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Galaxy clusters and surrounding medium, can be studied using X-ray bremsstrahlung emission and Sunyaev Zel’dovich (SZ) effect. Both astrophysical probes, sample the same environment with different parameters dependance. The SZ effect is relatively more sensitive in low density environments and thus is useful to study the filamentary structures of the cosmic web. In addition, observations of the matter distribution require high angular resolution in order to be able to map the matter distribution within and around galaxy clusters. MISTRAL is a camera working at 90GHz which, once coupled to the Sardinia Radio Telescope (SRT), can reach 12″ angular resolution over 4′ field of view (f.o.v.). The forecasted sensitivity drives to a Noise Equivalent Flux Density of ≃ 10–15 mJy √s and the mapping speed is MS = 380′2 mJy−2 h−1. MISTRAL was recently installed at the focus of the SRT and soon will take its first photons.

Broad and unexplored kinematic regions can be accessed at the LHC with fixed-target $pp$, $pA$ and $PbA$ collisions at $\sqrt{s_{\rm{NN}}}=72-115~\rm{GeV}$. The LHCb detector is a fully-instrumented forward spectrometer able to run in fixed-target mode, and currently hosts a target gas cell to take data in the upcoming Run 3. The LHCspin project aims at extending this physics program to Run 4 and to bring polarised physics at the LHC. An overview of the physics potential and a description of the LHCspin experimental setup are presented.

Pregnancy- associated melanoma (PAM) is reported between 2.8 and 5.0 per 100,000 pregnancies and approximately 35% of women with melanoma are of childbearing age. The diagnosis and treatment of melanoma during pregnancy needs a balance of risks and benefits for both maternal and fetal well-being. It is a type of malignancy, which requires a multidisciplinary approach, not limited to the obstetrician, but also to oncologists, neonatologists, pharmacists and psychologists. We present a case of a 36-year-old pregnant woman, who was admitted to our 3rd level Unit of Obstetrics and Gynecology (ARNAS Garibaldi Nesima) at 27 weeks and 2 days of gestation, with a diagnosis of suspected infection, then diagnosed as an advanced melanoma, which caused a premature delivery. A review of the literature of the last ten years from the international electronic bibliographic databases PUBMED was performed following the PRISMA Statement (Preferred Reporting Items for Systematic Reviews and Meta-Analysis). The search was limited to studies reported in the English language. We only included articles that followed our eligibility criteria, represented by: pregnant women with a diagnosis of advanced melanoma in pregnancy, with special reference to maternal, fetal or perinatal outcomes. The patient was affected by an 11 cm pregnancy-associated melanoma in the lower part back, with 2 hepatic metastasis. Due to the quickly development of general symptoms of sepsis it was decided to perform an urgent C-section. For the systematic review, we found 11 articles of advanced clinical melanoma, providing data from 12 patients. Maternal-perinatal outcomes is different depending on gestational age, general clinical condition, stage at diagnosis. Advanced melanoma is usually associated with a higher rate of termination of pregnancy, If the pregnancy continues, for the mother is associated with an higher risk of Cesarean section, sepsis, maternal progression of disease; for the baby is associated with prematurity, low birth weight, neonatal metastatic disease, neonatal morbidity and mortality. The future aim of clinicians should be the creation of an international database of the clinical cases of pregnancy-associated melanoma, to evaluate the same data, to improve treatments, to develop common protocols, and, finally, to improve the obstetric and perinatal outcomes. [ABSTRACT FROM AUTHOR]

An abstract of the article "Customised fetal growth curves in twin pregnancies: an Italian multicentre study" by T. Ghi and colleagues is presented.

Bariatric surgery as laparoscopic Roux-en-Y gastric bypass (LRYGB) is increasing throughout the world and women represent the majority (70%) of patients. Most of them are of reproductive age. As a consequence, surgeons will have to treat more and more pregnant patients with a history of LRYGB for surgical abdominal pain. Reported incidence of small bowel obstruction (SBO) varies from 1.5% to 3.5% after LRYGB including internal hernias, intussusception and volvulus. As two cases of maternal postoperative death have been reported in the literature, diagnosis and surgical treatment shouldn’t be delayed especially during pregnancy. To underline the necessity of a rapid diagnosis and surgical treatment, we reported two cases of severe SBO during pregnancy. [ABSTRACT FROM PUBLISHER]

