerts a protective effect. A clinical score including the type of F8 mutation, family history of inhibitors and intensive treatment has been recently validated for predicting inhibitor risk. Because of the lack of useful data regarding the role of different types of FVIII concentrates, the stratification of risk in patients starting replacement treatment together with the careful evaluation of indications, doses and duration of treatment at first exposures and further efforts for overcoming barriers to early implementation of prophylaxis are encouraged, particularly for patients with a predictable high inhibitor risk. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Hereditary periodic fever syndromes (HPFs) develop as a result of uncontrolled activation of the inflammatory response, with a substantial contribution from interleukin-1beta or tumor necrosis factor alpha (TNFalpha). The HPFs include familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), TNF receptor-associated syndrome (TRAPS), and cryopyrinopathies, which are attributable to mutations of the MEFV, MVK, TNFRSF1A, and CIAS1 genes, respectively. However, in many patients, the mutated gene has not been determined; therefore, the condition in these patients with an HPF-like clinical picture is referred to as idiopathic periodic fever (IPF). The aim of this study was to assess involvement of X-linked inhibitor of apoptosis (XIAP), which plays a role in caspase inhibition and NF-kappaB signaling, both of which are processes that influence the development of inflammatory cells. METHODS: The XIAP gene (X-linked) was sequenced in 87 patients with IPF, 46 patients with HPF (13 with HIDS, 17 with TRAPS, and 16 with FMF), and 182 healthy control subjects. The expression of different alleles was evaluated by sequencing XIAP-specific complementary DNA mini-libraries and by real-time polymerase chain reaction and Western blot analyses. The functional effect of XIAP on caspase 9 activity was assessed by a fluorimetric assay, and cytokine secretion was evaluated by enzyme-linked immunosorbent assay. RESULTS: Sequencing disclosed a 1268A>C variation that caused a Q423P amino acid substitution. The frequency of 423Q-homozygous female patients and 423Q-hemizygous male patients was significantly higher in the IPF group than in the control group (69% versus 51%; odds ratio 2.17, 95% confidence interval 1.23-3.87, P = 0.007), whereas no significant difference was detected in the HPF group (59%) compared with controls. In primary lymphocytes and transfected cell lines, 423Q, as compared with 423P, was associated with higher XIAP protein and messenger RNA expression and lower caspase 9 activation. In lipopolysaccharide-activated monocytes, 423Q was associated with higher secretion of TNFalpha. CONCLUSION: These results suggest that 423Q is a predisposing factor for IPF development, possibly through its influence on monocyte function. [ABSTRACT FROM AUTHOR]

The use of ReFacto Laboratory Standard(RLS) in the one-stage clotting assay was proposed to reduce the underestimation of factor VIII (FVIII) plasma concentration after the infusion of ‘ReFacto®’ (B-domain deleted recombinant FVIII) in haemophilia A patients. Both ReFacto® and RLS were recently recalibrated, with the resulting materials containing approximately 20% more protein than the previous products. The aim of this study was to evaluate the performance of recalibrated RLS in the measurement of FVIII plasma concentration after the infusion of recalibrated ReFacto®. In 13 severe haemophilia A patients, 25 IU kg−1 of ReFacto® were injected intravenously. Venous blood samples were collected at 0.25, 0.5, 1, 3, 6, 9, 24, 28 and 32 h after the end of the infusion. Pharmacokinetic parameters were measured for the chromogenic and one-stage assays using International Plasma Standard (IPS) and RLS for both assays and assuming a non-compartmental drug disposition. Comparisons among assays and standards were performed usinganova. Pharmacokinetic estimates obtained with the chromogenic method were in agreement with those published in the literature. The one-stage method was confirmed to be more sensitive to lower plasma concentrations of FVIII. The measured maximum plasma concentration ( Cmax) was slightly higher than theoretical values and independent of the assay used. Cmax, area under the curve(AUC) and volume of distribution at steady state ( Vss) presented non-significant differences among the methods and standards used. The clinical utility of RLS in the evaluation of FVIII concentration after the infusion of ReFacto® seems to be reduced since recalibration of the product. [ABSTRACT FROM AUTHOR]

