C-STIM: Protocol for a randomized, single-blind, crossover study of cerebellar repetitive transcranial magnetic stimulation (rTMS) for postural instability in people with progressive supranuclear palsy (PSP).

Background: Methods for modulating the cerebellum with transcranial magnetic stimulation (TMS) are well established, and preliminary data from our group and others has shown evidence of transient improvements in balance after cerebellar repetitive transcranial magnetic stimulation (rTMS) in progressive suprancuclear palsy (PSP). This study examines extensive posturography measures before and after 10 sessions of cerebellar rTMS and sham TMS in PSP. Methods: Thirty subjects with PSP and postural instability will undergo cerebellar active and sham rTMS in a single-blind, crossover design with a randomized order of a 10-day intervention. Primary outcomes will be changes in sway area and medio-lateral range of sway with eyes open while standing on a stationary force-plate, and safety, tolerability, and blindedness. Secondary outcomes will include posturography and gait analysis with body-worn, triaxial inertial sensors, clinical balance scales and questionnaires, and a bedside test of vestibular function. Exploratory outcomes are changes in functional near infrared spectroscopy (fNIRS) signal over the prefrontal, supplementary motor, and primary motor cortices while standing and walking, and speech samples for future analysis. Discussion: The C-STIM crossover intervention study adds a longer duration of stimulation and extensive posturography measures to more finely measure the improvements in balance and exploratory functional near-infrared spectroscopy (fNIRS) over the prefronal, supplementary motor, and primary motor cortices during balance assessments before and after 10 sessions of cerebellar rTMS and 10 sessions of sham cerebellar TMS. This project will improve our understanding of the importance of the cerebellum for control of postural stability in PSP.

Correlation between bituberous diameter and mode of delivery in a cohort of low-risk nulliparous women.

OBJECTIVE: The aim our study was to evaluate the association between the antepartum clinical measurement of the Bituberous Diameter (BTD) and the occurrence of unplanned obstetrical intervention (UOI) due to labor dystocia, including either operative vaginal delivery or caesarean section in a cohort of low-risk, nulliparous at term. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Tertiary maternity care. INTERVENTIONS: With the women lying in lithotomic the distance between two ischial tuberosities was assessed using a tape measure during the routine antenatal booking between 37 and 38 weeks of gestation. MEASUREMENTS AND FINDINGS: Overall, 116 patient were included, and of these 23(19.8%) were submitted to an UOI due to labor dystocia. Compared to women that had a spontaneous vaginal delivery, women submitted to an UOI had a shorter BTD (8.25 + 0.843 vs 9.60 + 1.12, p < 0.001), a higher frequency of epidural analgesia (21/23 or 91.3% vs 50/93 or 53.8%; p = 0.002) and of augmentation of labor (14/23 or 60.9% vs 19/93 or 20.4%; p < 0.001) as well as a longer first [455 (IQR 142-455 min vs 293 (IQR 142-455) min] and second stages of labor [129 (IQR 85-155) min vs 51 (IQR 27-78) min]. Multivariable logistic regression showed that the BTD (aOR 0.16, 95% CI 0.04-0.60; p = 0.007) and the length of the second stage of labor (aOR 6.83, 95% CI 2.10-22.23; p = 0.001) were independently associated with UOI. When evaluating the diagnostic accuracy of the BTD for the prediction of UOI due to labor dystocia, the BTD showed an AUC of 0.82 (95 %CI 0.73-0.91; p < 0.001) with an optimal cut-off value of 8.6 cm (78.3% (95 %CI 56.3-92.5) sensitivity, 77.4% (95 %CI 67.6-85.4) specificity, 46.2% (95% CI 30.1-62.8) PPV, 93.5% (95% CI 85.5-97.9) NPV, 3.5 (95% CI 2.3-5.4) positive LR, and 0.28 (95% CI 0.13-0.61) negative LR. A significant inverse correlation between the length of the second stage of labour and the BTD in patients that had a vaginal delivery was also demonstrated (Spearman's rho = -0.24, p = 0.01). KEY CONCLUSIONS: Our study suggests that antepartum clinical assessment of the BTD might be used as a reliable predictor of UOI due to labor dystocia in low-risk, nulliparous women at term gestation. IMPLICATIONS FOR PRACTICE: Antenatal identification of women at higher risk for labor dystocia might trigger some interventions during the second stage of labor, such as maternal position shifting, to increase the pelvic capacity and potentially improve outcomes or might prompt a referral of the patient to a district hospital prior to the onset of labor.