Background and Purpose: Coma is an independent predictor of poor clinical outcomes in cerebral venous thrombosis (CVT). We aimed to describe the association of age, sex, and radiological characteristics of adult coma patients with CVT., Methods: We used data from the international, multicentre prospective observational BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis) study. Only positively associated variables with coma with <10% missing data in univariate analysis were considered for the multivariate logistic regression model., Results: Of the 596 adult patients with CVT (75.7% women), 53 (8.9%) patients suffered coma. Despite being a female-predominant disease, the prevalence of coma was higher among men than women (13.1% vs. 7.5%, p = 0.04). Transverse sinus thrombosis was least likely to be associated with coma (23.9% vs. 73.3%, p < 0.001). The prevalence of superior sagittal sinus thrombosis was higher among men than women in the coma sample (73.6% vs. 37.5%, p = 0.01). Men were significantly older than women, with a median (interquartile range) age of 51 (38.5-60) versus 40 (33-47) years in the coma (p = 0.04) and 44.5 (34-58) versus 37 (29-48) years in the non-coma sample (p < 0.001), respectively. Furthermore, an age- and superior sagittal sinus-adjusted multivariate logistic regression model found male sex (odds ratio = 1.8, 95% confidence interval [CI] = 1.0-3.4, p = 0.04) to be an independent predictor of coma in CVT, with an area under the receiver operating characteristic curve of 0.61 (95% CI = 0.52-0.68, p = 0.01)., Conclusions: Although CVT is a female-predominant disease, men were older and nearly twice as likely to suffer from coma than women., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Objectives: Gene-gene interactions likely contribute to the etiology of multifactorial diseases such as cerebral venous thrombosis (CVT) and could be one of the main sources of known missing heritability. We explored Factor XI ( F11 ) and ABO gene interactions among patients with CVT., Methods: Patients with CVT of European ancestry from the large Bio-Repository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) international collaboration were recruited. Codominant modelling was used to determine interactions between genome-wide identified F11 and ABO genes with CVT status., Results: We studied 882 patients with CVT and 1,205 ethnically matched control participants (age: 42 ± 15 vs 43 ± 12 years, p = 0.08: sex: 71% male vs 68% female, p = 0.09, respectively). Individuals heterozygous (AT) for the risk allele (T) at both loci (rs56810541/ F11 and rs8176645/ ABO ) had a 3.9 (95% CI 2.74-5.71, p = 2.75e-13) increase in risk of CVT. Individuals homozygous (TT) for the risk allele at both loci had a 13.9 (95% CI 7.64-26.17, p = 2.0e-15) increase in risk of CVT. The presence of a non-O blood group (A, B, AB) combined with TT/rs56810541/ F11 increased CVT risk by OR = 6.8 (95% CI 4.54-10.33, p = 2.00e15), compared with blood group-O combined with AA., Discussion: Interactions between factor XI and ABO genes increase risk of CVT by 4- to 14-fold.

High plasma levels of factor VIII (FVIII) and von Willebrand factor (VWF) have been indicated as independent risk factors for venous thromboembolism. However, the genetic factors responsible for their increase remain poorly known. In a large Italian family with high FVIII/VWF levels and thrombotic episodes, whole exome sequencing (WES) was performed on 12 family members to identify variants/genes involved in FVIII/VWF increase. Twenty variants spread over a 8300 Kb region on chromosome 5 were identified in 12 genes, including the low frequency rs13158382, located upstream of the MIR143/145 genes, which might affect miR-143/145 transcription or processing. The expression of miR-143/145 and VWF mRNA were evaluated in the peripheral blood mononuclear cells of six family members. Members with the variant (n = 3) showed lower levels of both miRNAs and higher levels of VWF mRNA compared to members without the variant (n = 3). An analysis of genetic and expression data from a larger cohort of individuals from the 1000 Genomes and GEUVADIS project confirmed a statistically significant reduction ( p -value = 0.023) in miR-143 in heterozygous (n = 35) compared to homozygous wild-type individuals (n = 386). This family-based study identified a new genetic variant potentially involved in VWF increase by affecting miR-143/145 expression.

Limited evidence exists on the effects of maternal dietary patterns on birth weight, and most studies conducted so far did not adjust their findings for gestational age and sex, leading to potentially biased conclusions. In the present study, we applied a novel method, namely the clustering on principal components, to derive dietary patterns among 667 pregnant women from Catania (Italy) and to evaluate the associations with birth weight for gestational age. We identified two clusters reflecting distinct dietary patterns: the first one was mainly characterized by plant-based foods (e.g., potatoes, cooked and raw vegetables, legumes, soup, fruits, nuts, rice, wholemeal bread), fish and white meat, eggs, butter and margarine, coffee and tea; the second one consisted mainly of junk foods (sweets, dips, salty snacks, and fries), pasta, white bread, milk, vegetable and olive oils. Regarding small gestational age births, the main predictors were employment status and primiparity, but not the adherence to dietary patterns. By contrast, women belonging to cluster 2 had higher odds of large for gestational age (LGA) births than those belonging to cluster 1 (OR = 2.213; 95%CI = 1.047-4.679; p = 0.038). Moreover, the odds of LGA increased by nearly 11% for each one-unit increase in pregestational BMI (OR = 1.107; 95%CI = 1.053-1.163; p < 0.001). To our knowledge, the present study is the first to highlight a relationship between adherence to an unhealthy dietary pattern and the likelihood of giving birth to a LGA newborn. This evidence adds to the current knowledge about the effects of diet on birth weight, which, however, remains limited and controversial.

Purpose: A retrospective study is presented to correlate the inter-judge consistency for the different psycho-perceptual parameters of the recently proposed Impression Noise Fluency Voicing (INFVo) perceptual rating scale for substitution voices, and the vocal function as perceived by the patient., Methods: The scale Voice-Related Quality of Life (V-RQoL) and the Self Evaluation of Communication Experiences After Laryngectomy scale (SECEL)-a self-evaluation questionnaire of communicative experience after laryngectomy surgery-were administered to 89 total laryngectomees, subdivided in four groups depending on their type of alaryngeal voice (i.e., tracheoesophageal and esophageal speakers, electro larynx users, voiceless patients), in order to evaluate the impact of the impairment of the phonatory function on the quality of life., Results: No significant differences exist among the various groups on their perception of QoL using subjective questionnaires, whereas the INFVo scale has proven to be a useful tool for the description and analysis of the psychoacoustic characteristics of the vocal signal and a reliable instrument to correctly classify the patients. It is also notable that the judgement of the patients on their own voice and those of the referees are highly significant., Conclusion: Although speech rehabilitation for the acquisition of a substitution voice offers a new way of communication for the laryngectomized patients, nonetheless, their QoL is not significantly related to the type of substitution voice. Therefore, improving the patient's adaptation to the new phonatory condition is mandatory.