The development of recombinant FVIII (rFVIII) products, fuelled by the need for improved safety of treatment arising from the dramatic widespread blood-borne virus transmission in the 1970–1980s revolutionized the care of children with haemophilia A over the last two decades. The larger availability of perceived safer replacement therapy associated with the introduction of rFVIII products reassured the haemophilia community and there was a strong push in some Western countries to treat haemophilic children only with rFVIII. Moreover, this significantly contributed in the 1990s to the diffusion outside Northern Europe of prophylactic regimens implemented at an early age to prevent bleeding and the resultant joint damage (i.e. primary prophylaxis), together with the possibility of home treatment. These changes led to a substantial improvement of the quality of life of haemophilic children and of their families. The general agreement that primary prophylaxis represents the first-choice treatment for haemophilic children has been recently supported by two randomized controlled trials carried out with rFVIII products, providing evidence on the efficacy of early prophylaxis over on-demand treatment in preserving joint health in haemophilic children. However, the intensity and optimal modalities of implementation of prophylaxis in children, in particular with respect to the issue of the venous access, are still debated. A number of studies also supports the role of secondary prophylaxis in children, frequently used in countries in which primary prophylaxis was introduced more recently. With viral safety now less than an issue and with the more widespread use of prophylaxis able to prevent arthropathy, the most challenging complication of replacement therapy for children with haemophilia remains the risk of inhibitor development. Despite conflicting data, there is no evidence that the type of FVIII concentrate significantly influences the complex multifactorial process leading to anti-FVIII alloantibodies, whereas other treatment-related factors are likely to increase (early intensive treatments due to surgery or severe bleeds) or reduce (prophylaxis) the risk. Although the optimal regimen is still uncertain, eradication of anti-FVIII antibodies by immune tolerance induction (ITI), usually with the same product administered at inhibitor detection, should be the first-choice treatment for all patients with recent onset inhibitors. This issue applies particularly to children, as most patients undergo ITI at an early age, when inhibitors usually appear. The availability of a stable and long-lasting venous access represents a leading problem also in this setting. These and other topics concerning rFVIII treatment of haemophilic children were discussed in a meeting held in Rome on 27 February 2008 and are summarized in this report. [ABSTRACT FROM AUTHOR]

While primary prophylaxis is a well-established and recommended method of care delivery for children with severe haemophilia, fewer studies have documented the benefits of secondary prophylaxis started in adolescence or adulthood. To evaluate the role of secondary prophylaxis started in adolescent and adult severe haemophiliacs, a retrospective observational cohort study was conducted in 10 Italian Centres that investigated 84 haemophiliacs who had bled frequently and had thus switched from on-demand to prophylactic treatment during adolescence ( n = 30) or adulthood ( n = 54). The consumption of clotting factor concentrates, the orthopaedic and radiological scores, quality of life and disease-related morbidity were compared before and after starting secondary prophylaxis. Prophylaxis reduced the mean annual number of total and joint bleeds (35.8 vs. 4.2 and 32.4 vs. 3.3; P < 0.01) and of days lost from work/school (34.6 vs. 3.0, P < 0.01). A statistically significant reduction in the orthopaedic score was observed during prophylaxis in adolescents, but not in the whole cohort. Patients used more factor concentrates with corresponding higher costs on prophylaxis, but experienced a better quality of life. With respect to on-demand treatment, higher factor consumption and cost of secondary prophylaxis were balanced by marked clinical benefits and greater well-being in this cohort of adolescent/adult haemophiliacs. [ABSTRACT FROM AUTHOR]

Idiopathic thrombocytopenic purpura (ITP) is often diagnosed in the elderly (age ≥65 yr), where it generally presents as a chronic disease. The objective of the present study was to describe the natural history of ITP in the elderly and to evaluate the risk of bleeding and the possible occurrence of other pathologies. We retrospectively evaluated 178 ITP patients (82 men, 96 women; mean age: 72 yr) diagnosed between 1981 and 1998. Therapy was started at diagnosis or during follow-up, depending on the platelet count and/or bleeding events. Sixty-six out of one hundred and seventy-eight patients (37%) initiated therapy at diagnosis; whereas in 11 of the 112 untreated patients (9.8%) therapy was necessary during the follow-up. Low-dose of prednisone was the first-line treatment in all patients (mean daily dose of 0.43 mg/kg). Forty-nine (63.6%) of the seventy-seven treated patients showed a response, 14 of these (28.6%) suffered a relapse. Another pathology occurred in 19 of the 178 patients (10.7%). We conclude that low-dose prednisone is an appropriate initial treatment for elderly persons. We also stress that an adequate follow-up is advisable, given that isolated thrombocytopenia could in some cases be the first sign of another underlying pathology. [ABSTRACT FROM AUTHOR]