Multiple beneficial effects of 1-year nutritional-behavioral intervention on anthropometric and metabolic parameters in overweight and obese boys.

PURPOSE: Childhood obesity is on the rise worldwide increasing the risk for metabolic, cardiovascular and liver diseases in children. Eating habits and lifestyle changes are currently the standard of care for treating pediatric obesity. Our study aimed to determine the impact of a dietary intervention based on the Mediterranean Diet (MD) and the Health Eating Plate, on anthropometric and metabolic parameters in obese and overweight boys. METHODS: We studied 126 overweight/obese boys with anthropometric measurements, blood biochemistry and nutrient intakes evaluation by means of Food Frequency Questionnaire (FFQ) at baseline, at 6 and 12 months after a nutritional-behavioral intervention. RESULTS: We observed a significant reduction in energy, macronutrients and micronutrients intakes. BMI-SDS significantly decreased after 1 year with the proportion of obese boys decreasing by 33% and of overweight boys by 41%, while also all fat mass measures decreased both in obese and overweight individuals. In obese boys, ALT decreased significantly after 1-year nutritional intervention and these changes correlated with BMI-SDS reduction. Insulin-resistance and secretion indexes correlated with fat mass and BMI-SDS. In obese boys, significant changes were observed at 6 months for insulin concentrations, 1/HOMA-IR and QUICKI. With regard to the lipid profile, significant decreases were observed for total and LDL cholesterol in obese boys. CONCLUSION: Metabolic and anthropometric risk factors in overweight and obese boys can be improved by a nutritional-behavioral intervention of 1-year duration.

Short-term physical exercise controls age-related hyperinsulinemia and improves hepatic metabolism in aged rodents.

PURPOSE: Aging is associated with changes in glucose homeostasis related to both decreased insulin secretion and/or impaired insulin action, contributing to the high prevalence of type 2 diabetes (T2D) in the elderly population. Additionally, studies are showing that chronically high levels of circulating insulin can also lead to insulin resistance. In contrast, physical exercise has been a strategy used to improve insulin sensitivity and metabolic health. However, the molecular alterations resulting from the effects of physical exercise in the liver on age-related hyperinsulinemia conditions are not yet fully established. This study aimed to investigate the effects of 7 days of aerobic exercise on hepatic metabolism in aged hyperinsulinemic rats (i.e., Wistar and F344) and in Slc2a4+/- mice (hyperglycemic and hyperinsulinemic mice). RESULTS: Both aged models showed alterations in insulin and glucose tolerance, which were associated with essential changes in hepatic fat metabolism (lipogenesis, gluconeogenesis, and inflammation). In contrast, 7 days of physical exercise was efficient in improving whole-body glucose and insulin sensitivity, and hepatic metabolism. The Slc2a4+/- mice presented significant metabolic impairments (insulin resistance and hepatic fat accumulation) that were improved by short-term exercise training. In this scenario, high circulating insulin may be an important contributor to age-related insulin resistance and hepatic disarrangements in some specific conditions. CONCLUSION: In conclusion, our data demonstrated that short-term aerobic exercise was able to control mechanisms related to hepatic fat accumulation and insulin sensitivity in aged rodents. These effects could contribute to late-life metabolic health and prevent the development/progression of age-related T2D.

TURN-IT: a novel turning intervention program to improve quality of turning in daily life in people with Parkinson's disease.

BACKGROUND: People with Parkinson's disease (PD) have a high fall rate and many falls are associated with turns. Despite this, there is minimal research on effects of rehabilitation on the quality of turns. Further, quantifying turns in the home may have broader implications since rehabilitation of turns would ideally improve turning in real world mobility. METHODS: Sixty people with PD and a history of falls will be randomized to receive either a novel TURNing InTervention (TURN-IT) or no intervention (control group). The TURN-IT group will be seen for 6 weeks (18 visits) for an individualized, progressive program that is based on the specific constraints of turning in PD. Wearable sensors will be used to measure 7 days of mobility, including turns, before and after intervention or control period. In addition, blinded assessments of gait, mobility and turns will occur before and after intervention for both groups and falls will be monitored for twelve months post intervention with bimonthly email questionnaires. DISCUSSION: This study has the potential to change how we rehabilitate and assess turning in people with PD and falls. There are several novel aspects to our study including a comprehensive turning-focused intervention that is tailored to the underlying constraints that impair turning in people with PD. Further, our outcome measure of turning quality during 7 days of daily life is novel and has implications for determining real-life changes after rehabilitation. The ultimate goal of this rehabilitation intervention is to improve how patients turn in daily life and to reduce falls. TRIALS REGISTRATION: This protocol is registered at clinicaltrials.gov; #NCT04897256; https://clinicaltrials.gov/ct2/show/NCT04897256?term=Horak&cond=Parkinson+Disease&draw=2&rank=4 .