Background: Cerebral venous thrombosis (CVT) is an uncommon cause of stroke in young adults. We aimed to determine the impact of age, gender and risk factors (including sex-specific) on CVT onset., Methods: We used data from the BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis), a multicentre multinational prospective observational study on CVT. Composite factors analysis (CFA) was performed to determine the impact on the age of CVT onset in males and females., Results: A total of 1309 CVT patients (75.3% females) aged ⩾18 years were recruited. The overall median (IQR-interquartile range) age for males and females was 46 (35-58) years and 37 (28-47) years ( p  < 0.001), respectively. However, the presence of antibiotic-requiring sepsis ( p  = 0.03, 95% CI 27-47 years) among males and gender-specific risk factors like pregnancy ( p  < 0.001, 95% CI 29-34 years), puerperium ( p  < 0.001, 95% CI 26-34 years) and oral contraceptive use ( p  < 0.001, 95% CI 33-36 years) were significantly associated with earlier onset of CVT among females. CFA demonstrated a significantly earlier onset of CVT in females, ~12 years younger, in those with multiple (⩾1) compared to '0' risk factors ( p  < 0.001, 95% CI 32-35 years)., Conclusions: Women suffer CVT 9 years earlier in comparison to men. Female patients with multiple (⩾1) risk factors suffer CVT ~12 years earlier compared to those with no identifiable risk factors., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© European Stroke Organisation 2023.)

Background: Factor V Leiden (FVL) and factor II c.∗97G>A (rs1799963) are genetic risk factors for venous thromboembolism. Their contribution to coronary artery disease (CAD) is less clear., Objectives: This study aimed to investigate the association between FVL, rs1799963, and premature CAD in Iranians., Methods: We performed a genetic case-control study of 944 cases and 1081 controls from the premature CAD Milano-Iran study, including patients aged 18-55 (female) and 18-45 years (male) who underwent coronary angiography at the Tehran Heart Centre (Iran) in 2004-2011. Cases had luminal stenosis ≥50% in at least 1 main coronary artery or branch. Controls were age- and sex-matched with no CAD history. FVL and rs1799963 were genotyped using TaqMan SNP genotyping assays. Association was tested by logistic regression adjusted for matching factors and ethnicity. Effect modification by sex and cardiovascular risk factors (metabolic [obesity, hypertension, hyperlipidemia, and diabetes], and smoking) was assessed., Results: The risk of premature CAD was increased by 50% in FVL carriers (adjusted odds ratio [adjOR] 1.54 [95% CI, 0.95-2.48]) and slightly reduced in rs1799963 carriers (adjOR 0.71 [95% CI, 0.40-1.27]). These effects were more pronounced in women than men (FVL, adjOR 1.66 vs 1.25; rs1799963, adjOR 0.60 vs 1.07). The risk of premature CAD was substantially increased in carriers of FVL with at least 1 metabolic risk factor compared with noncarriers without metabolic risk factors (adjOR 25.14 [95% CI, 12.51-50.52])., Conclusion: FVL but not FII rs1799963 was associated with an increased risk of CAD in young Iranians. This risk increased considerably when combined with metabolic cardiovascular risk factors., (© 2023 The Authors.)

A maternal diet, before and during pregnancy, plays a key role in ensuring maternal and newborn health. The COVID-19 pandemic, however, may have compromised dietary habits in the general population and in specific subgroups of individuals. Here, we evaluated the impact of COVID-19 on the diet of pregnant women, using data from two mother-child cohorts in Sicily (Italy). Dietary data were collected using a food frequency questionnaire and analyzed through the Mediterranean diet (MD) score and principal component analysis (PCA). The comparison of maternal dietary consumption before and during the COVID-19 pandemic showed differences in terms of vegetables (p < 0.001), fruit (p < 0.001), dairy products (p < 0.001), fish (p < 0.001), and legumes (p = 0.001). Accordingly, after adjusting for covariates, mothers enrolled during the pandemic were more likely to report low adherence to MD than those enrolled before (OR = 1.65; 95%CI = 1.12−2.42; p = 0.011). A similar result was obtained by analyzing the adherence to a prudent dietary pattern, derived through PCA and characterized by high intake of cooked and row vegetables, legumes, fruit, fish, and soup. Overall, these findings suggested that the COVID-19 pandemic may have influenced maternal diet during pregnancy. However, further efforts are needed to investigate the main causes and consequences of this change.

Introduction: Inhibitor development affects about 30% of patients with severe haemophilia A (HA) and results from different environmental and genetic risk factors. Previously, we identified the missense variant rs3754689 in the LCT gene linked with this predisposition. Since rs3754689 variant is benign and is located in a conserved haplotype region, we hypothesized that the association signal captured by this variant is located in coinherited, neighbouring genes., Aim: To identify novel genetic risk factors associated with inhibitor development in coding regions of R3HDM1, UBXN4, CXCR4, MCM6, DARS and miR128-1 genes., Methods: Targeted sequencing was performed in 246 severe HA patients (72 with and 174 without inhibitor): 181 previously and 65 newly enrolled., Results: Forty-one common and 152 rare variants passed the quality control. Logistic regression analysis of common variants identified rs3754689 and four additional variants (.011 < P < .047; FDR ranging .2-.38). Logistic regression analysis performed only in the 220 Italian patients showed similar results (.004 < P < .05; FDR ranging .12-.22). Three of these variants (rs3213892 and rs3816155 in the LCT intron 13 and rs961360 in the R3HDM1 intron10-exon11 junction) may affect the expression of UBXN4 and R3HDM1, respectively. Rare variants did not show association with inhibitor development. Identified variants were not replicated in the multi-ethnic SIPPET cohort of 230 severe HA patients., Conclusion: Due to the limited sample size that may be responsible of the high FDR values, we could not confirm with certainty the analysed association. Further evaluation of the expression levels of analysed genes will confirm or not their role in inhibitor development., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Background: Remote Ischemic Conditioning (RIC) has been proposed as a therapeutic intervention to circumvent the ischemia/reperfusion injury (IRI) that is inherent to organ transplantation. Using a porcine kidney transplant model, we aimed to decipher the subclinical molecular effects of a RIC regime, compared to non-RIC controls., Methods: Kidney pairs (n = 8 + 8) were extracted from brain dead donor pigs and transplanted in juvenile recipient pigs following a period of cold ischemia. One of the two kidney recipients in each pair was subjected to RIC prior to kidney graft reperfusion, while the other served as non-RIC control. We designed an integrative Omics strategy combining transcriptomics, proteomics, and phosphoproteomics to deduce molecular signatures in kidney tissue that could be attributed to RIC., Results: In kidney grafts taken out 10 h after transplantation we detected minimal molecular perturbations following RIC compared to non-RIC at the transcriptome level, which was mirrored at the proteome level. In particular, we noted that RIC resulted in suppression of tissue inflammatory profiles. Furthermore, an accumulation of muscle extracellular matrix assembly proteins in kidney tissues was detected at the protein level, which may be in response to muscle tissue damage and/or fibrosis. However, the majority of these protein changes did not reach significance (p < 0.05)., Conclusions: Our data identifies subtle molecular phenotypes in porcine kidneys following RIC, and this knowledge could potentially aid optimization of remote ischemic conditioning protocols in renal transplantation., (© 2022. The Author(s).)