Factor VIII gene inversion of intron 1 has recently been reported to be the mutation responsible for haemophilia A in about 5% of severe cases. In our series of patients, which is made up of 77 Italian cases negative for intron 22 inversion, the mutation was found in three sporadic and in one familial patients, with an overall frequency of 5.2%. The carrier status of the patients’ female relatives was assessed by mutation analysis and showed that only two-thirds of cases could be considered truly sporadic. The germ-line origin of the mutation was investigated in the two sporadic families by haplotype analysis on genomic DNA of the patients’ maternal grandparents. These studies indicated that both mutation events had occurred in the germ cell lines of the patients’ healthy grandfather, suggesting that, as already demonstrated for the inversion of intron 22, the male germ cell line is more susceptible to the intrachromosome recombination which leads to the inversion of intron 1. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article regarding the effectiveness of rituximab treatment in postpartum acquired haemophilia A.

A letter to the editor is presented concerning remission of acquired von Willebrand syndrome.

Aim: we sought to test the inter-center reproducibility of 16 echo laboratories involved in the EACVI-Afib Echo Europe., Methods: This was done on a dedicated setting of 10 patients with sinus rhythm (SR) and 10 with persistent atrial fibrillation (AF), collected by the Principal Investigator. Images and loops of echo-exams were stored and made available for labs. The tested measurements included main echo-Doppler parameters, global longitudinal strain (GLS) and peak atrial longitudinal strain (PALS)., Results: Single measures interclass correlation coefficients (ICCs) of left ventricular mass and ejection fraction were suboptimal in both patients with SR and AF. Among diastolic parameters, ICCs of deceleration time were poor, in particular in AF (=.50). ICCs of left atrial size and function, besides optimal in AF, showed an acceptable despite moderate concordance in SR. ICC of GLS was .81 and .78 in SR and AF respectively. ICCs of PALS were suitable but lower in 4-chamber than in 2-chamber view. By depicting the boxplot of the 16 laboratories, GLS distribution was completely homogeneous in SR, whereas GLS of AF and PALS of both SR and AF presented a limited number of outliers. GLS mean ± SE of the 16 labs was 19.7 ± .36 (95% CI: 18.8-20.4) in SR and 16.5 ± .29 (95% CI: 15.9-17.1) in AF, whereas PALS mean ± SE was 43.8 ± .70 (95% CI: 42.3-45.3) and 10.2 ± .32 (95% CI: 9.5-10.9) respectively., Conclusion: While the utilization of some standard-echo variables should be discouraged in registries, the application of GLS and PALS could be largely promoted because their superior reproducibility, even in AF., (© 2023 The Authors. Echocardiography published by Wiley Periodicals LLC.)

Coronary flow reserve is the capacity of the coronary circulation to augment the blood flow in response an increase in myocardial metabolic demands and has a powerful prognostic significance in different clinical situations. It might assess with invasive and noninvasive technique. Transthoracic echocardiography Doppler is an emerging diagnostic technique, noninvasive, highly feasible, safe for patient and physician, without radiation, and able to detect macrovascular and microvascular anomalies in the coronary circulation. This review aims to describe the benefit and limits of echocardiographic assessment of coronary flow reserve., (© 2021 The Authors. Echocardiography published by Wiley Periodicals LLC.)