Hand grip support for rehabilitation and assistance: from patent to TRL5.

In the last decades, the continuous increase in the number of the vast cohort of chronic patients that constantly need medical assistance and supervision, and the widespread lack of therapist has brought to an increased interest in the role of medical technologies in rehabilitative programs and assistive scenarios. Current clinical evidence in rehabilitation demonstrates that there is an important and increasing demand for innovative therapeutic solutions to recover the hand functions to prevent patients to need assistance in performing daily life activities. This works describes the pathway from patent to TRL5 of a device to support hand grip actions and interaction with daily life objects. E-KIRO is based on the use of electromagnets, which are able to attach/detach interactive objects equipped with a ferromagnetic plate. Five end-users used the device and scored it with excellent usability based on the System Usability Scale.

Domestic trauma with penile and scrotum skin degloving and testicular avulsion.

Traumatic lesions of male external genitalia are certainly less frequent than the other body sites and in the majority of cases they are caused by work accidents in the metalworking environment or by gunshot wounds. We present a rare case of traumatic degloving lesion of the male external genitalia with avulsion of the left testis caused by an accidental fall from the ladder. Reconstructive surgery was carried out in a single procedure, obtaining an excellent esthetic and functional result.

Involvement of transcribed lncRNA uc.291 and SWI/SNF complex in cutaneous squamous cell carcinoma.

While non-melanoma skin cancers (NMSCs) are the most common tumours in humans, only the sub-type cutaneous squamous cell carcinoma (cSCC), might become metastatic with high lethality. We have recently identified a regulatory pathway involving the lncRNA transcript uc.291 in controlling the expression of epidermal differentiation complex genes via the interaction with ACTL6A, a component of the chromatin remodelling complex SWI/SNF. Since transcribed ultra-conserved regions (T-UCRs) are expressed in normal tissues and are deregulated in tumorigenesis, here we hypothesize a potential role for dysregulation of this axis in cSCC, accounting for the de-differentiation process observed in aggressive poorly differentiated cutaneous carcinomas. We therefore analysed their expression patterns in human tumour biopsies at mRNA and protein levels. The results suggest that by altering chromatin accessibility of the epidermal differentiation complex genes, down-regulation of uc.291 and BRG1 expression contribute to the de-differentiation process seen in keratinocyte malignancy. This provides future direction for the identification of clinical biomarkers in cutaneous SCC. Analysis of publicly available data sets indicates that the above may also be a general feature for SCCs of different origins.

Controlled obesity status: a rarely used concept, but with particular importance in the COVID-19 pandemic and beyond.

Obesity is a chronic disease that causes and aggravates several other diseases, and early reports suggest it is an important risk factor for COVID-19 severity. Although a deeper understanding of this relationship is vital, it is also important to inform the general public about the risks and, ideally, offer strategies to mitigate the risks. As "resolution" of obesity in the short-term is not feasible, it is indeed possible that smaller weight losses and increase in physical activity can actually reduce the risks. In this context, we propose that a term called "controlled obesity" be more often used and studied, in which those who have lost over 10% of their maximal weight and, ideally, are physically active are considered healthier. This context can have much broader usefulness, beyond the pandemics, as evidence points that weight loss over 10% can significant reduce overall health risks, irrespective of final BMI.

A new species of Contracaecum (Nematoda: Anisakidae) found parasitizing Nannopterum brasilianus (Suliformes: Phalacrocoracidae) and Hoplias argentinensis (Characiformes: Erythrinidae) in South America: morphological and molecular characterization of larval and adult stages.