Objective: Cerebral venous thrombosis (CVT) is an uncommon form of stroke affecting mostly young individuals. Although genetic factors are thought to play a role in this cerebrovascular condition, its genetic etiology is not well understood., Methods: A genome-wide association study was performed to identify genetic variants influencing susceptibility to CVT. A 2-stage genome-wide study was undertaken in 882 Europeans diagnosed with CVT and 1,205 ethnicity-matched control subjects divided into discovery and independent replication datasets., Results: In the overall case-control cohort, we identified highly significant associations with 37 single nucleotide polymorphisms (SNPs) within the 9q34.2 region. The strongest association was with rs8176645 (combined p = 9.15 × 10 -24 ; odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.76-2.31). The discovery set findings were validated across an independent European cohort. Genetic risk score for this 9q34.2 region increases CVT risk by a pooled estimate OR = 2.65 (95% CI = 2.21-3.20, p = 2.00 × 10 -16 ). SNPs within this region were in strong linkage disequilibrium (LD) with coding regions of the ABO gene. The ABO blood group was determined using allele combination of SNPs rs8176746 and rs8176645. Blood groups A, B, or AB, were at 2.85 times (95% CI = 2.32-3.52, p = 2.00 × 10 -16 ) increased risk of CVT compared with individuals with blood group O., Interpretation: We present the first chromosomal region to robustly associate with a genetic susceptibility to CVT. This region more than doubles the likelihood of CVT, a risk greater than any previously identified thrombophilia genetic risk marker. That the identified variant is in strong LD with the coding region of the ABO gene with differences in blood group prevalence provides important new insights into the pathophysiology of CVT. ANN NEUROL 2021;90:777-788., (© 2021 American Neurological Association.)

Background: We previously described the association between rare ADAMTS13 single nucleotide variants (SNVs) and deep vein thrombosis (DVT). Moreover, DVT patients with at least one rare ADAMTS13 SNV had a lower ADAMTS13 activity than non-carriers., Aims: To confirm ADAMTS13 variants association with DVT and reduced plasma ADAMTS13 activity levels in a larger population. To investigate the role of VWF and F8 variants., Methods: ADAMTS13, VWF and F8 were sequenced using next-generation sequencing in 594 Italian DVT patients and 571 controls. Genetic association testing was performed using logistic regression and gene-based tests. The association between rare ADAMTS13 variants and the respective plasmatic activity, available for 365 cases and 292 controls, was determined using linear regression. All analyses were age-, sex- adjusted., Results: We identified 48 low-frequency/common and 272 rare variants. Nine low-frequency/common variants had a P<0.05, but a false discovery rate between 0.06 and 0.24. Of them, 7 were found in ADAMTS13 (rs28641026, rs28503257, rs685523, rs3124768, rs3118667, rs739469, rs3124767; all protective) and 2 in VWF (rs1800382 [risk], rs7962217 [protective]). Rare ADAMTS13 variants were significantly associated with DVT using the burden, variable threshold (VT) and UNIQ (P<0.05), but not with C-ALPHA, SKAT and SKAT-O tests. Rare VWF and F8 variants were not associated with DVT. Carriers of rare ADAMTS13 variants had lower ADAMTS13 activity than non-carriers (ß -6.2, 95%CI -11,-1.5). This association was stronger for DVT patients than controls (ß -7.5, 95%CI -13.5,-1.5 vs. ß -2.9, 95%CI -10.4,4.5)., Conclusions: ADAMTS13 and VWF low-frequency/common variants mainly showed a protective effect, although their association with DVT was not confirmed. DVT patients carrying a rare ADAMTS13 variants had slightly reduced ADAMTS13 activity levels, but a higher DVT risk. Rare VWF and FVIII variants were not associated with DVT suggesting that other mechanisms are responsible for the high VWF and FVIII levels measured in DVT patients., Competing Interests: F. P. reports participation at educational meetings and advisory board of Sanofi, Sobi, Takeda and Roche. I. M. received honoraria for participating as a speaker at educational meetings organized by Instrumentation Laboratory and Sanofi-Genzyme. The other authors state that they have no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30-50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23); heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (β -3.34, 95%CI -6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy.