Up to 30% immune thrombocytopenia (ITP) patients achieve a sustained remission off-treatment (SROT) after discontinuation of thrombopoietin receptor agonists (TPO-RAs). Factors predictive of response are lacking. Patients aged ≥18 years with newly diagnosed or persistent ITP were treated with eltrombopag for 24 weeks. Primary end-point was SROT: the proportion of responders that were able to taper and discontinue eltrombopag maintaining the response during a period of observation (PO) of six months. Secondary end-points included the association between some immunological parameters (TPO serum levels, cytokines and lymphocyte subsets) and response. Fifty-one patients were evaluable. Primary end-point was achieved in 13/51 (25%) treated patients and 13/34 (38%) patients who started the tapering. Baseline TPO levels were not associated with response at week 24 nor with SROT. Higher baseline levels of IL-10, IL-4, TNF-α and osteopontin were negative factors predictive of response (P = 0·001, 0·008, 0·02 and 0·03 respectively). This study confirms that SROT is feasible for a proportion of ITP patients treated with eltrombopag. Some biological parameters were predictive of response., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Immune thrombocytopenia (ITP) is now well-known to reduce patients' health-related quality of life. However, data describing which signs and symptoms patients and physicians perceive as having the greatest impact are limited, as is understanding the full effects of ITP treatments. I-WISh (ITP World Impact Survey) was an exploratory, cross-sectional survey designed to establish the multifaceted impact of ITP, and its treatments, on patients' lives. It focused on perceptions of 1507 patients and 472 physicians from 13 countries regarding diagnostic pathway, frequency and severity of signs and symptoms, and treatment use. Twenty-two percent of patients experienced delayed diagnosis (caused by several factors), 73% of whom felt anxious as a result. Patients rated fatigue among the most frequent, severe symptom associated with ITP at diagnosis (58% most frequent; 73% most severe), although physicians assigned it lower priority (30%). Fatigue was one of the few symptoms persisting at survey completion (50% and 65%, respectively) and was the top symptom patients wanted resolved (46%). Participating physicians were experienced at treating ITP, thereby recognizing the need to limit corticosteroid use to newly-diagnosed or first-relapse patients and espoused increased use of thrombopoietin receptor agonists and anti-CD20 after relapse in patients with persistent/chronic disease. Patient and physicians were largely aligned on diagnosis, symptoms, and treatment use. I-WISh demonstrated that patients and physicians largely align on overall ITP symptom burden, with certain differences, for example, fatigue. Understanding the emotional and clinical toll of ITP on the patient will facilitate shared decision-management, setting and establishment of treatment goals and disease stage-appropriate treatment selection., (© 2020 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Immune thrombocytopenia (ITP) has a substantial, multifaceted impact on patients' health-related quality of life (HRQoL). Data describing which aspects of ITP physicians and patients perceive as having the greatest impact are limited. The ITP World Impact Survey (I-WISh) was a cross-sectional survey, including 1507 patients and 472 physicians, to establish the impact of ITP on HRQoL and productivity from patient and physician perspectives. Patients reported that ITP reduced their energy levels (85% of patients), capacity to exercise (77%), and limited their ability to perform daily tasks (75%). Eighty percent of physicians reported that ITP symptoms reduced patient HRQoL, with 66% reporting ITP-related fatigue substantially reduced patient HRQoL. Patients believed ITP had a substantial impact on emotional well-being (49%) and 63% worried their condition would worsen. Because of ITP, 49% of patients had already reduced, or seriously considered reducing their working hours, and 29% had considered terminating their employment. Thirty-six percent of patients employed at the time of the survey felt ITP decreased their work productivity, while 51% of patients with high/very high symptom burden reported that ITP affected their productivity. Note, I-WISh demonstrated substantive impact of ITP on patients' HRQoL both directly for patients and from the viewpoint of their physicians. Patients reported reduced energy levels, expressed fears their condition might worsen, and those who worked experienced reduced productivity. Physicians should be aware not only of platelet counts and bleeding but also the multi-dimensional impact of ITP on patients' lives as an integral component of disease management., (© 2020 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

The anticoagulant treatment for patients with hematologic malignancies is low molecular weight heparin (LMWH), which is considered the safest in this particular patients setting. Although direct oral anticoagulants (DOACs) have proven their efficacy and safety in patients with cancer, their use can be challenging in patients with hematologic malignancies due to the peculiarity of these neoplasms: high thrombotic risk, possible onset of thrombocytopenia and concomitant anticancer therapies. The aim of our study was to evaluate the efficacy and safety of DOACs for venous thromboembolism or atrial fibrillation in patients with hematologic malignancies and plasmatic DOACs level during anticancer therapy and at time of bleeding or thrombotic complications. We evaluated patients with hematologic malignancies treated with DOACs for venous thromboembolism or atrial fibrillation-therapy was maintained until the platelet count was ≥50 × 10 9 /L. In case of concomitant anticancer treatment and haemorrhagic or thrombotic events, we checked DOACs plasma levels (trough and peak). The patients evaluated were 135: 104/135 were on anticancer therapy. We did not observe either thrombotic or major haemorrhagic adverse events. Minor bleedings occurred in 10 patients and clinical relevant non-major (CRNM) in two patients. There was a statistically significant correlation between bleedings and myelodysplastic syndrome. DOACs resulted effective and safe in patients with hematologic malignancies. DOACs plasma level can be helpful in suggesting an early dose adjustment to prevent haemorrhagic adverse event in patients on concomitant anticancer therapy. Larger prospective studies including hematologic patients are warranted to confirm the safety and efficacy of DOACs., (© 2020 John Wiley & Sons Ltd.)

Introduction: Limited data are available regarding the evaluation of right ventricular (RV) performance in patients with aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI)., Objective: To evaluate the prevalence of RV dysfunction in patients with severe AS undergoing TAVI and long-term changes., Methods: Consecutive patients with severe AS undergoing TAVI from January 2016 to July 2017 were included. RV anatomical and functional parameters were analyzed: RV diameters, fractional area change, tricuspid annular plane systolic excursion (TAPSE), S-wave tissue Doppler of the tricuspid annulus (RV-S'TDI), global longitudinal strain (RV-GLS), and free wall strain (RV-FWS). Preprocedure and 1-year echo were analyzed., Results: Final population included 114 patients, mean age 83.63 ± 6.31 years, and 38.2% women. The prevalence of abnormal RV function was high, variable depending on the parameter that we analyzed, and it showed a significant reduction 1 year after TAVI implantation: 13.9% vs 6.8% (TAPSE < 17mm), P = .04; 26.3% vs 20% (fractional area change < 35%), P = .048; 41.2% vs 29.2% (RV-S'TDI < 9.5cm/s), P = .04; 48.7% vs 39.5% (RV-GLS > [20]), P = .049; and 48.7% vs 28.9% (RV-FWS > [20]), P = .03. Significant differences were noted between patients with low-flow (LF) vs normal-flow (NF) AS in RV dysfunction prevalence as well as in RV function recovery which is less evident in LF compared with NF patients., Conclusions: RV dysfunction is high among symptomatic AS patients undergoing TAVI, with variable prevalence depending on the echocardiographic parameter used., (© 2020 Wiley Periodicals, Inc.)

Background: Speckle tracking advancements make now available the analysis of layer-specific myocardial deformation. This study investigated multilayer longitudinal strain in Anderson-Fabry disease (AFD) patients at diagnosis., Methods: In a case-control study, 33 newly diagnosed, untreated AFD patients and 33 healthy age- and sex-matched healthy controls underwent a complete echocardiogram, including assessment of left ventricular (LV) transmural global longitudinal strain (GLS), subendocardial longitudinal strain (LSsubendo), subepicardial longitudinal strain (LSsubepi), and strain gradient (LSsubendo-LSsubpepi)., Results: Anderson-Fabry disease patients had similar blood pressure, heart rate, and ejection fraction but higher body mass index in comparison with controls. LV mass index, maximal, and relative wall thickness were significantly greater in AFD patients. LSsubendo was significantly higher than LSsubepi in both groups, but GLS (P < 0.0001), LSsubendo (P = 0.003), and particularly LSsubepi (21.4 ± 1.7 vs 18.8 ± 1.4%, P < 0.0001) were lower in AFD patients than in controls. Accordingly, LS gradient was higher in AFD patients (P = 0.003). Three patients symptomatic for dyspnoea presented a combination of LV hypertrophy and reduced LSsubepi. After adjusting for confounders by multivariate analyses, LV mass index or maximal wall thickness were independently and inversely associated with transmural GLS and LSsubepi, but not with LSsubendo in the AFD group. At receiver operating curve curves, LSsubepi best discriminated AFD and normals., Conclusions: In newly diagnosed, untreated AFD patients, layer-specific strain imaging highlights an impairment of LV longitudinal deformation, mainly involving subepicardial strain and causing increase in longitudinal strain myocardial gradient. These findings could be useful for identifying the mechanisms underlying early LV dysfunction in AFD patients., (© 2019 Wiley Periodicals, Inc.)

In the recent past, new ultrasound technologies, such as three-dimensional echocardiography and strain imaging echocardiography, raised up in clinical practice leading to a better assessment of cardiac morphology and performance. These tools may assess regional cardiac mechanics, detecting clinical and subclinical myocardial dysfunction in different settings such as ischemic heart disease, cardiomyopathies, and heart valve diseases. Interesting results derive from patients affected from hypertrophic cardiomyopathy (HCM). Particularly, the mentioned techniques are progressively redefining the role of echocardiography in diagnostic evaluation of HCM variants such as apical HCM, detection of the underlying conditions of increased wall thickness, assessment of subclinical myocardial impairment, and potentially refine risk stratification and prognosis. In this review, we describe the clinical uses of these methodologies and the perspective application in HCM patients., (© 2018 Wiley Periodicals, Inc.)