Introduction: A caesarean scar pregnancy is a complex iatrogenic pathology, which represents a consequence of a previous caesarean section. It increased in recent years due to parallel increase of cesarean sections., Material and Methods: We present a retrospective study on patients with caesarean scar pregnancy diagnosed in our department from June 2016 to June 2019. Stable women with an embryo (with or without cardiac activity) who accepted our experimental protocol were treated with single dose of methotrexate (50 mg administered locally intracavitary + 50 mg administered intramuscularly) and folinic acid (15 mg/day orally for 30 days). Clinically stable women with embryo (without cardiac activity) who decided to wait, were monitored by serial assays of b-hCG and clinical and ultrasonographic follow up. Women who were clinically unstable with embryo (without cardiac activity), were referred for urgent surgical treatment with dilation and curettage., Results: Caesarean scar pregnancy was diagnosed in sixteen women. Among these women, seven were treated according to our experimental protocol with methotrexate and folinic acid and only one had profuse bleeding, which required a laparotomic hysterectomy. Four women were treated urgently with dilatation and curettage. Five women chose to wait: they were monitored and all spontaneously had a miscarriage., Conclusions: In our preliminary study, we highlighted how our experimental protocol gave encouraging results in the first 10 weeks of caesarean scar pregnancy. However, caution is needed in patients with advanced gestational age, a gestational sac with large diameter, higher CRL and presence of embryonic cardiac activity., Competing Interests: The authors report no conflict of interest, (Copyright © 2020 Termedia.)

Background: General practitioners play an important role in diagnosis and ongoing management of pregnancies. Some GP registrars entering GP training may have had no post-graduate experience in obstetrics and gynaecology. GP registrars' involvement in antenatal care is under-researched., Aims: This study aimed to determine the prevalence and associations of Australian GP registrars' clinical consultations involving antenatal care., Materials and Methods: A cross-sectional analysis from the Registrar Clinical Encounters in Training (ReCEnT) cohort study. GP registrars record details of 60 consecutive consultations during each of three six-month training terms. Associations of managing pregnancy-related problems (compared to all other problems) were analysed using univariate and multivariable logistic regression. Independent variables included registrar, practice, patient, consultation and educational factors., Results: Antenatal care comprised 3277 (1.1%) of registrar problems/diagnoses. Consultations involving pregnancy-related problems were significantly associated with registrars being female, in term three, younger, and having post-graduate qualifications in obstetrics/gynaecology. Patients were significantly more likely to be from a non-English speaking background. Pregnancy-related problems/diagnoses were more likely to be seen in lower socioeconomic areas. Consultation factors significantly associated with a pregnancy-related problem/diagnosis included ordering imaging, ordering pathology, arranging referrals, and a longer duration of consultation. Registrars were less likely to prescribe medication or generate learning goals., Conclusions: GP registrars see fewer antenatal problems compared to established GPs. Male registrars, especially, have significantly less exposure to antenatal care, suggesting potential limitation of opportunity to gain skills and experience in antenatal care., (© 2019 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Primary platelet secretion defects constitute a heterogeneous group of functional defects characterized by reduced platelet granule secretion upon stimulation by different agonists. The clinical and laboratory heterogeneity of primary platelet secretion defects warrants a tailored approach. We performed a pilot study in order to develop DNA sequence analysis pipelines for gene discovery and to create a list of candidate causal genes for platelet secretion defects. Whole-exome sequencing analysis of 14 unrelated Italian patients with primary secretion defects and 16 controls was performed on Illumina HiSeq. Variant prioritization was carried out using two filtering approaches: identification of rare, potentially damaging variants in platelet candidate genes or by selecting singletons. To corroborate the results, exome sequencing was applied in a family in which platelet secretion defects and a bleeding diathesis were present. Platelet candidate gene analysis revealed gene defects in 10/14 patients, which included ADRA2A , ARHGAP1 , DIAPH1 , EXOC1 , FCGR2A , ITPR1 , LTBP1 , PTPN7 , PTPN12 , PRKACG , PRKCD , RAP1GAP , STXBP5L , and VWF The analysis of singletons identified additional gene defects in PLG and PHACTR2 in two other patients. The family analysis confirmed a missense variant p.D1144N in the STXBP5L gene and p.P83H in the KCNMB3 gene as potentially causal. In summary, exome sequencing revealed potential causal variants in 12 of 14 patients with primary platelet secretion defects, highlighting the limitations of the genomic approaches for causal gene identification in this heterogeneous clinical and laboratory phenotype., (Copyright© 2019 Ferrata Storti Foundation.)

Background: Cerebral vein thrombosis (CVT) is a rare, life-threatening disease affecting one adult per 100,000 per year. Genetic risk factors are deficiencies of the natural anticoagulant proteins antithrombin, protein C, protein S or single nucleotide polymorphisms such as factor V Leiden and prothrombin 20210A. In 20% of patients, the cause of CVT remains unknown., Aim: To identify novel genetic risk factors for CVT using targeted next-generation DNA sequencing (NGS)., Methods: We investigated 171 CVT patients and 298 healthy controls. Patients were selected using the following criteria: objective diagnosis of CVT, no active cancer. We performed targeted NGS analysis of the protein-coding regions of 734 candidate genes related to hemostasis and inflammation, 150 ancestry informative markers and 28 thrombosis-associated variants., Results: We identified 3723 common and low frequency variants with minor allele frequency (MAF) >1% in 590 genes. Single variant association testing using logistic regression analysis identified rs8176719 insertion/deletion (indel) variant in the ABO gene associated with CVT (age and sex adjusted OR 2.03; 95% CI 1.52-2.73; P = 2.07 × 10 -6 ; Bonferroni P = 0.008). In addition, we identified 8839 rare variants (MAF ≤ 1%) in 723 genes. Gene-based association analysis of these rare variants using a burden test revealed only a tentative association of non-coding variants located in the F8 locus with CVT., Conclusion: Targeted NGS identified a common indel variant rs8176719 in the ABO gene. Gene-based tests of association failed to reveal genomic loci with a cumulative burden of rare variants associated with CVT., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