UBE2A deficiency is a syndromic condition of X-linked intellectual disability (ID) characterized by typical dysmorphic features that include synophrys, prominent supraorbital ridges, almond-shaped, and deep-set eyes, large ears, wide mouth, myxedematous appearance, hirsutism, micropenis, and onychodystrophy. To date, only seven familial UBE2A intragenic mutations and nine larger microdeletions encompassing UBE2A have been reported. Here, we describe two siblings with X-linked ID and typical clinical features of UBE2A deficiency caused by a novel hemizygous variant, identified by massively parallel sequencing of X-exome. The synonymous c.330G>A substitution in UBE2A modifies the last nucleotide of exon 5, causing the exon skipping and resulting in an out-of-frame transcript, likely encoding for a truncated form of the ubiquitin-conjugating enzyme E2 A. As confirmed by deep sequencing, the c.330G>A substitution in UBE2A was undetectable in genomic DNA from maternal blood cells, suggesting that the recurrent UBE2A deficiency observed in males of this family is caused by a maternal germline mosaicism., (© 2017 Wiley Periodicals, Inc.)

Moyamoya syndrome (MMS) is the most common cerebral vasculopathy among children with neurofibromatosis type 1 (NF1). In this study, we clinically, radiologically, and genetically examined a cohort that was not previously described, comprising European children with NF1 and MMS. The NF1 genotyping had been registered. This study included 18 children. The mean age was 2.93 ± 3.03 years at the NF1 diagnosis and 7.43 ± 4.27 years at the MMS diagnosis. In seven patients, MMS was diagnosed before or at the same time as NF1. Neuroimaging was performed in 10 patients due to clinical symptoms, including headache (n = 6), cerebral infarction (n = 2), and complex partial seizures (n = 2). The remaining eight children (47%) had MMS diagnosed incidentally. Sixteen children were characterized molecularly. The features of MMS were similar between patients with and without NF1. Additionally, the NF1 phenotype and genotype were similar between children with and without MMS. Interestingly, three children experienced tumors with malignant histology or behavior. The presence of two first cousins in our cohort suggested that there may be potential genetic factors, not linked to NF1, with an additional role respect of NF1 might play a role in MMS pathogenesis. The incidental diagnosis of MMS, and the observation that, among children with NF1, those with MMS were clinically indistinguishable from those without MMS, suggested that it might be worthwhile to add an angiographic sequence to brain MRIs requested for children with NF1. A MMS diagnosis may assist in properly addressing an NF1 diagnosis in very young children who do not fulfill diagnostic criteria., (© 2017 Wiley Periodicals, Inc.)

The main objective of this study was to compare health-related quality of life (HRQOL) of primary immune thrombocytopenia (pITP) patients with that of general population, overall, and by patient group (i.e., newly diagnosed, persistent, and chronic patients). Fatigue was also investigated as a secondary objective. Overall, 424 adult patients were enrolled in a multicenter observational study and the control group consisted of a representative sample from the general population. Propensity score matching plus further multivariate linear regression adjustment was used to compare HRQOL outcomes between pITP patients and general population. Mean age of patients was 54 years. Of those with HRQOL assessment, 99 patients (23.6%) were newly diagnosed, 53 (12.6%) were persistent, and 268 (63.8%) were chronic pITP patients. Comparison by patient group versus their respective peers in the general population revealed greater impairments in persistent pITP patients. Persistent pITP patients reported clinically meaningful impairments in physical functioning (-15; 95% CI -24.1 to -5.8; P = 0.002), social functioning (-15.3; 95% CI -25.5 to -5.1; P = 0.004), role physical (-28.4; 95% CI -43.1 to -13.7; P < 0.001), role emotional (-23.9; 95% CI -40.1 to -7.7; P = 0.004), and mental health scales (-11.3; 95% CI -21.2 to -1.4; P = 0.026) of the SF-36 questionnaire. Higher fatigue severity was associated with lower physical and mental HRQOL outcomes. Our findings suggest that the burden of the disease and treatment might depend on the disease phase and that persistent pITP patients are the most vulnerable subgroup. Am. J. Hematol. 91:995-1001, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