High platelet to lymphocyte ratio (PLR) and neutrophil to lymphocyte ratio (NLR) are associated with an increased risk of arterial thrombosis, but their role in venous thromboembolism (VTE) has not been fully investigated. A case-control study, of 486 patients with VTE, 100 with cerebral vein thrombosis (CVT), and 299 healthy individuals, was carried out to investigate whether high PLR or NLR values are associated with an increased risk of VTE. Patients with high PLR or NLR did not have an increased risk of VTE (odds ratio [OR] 0.89, 95% confidence interval [CI]: 0.46-1.76; OR: 0.69, 95% CI: 0.34-1.39, respectively) or CVT (OR: 1.65, 95% CI: 0.68-4.00; OR: 0.39, 95% CI: 0.09-1.72, respectively). Subgroups analysis showed that high PLR values were associated with the risk of provoked CVT (OR: 2.65, 95% CI: 1.02-6.92), and there was an interaction with thrombophilia abnormalities (OR: 7.67, 95% CI: 1.67-35.27) in patients with CVT. In conclusion, high PLR and NLR values are not associated with an overall increased risk of VTE or CVT. High PLR values increase the risk of provoked CVT and interact with thrombophilia abnormalities in patients with CVT.

Brown adipose tissue (BAT) has a unique capacity to expend calories by decoupling energy expenditure from ATP production, therefore BAT could realize therapeutic potential to treat metabolic diseases such as obesity and type 2 diabetes. Recent studies have investigated markers and function of native BAT, however, successful therapies will rely on methods that supplement the small existing pool of brown adipocytes in adult humans. In this study, we engineered BAT from both human and rat adipose precursors and determined whether these ex vivo constructs could mimic in vivo tissue form and metabolic function. Adipose-derived stem cells (ASCs) were isolated from several sources, human white adipose tissue (WAT), rat WAT, and rat BAT, then differentiated toward both white and brown adipogenic lineages in two-dimensional and three-dimensional (3D) culture conditions. ASCs derived from WAT were successfully differentiated in 3D poly(ethylene glycol) hydrogels into mature adipocytes with BAT phenotype and function, including high uncoupling protein 1 (UCP1) mRNA and protein expression and increased metabolic activity (basal oxygen consumption, proton leak, and maximum respiration). By utilizing this "browning" process, the abundant and accessible WAT stem cell population can be engineered into 3D tissue constructs with the metabolic capacity of native BAT, ultimately for therapeutic intervention in vivo and as a tool for studying BAT and its metabolic properties.

Sustained signalling at the immune synapse (IS) requires the synaptic delivery of recycling endosome-associated T cell antigen receptors (TCRs). IFT20, a component of the intraflagellar transport system, controls TCR recycling to the IS as a complex with IFT57 and IFT88. Here, we used quantitative mass spectrometry to identify additional interaction partners of IFT20 in Jurkat T cells. In addition to IFT57 and IFT88, the analysis revealed new binding partners, including IFT54 (also known as TRAF3IP1), GMAP-210 (also known as TRIP11), Arp2/3 complex subunit-3 (ARPC3), COP9 signalosome subunit-1 (CSN1, also known as GPS1) and ERGIC-53 (also known as LMAN1). A direct interaction between IFT20 and both IFT54 and GMAP-210 was confirmed in pulldown assays. Confocal imaging of antigen-specific conjugates using T cells depleted of these proteins by RNA interference showed that TCR accumulation and phosphotyrosine signalling at the IS were impaired in the absence of IFT54, ARPC3 or ERGIC-53. Similar to in IFT20-deficient T cells, this defect resulted from a reduced ability of endosomal TCRs to polarize to the IS despite a correct translocation of the centrosome towards the antigen-presenting cell contact. Our data underscore the traffic-related role of an IFT20 complex that includes components of the intracellular trafficking machinery in IS assembly., (© 2017. Published by The Company of Biologists Ltd.)

Introduction: Cerebral venous thrombosis (CVT) is a rare cerebrovascular condition accounting for <1% of all stroke cases and mainly affects young adults. Its genetic aetiology is not clearly elucidated., Methods and Analysis: To better understand the genetic basis of CVT, we have established an international biobank of CVT cases, Biorepository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) which aims to recruit highly phenotyped cases initially of European descent and later from other populations. To date we have recruited 745 CVT cases from 12 research centres. As an initial step, the consortium plans to undertake a genome-wide association analysis of CVT using the Illumina Infinium HumanCoreExome BeadChip to assess the association and impact of common and low-frequency genetic variants on CVT risk by using a case-control study design. Replication will be performed to confirm putative findings. Furthermore, we aim to identify interactions of genetic variants with several environmental and comorbidity factors which will likely contribute to improve the understanding of the biological mechanisms underlying this complex disease., Ethics and Dissemination: BEAST meets all ethical standards set by local institutional review boards for each of the participating sites. The research outcomes will be published in international peer-reviewed open-access journals with high impact and visibility. The results will be presented at national and international meetings to highlight the contributions into improving the understanding of the mechanisms underlying this uncommon but important disease. This international DNA repository will become an important resource for investigators in the field of haematological and vascular disorders., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

The development of neutralizing antibodies (inhibitors) against coagulation factor VIII (FVIII) is the most problematic and costly complication of FVIII replacement therapy that affects up to 30% of previously untreated patients with severe hemophilia A. The development of inhibitors is a multifactorial complication involving environmental and genetic factors. Among the latter, F8 gene mutations, ethnicity, family history of inhibitors, and polymorphisms affecting genes involved in the immune response have been previously investigated. To identify novel genetic elements underling the risk of inhibitor development in patients with severe hemophilia A, we applied whole-exome sequencing (WES) and data analysis in a selected group of 26 Italian patients with (n = 17) and without (n = 9) inhibitors. WES revealed several rare, damaging variants in immunoregulatory genes as novel candidate mutations. A case-control association analysis using Cochran-Armitage and Fisher's exact statistical tests identified 1364 statistically significant variants. Hierarchical clustering of these genetic variants showed 2 distinct patterns of homozygous variants with a protective or harmful role in inhibitor development. When looking solely at coding variants, a total of 28 nonsynonymous variants were identified and replicated in 53 inhibitor-positive and 174 inhibitor-negative Italian severe hemophilia A patients using a TaqMan genotyping assay. The genotyping results revealed 10 variants showing estimated odds ratios in the same direction as in the discovery phase and confirmed the association of the rs3754689 missense variant (OR 0.58; 95% CI 0.36-0.94; P = .028) in a highly conserved haplotype region surrounding the LCT locus on chromosome 2q21 with inhibitor development., (© 2016 by The American Society of Hematology.)

Rare mutations in PROC, PROS1 or SERPINC1 as well as common variants in F5, F2, F11 and SERPINC1 have been identified as risk factors for deep vein thrombosis (DVT). To identify novel genetic risk factors for DVT, we have developed and applied next-generation DNA sequencing (NGS) of the coding area of hemostatic and proinflammatory genes. Using this strategy, we previously identified a single nucleotide variant (SNV) rs6050 in the FGA gene and novel, rare SNVs in the ADAMTS13 gene associated with DVT. To identify novel coding variants in the genetic predisposition to DVT, we applied NGS analysis of the coding area of 186 hemostatic and proinflammatory genes in 94 DVT cases and 98 controls and we identified 18 variants with putative role in DVT. A group of 585 Italian idiopathic DVT patients and 550 healthy controls was used to genotype all the 18 risk-associated variants identified by NGS. Replication study in the Italian population identified the rs2232710 variant in the protein Z-dependent protease inhibitor (ZPI) gene to be associated with an increased risk of DVT (OR 2.74; 95% CI 1.33-5.65; P = 0.0045; Bonferroni P = 0.081). However, the rs2232710 SNV showed no association with DVT in two Dutch replication cohorts the LETS study (454 patients and 451 controls) and the MEGA study (3799 patients and 4399 controls), indicating that the rs2232710 variant is not a risk factor for DVT.

Background: This study addresses a recurrent biological problem, that is to define a formal clustering structure for a set of tissues on the basis of the relative abundance of multiple alternatively spliced isoforms mRNAs generated by the same gene. To this aim, we have used a model-based clustering approach, based on a finite mixture of multivariate Gaussian densities. However, given we had more technical replicates from the same tissue for each quantitative measurement, we also employed a finite mixture of linear mixed models, with tissue-specific random effects., Results: A panel of human tissues was analysed through quantitative real-time PCR methods, to quantify the relative amount of mRNA encoding different IGF-1 alternative splicing variants. After an appropriate, preliminary, equalization of the quantitative data, we provided an estimate of the distribution of the observed concentrations for the different IGF-1 mRNA splice variants in the cohort of tissues by employing suitable kernel density estimators. We observed that the analysed IGF-1 mRNA splice variants were characterized by multimodal distributions, which could be interpreted as describing the presence of several sub-population, i.e. potential tissue clusters. In this context, a formal clustering approach based on a finite mixture model (FMM) with Gaussian components is proposed. Due to the presence of potential dependence between the technical replicates (originated by repeated quantitative measurements of the same mRNA splice isoform in the same tissue) we have also employed the finite mixture of linear mixed models (FMLMM), which allowed to take into account this kind of within-tissue dependence., Conclusions: The FMM and the FMLMM provided a convenient yet formal setting for a model-based clustering of the human tissues in sub-populations, characterized by homogeneous values of concentrations of the mRNAs for one or multiple IGF-1 alternative splicing isoforms. The proposed approaches can be applied to any cohort of tissues expressing several alternatively spliced mRNAs generated by the same gene, and can overcome the limitations of clustering methods based on simple comparisons between splice isoform expression levels.