In patients with immune thrombocytopenia (ITP) refractory to corticosteroids and intravenous immunoglobulins (IVIG), splenectomy may result at higher risk of peri-operative complications and, for this reason, potentially contraindicated. The thrombopoietin receptor agonists (TPO-RAs) romiplostim and eltrombopag have shown high therapeutic activity in primary ITP, but data of efficacy and safety regarding their use in preparation for splenectomy are missing. Thirty-one adult patients, median age 50 years, with corticosteroids and/or IVIG refractory persistent and chronic ITP who were treated with TPO-RAs (romiplostim= 24; eltrombopag= 7) with the aim to increase platelet count and allow a safer execution of splenectomy were retrospectively evaluated. Twenty-four patients (77%) responded to the use of TPO-RAs with a median platelet count that increased from 11 × 10(9) /L before starting TPO-RAs to 114 × 10(9) /L pre-splenectomy, but a concomitant treatment with corticosteroids and/or IVIG was required in 19 patients. Twenty-nine patients underwent splenectomy while two patients who responded to TPO-RAs subsequently refused surgery. Post-splenectomy complications were characterized by two Grade 3 thrombotic events (1 portal vein thrombosis in the patient with previous history of HCV hepatitis and 1 pulmonary embolism), with a platelet count at the time of thrombosis of 260 and 167 × 10(9) /L, respectively and one Grade 3 infectious event. TPO-RAs may represent a therapeutic option to improve platelet count and reduce the risk of peri-operative complications in ITP candidates to splenectomy. An increased risk of post-splenectomy thromboembolic events cannot be ruled out and thromboprophylaxis with low-molecular weight heparin is generally recommended., (© 2016 Wiley Periodicals, Inc.)

Spleen enlargement, present in 10-20% of Essential Thrombocythemia (ET) patients at diagnosis, is a feature clinically easy to assess, confirmable by echography with a very low chance of misinterpretation. Nonetheless, the clinical and prognostic role of splenomegaly has been seldom evaluated. From 1979 to 2013, 1297 ET patients retrospectively collected in the database of the Lazio Cooperative Group and Bologna University Hospital were evaluable for spleen enlargement at diagnosis and included in the analysis. On the whole, spleen was enlarged in 172/1297 (13.0%) patients; in most cases (94.8%) splenomegaly was mild (≤5 cm). Patients with splenomegaly were younger, predominantly male, presented higher platelet count and JAK2V617F allele burden and had a lower incidence of concomitant cardiovascular risk factors. At least one thrombotic event during follow-up occurred in 97/1,125 (8.6%) patients without spleen enlargement compared to 27/172 (15.7%) patients with spleen enlargement (P = 0.003). Despite comparable use of cytoreductive/antiplatelet therapies in the two groups, the cumulative risk of thrombosis at 5 years was significantly higher in patients with baseline splenomegaly (9.8% versus 4.4% in patients without splenomegaly, P = 0.012). In multivariate analysis exploring risk factors for thrombosis, splenomegaly retained its negative prognostic role, together with previous thrombosis, leucocyte count and male gender. Baseline splenomegaly seems to be an independent additional risk factor for thrombosis in nonstrictly WHO-defined ET patients. This data could be useful in the real-life clinical management of these patients., (© 2016 Wiley Periodicals, Inc.)

Background: Gold standard for pulse-wave velocity (PWV) measurement is determination of the carotid-femoral cfPWV, reflecting regional aortic PWV. Nevertheless, in several echocardiographic laboratories, PWV is measured locally, most commonly at the common carotid artery (CCA). The aim of this study was to compare regional and local PWV values in healthy volunteers., Methods: The study population consisted of 22 prospectively enrolled healthy subjects, mean age 38.7 ± 11.1 years, 50% male. For regional PWV measurement, we evaluated cfPWV with a standard echo scanner. Regional PWV was measured at the CCA, with semiautomated dedicated software (MyLab, EsaOte, Italy)., Results: cfPWV and local PWV values correlated significantly with high Pearson correlation coefficient (0.62, P = 0.002). Mean regional cfPWV (9.29 ± 3.73 m/s), however, was significantly higher than mean local PWV value (5.96 ± 1.08 m/s) (P < 0.001). The difference persisted in the subgroup analysis using different cfPWV cutoff values (10, 9, 8, and 7 m/s), except for subjects with cfPWV ≤7 m/s, where regional and local PWV values were similar., Conclusion: In a group of healthy volunteers, regional and local PWV values showed a good correlation. However, regional PWV was significantly higher than local PWV. These findings should be carefully taken into account when using this technique in the clinical setting., (© 2015, Wiley Periodicals, Inc.)