Leptospirosis is a life-threatening and emerging zoonotic disease with a worldwide annual occurrence of more than 1 million cases. Leptospirosis is caused by spirochetes belonging to the genus Leptospira. The mechanisms of disease manifestation in the host remain elusive, and the roles of leptospiral exoproteins in these processes have yet to be determined. Our aim in this study was to assess the composition and quantity of exoproteins of pathogenic Leptospira interrogans and to construe how these proteins contribute to disease pathogenesis. Label-free quantitative mass spectrometry of proteins obtained from Leptospira spirochetes cultured in vitro under conditions mimicking infection identified 325 exoproteins. The majority of these proteins are conserved in the nonpathogenic species Leptospira biflexa, and proteins involved in metabolism and energy-generating functions were overrepresented and displayed the highest relative abundance in culture supernatants. Conversely, proteins of unknown function, which represent the majority of pathogen-specific proteins (presumably involved in virulence mechanisms), were underrepresented. Characterization of various L. interrogans exoprotein mutants in the animal infection model revealed host mortality rates similar to those of hosts infected with wild-type L. interrogans. Collectively, these results indicate that pathogenic Leptospira exoproteins primarily function in heterotrophic processes (the processes by which organisms utilize organic substances as nutrient sources) to maintain the saprophytic lifestyle rather than the virulence of the bacteria. The underrepresentation of proteins homologous to known virulence factors, such as toxins and effectors in the exoproteome, also suggests that disease manifesting from Leptospira infection is likely caused by a combination of the primary and potentially moonlight functioning of exoproteins., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Unlabelled: Cytotoxic T cells substantially contribute to the control of intracellular pathogens such as human immunodeficiency virus type 1 (HIV-1). Here, we evaluated the immunopeptidome of Jurkat cells infected with the vaccine candidate MVA.HIVconsv, which delivers HIV-1 conserved antigenic regions by using modified vaccinia virus Ankara (MVA). We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify 6,358 unique peptides associated with the class I human leukocyte antigen (HLA), of which 98 peptides were derived from the MVA vector and 7 were derived from the HIVconsv immunogen. Human vaccine recipients responded to the peptide sequences identified by LC-MS/MS. Peptides derived from the conserved HIV-1 regions were readily detected as early as 1.5 h after MVA.HIVconsv infection. Four of the seven conserved peptides were monitored between 0 and 3.5 h of infection by using quantitative mass spectrometry (Q-MS), and their abundance in HLA class I associations reflected levels of the whole HIVconsv protein in the cell. While immunopeptides delivered by the incoming MVA vector proteins could be detected, all early HIVconsv-derived immunopeptides were likely synthesized de novo. MVA.HIVconsv infection generally altered the composition of HLA class I-associated human (self) peptides, but these changes corresponded only partially to changes in the whole cell host protein abundance., Importance: The vast changes in cellular antigen presentation after infection of cells with a vectored vaccine, as shown here for MVA.HIVconsv, highlight the complexity of factors that need to be considered for efficient antigen delivery and presentation. Identification and quantitation of HLA class I-associated peptides by Q-MS will not only find broad application in T-cell epitope discovery but also inform vaccine design and allow evaluation of efficient epitope presentation using different delivery strategies., (Copyright © 2015, Ternette et al.)

Background: Sudden sensorineural hearing loss (ISSHL) is idiopathic in 85% of cases and cochlear micro-thrombosis has been hypothesized as pathogenic mechanism. The role of thrombophilia and cardiovascular risk factors in ISSHL is controversial and whether these risk factors influence the clinical outcome of ISSHL is unknown., Methods: and patients To investigate the role of thrombophilia and cardiovascular risk factors in ISSHL and to evaluate their influence on clinical outcome of the disease, 118 patients with a first episode of ISSHL and 415 healthy controls were investigated. Thrombophilia screening included measurements of antithrombin, protein C, protein S, factor V Leiden, prothrombin G20210A, antiphospholipid antibodies, fibrinogen, factor VIII and homocysteine., Results: Deficiencies of antithrombin, protein C or S taken together, high factor VIII and hyperhomocysteinemia were significantly associated with ISSHL (OR [95%CI]: 7.55 [1.05-54.47], 2.91 [1.31-6.44] and 2.69 [1.09-6.62], respectively), whereas no association was found with the remaining thrombophilia markers. A 2-fold increased risk of poor clinical outcome was observed for every 5 μmol/L increase of fasting homocysteine levels (adjusted OR [95%CI]) 2.13 [1.02-4.44]) until levels of approximately 15 μmol/L, then the risk increased slowly. Cardiovascular risk factors (arterial hypertension, hyperlipidemia, diabetes and smoking) were associated with an increased risk of ISSHL (OR [95%CI] 1.88 [1.17-3.03]) and with a poor clinical outcome (OR [95%CI] 2.22 [0.93-5.26])., Conclusions: Hyperhomocysteinemia, high factor VIII and, with more uncertainty, deficiencies of antithrombin, protein C or S and cardiovascular risk factors increase the risk of ISSHL. Hyperhomocysteinemia and cardiovascular risk factors are associated with a poor clinical outcome of ISSHL., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: To assess the impact of neoadjuvant chemoradiotherapy (NCRT) on anastomotic leakage (AL) and other postoperative outcomes after esophageal cancer (EC) resection., Background: Conflicting data have emerged from randomized studies regarding the impact of NCRT on AL., Methods: Among 2944 consecutive patients operated on for EC between 2000 and 2010 in 30 European centers, patients treated by NCRT after surgery (n=593) were compared with those treated by primary surgery (n=1487). Multivariable analyses and propensity score matching were used to compensate for the differences in some baseline characteristics., Results: Patients in the NCRT group were younger, with a higher prevalence of male sex, malnutrition, advanced tumor stage, squamous cell carcinoma, and surgery after 2005 when compared with the primary surgery group. Postoperative AL rates were 8.8% versus 10.6% (P=0.220), and 90-day postoperative mortality and morbidity rates were 9.3% versus 7.2% (P=0.110) and 33.4% versus 32.1% (P=0.564), respectively. Pulmonary complication rates did not differ between groups (24.6% vs 22.5%; P=0.291), whereas chylothorax (2.5% vs 1.2%; P=0.020), cardiovascular complications (8.6% vs 0.1%; P=0.037), and thromboembolic events (8.6% vs 6.0%; P=0.037) were higher in the NCRT group. After propensity score matching, AL rates were 8.8% versus 11.3% (P=0.228), with more chylothorax (2.5% vs 0.7%; P=0.030) and trend toward more cardiovascular and thromboembolic events in the NCRT group (P=0.069). Predictors of AL were high American Society of Anesthesiologists scores, supracarinal tumoral location, and cervical anastomosis, but not NCRT., Conclusions: Neoadjuvant chemoradiotherapy does not have an impact on the AL rate after EC resection (NCT 01927016).