Nematode species of the genus Contracaecum Railliet & Henry, 1912 have been reported around the world in many species of fish-eating birds and seals. Here, Contracaecum jorgei n. sp. is morphologically described using light and scanning electron microscopy for adults and fourth-stage larvae (L4) found in the bird Nannopterum brasilianus and third-stage larvae (L3) found in the freshwater fish Hoplias argentinensis, both from the province of Córdoba, Argentina. Additionally, sequences of cytochrome c oxidase subunit II were obtained from these specimens and molecular phylogenetic analysis was used to determine its relationships within the genus. The present species is distinguished from other species by the number and disposition of cephalic papillae; shape and size of the interlabia; length of the spicules; and number and arrangement of papillae in the posterior end of the male. Furthermore, in the molecular analyses, sequences obtained from adult L4 and L3 specimens of C. jorgei n. sp. were similar and grouped, forming an independent lineage, thus confirming it as a distinct species. Thus, morphological characteristics associated with molecular data support the proposal of a new species.

Preclinical Molecular Imaging for Precision Medicine in Breast Cancer Mouse Models.

Precision and personalized medicine is gaining importance in modern clinical medicine, as it aims to improve diagnostic precision and to reduce consequent therapeutic failures. In this regard, prior to use in human trials, animal models can help evaluate novel imaging approaches and therapeutic strategies and can help discover new biomarkers. Breast cancer is the most common malignancy in women worldwide, accounting for 25% of cases of all cancers and is responsible for approximately 500,000 deaths per year. Thus, it is important to identify accurate biomarkers for precise stratification of affected patients and for early detection of responsiveness to the selected therapeutic protocol. This review aims to summarize the latest advancements in preclinical molecular imaging in breast cancer mouse models. Positron emission tomography (PET) imaging remains one of the most common preclinical techniques used to evaluate biomarker expression in vivo, whereas magnetic resonance imaging (MRI), particularly diffusion-weighted (DW) sequences, has been demonstrated as capable of distinguishing responders from nonresponders for both conventional and innovative chemo- and immune-therapies with high sensitivity and in a noninvasive manner. The ability to customize therapies is desirable, as this will enable early detection of diseases and tailoring of treatments to individual patient profiles. Animal models remain irreplaceable in the effort to understand the molecular mechanisms and patterns of oncologic diseases.

Cerebellar rTMS for motor control in progressive supranuclear palsy.

BACKGROUND: Stimulatory cerebellar TMS is a promising tool to improve motor control in neurodegenerative disorders. OBJECTIVE/HYPOTHESIS: Our goal was to use 10Hz cerebellar rTMS to augment cerebellar-brain inhibition (CBI) for improved postural stability and speech in patients with progressive supranuclear palsy (PSP). METHODS: We performed CBI assessments with neuronavigation before and after high frequency cerebellar rTMS or sham TMS in two patients with PSP, using a double cone coil for the conditioning pulse and a figure-of-eight coil for the test pulse and treatments. We collected posturography data and speech samples before and after treatment. RESULTS: After treatment, CBI increased by 50% in subject 1 and by 32% in subject 2, and postural stability and speech improved. The protocol was well tolerated, but the sham was not consistently believable. CONCLUSION: Cerebellar rTMS may improve postural stability and speech in PSP, but cooled coils with vibrotactile sham capability are needed for larger future studies.

Noninvasive Ultrasound Monitoring of Embryonic and Fetal Development in Chinchilla lanigera to Predict Gestational Age: Preliminary Evaluation of This Species as a Novel Animal Model of Human Pregnancy.

Ultrasound is a noninvasive routine method that allows real-time monitoring of fetal development in utero to determine gestational age and to detect congenital anomalies and multiple pregnancies. To date, the developmental biology of Chinchilla lanigera has not yet been characterized. This species has been found to undergo placentation, long gestation, and fetal dimensions similar to those in humans. The aim of this study was to assess the use of high-frequency ultrasound (HFUS) and clinical ultrasound (US) to predict gestational age in chinchillas and evaluate the possibility of this species as a new animal model for the study of human pregnancy. In this study, 35 pregnant females and a total of 74 embryos and fetuses were monitored. Ultrasound examination was feasible in almost all chinchilla subjects. It was possible to monitor the chinchilla embryo with HFUS from embryonic day (E) 15 to 60 and with US from E15 to E115 due to fetus dimensions. The placenta could be visualized and measured with HFUS from E15, but not with US until E30. From E30, the heartbeat became detectable and it was possible to measure fetal biometrics. In the late stages of pregnancy, stomach, eyes, and lenses became visible. Our study demonstrated the importance of employing both techniques while monitoring embryonic and fetal development to obtain an overall and detailed view of all structures and to recognize any malformation at an early stage. Pregnancy in chinchillas can be confirmed as early as the 15th day postmating, and sonographic changes and gestational age are well correlated. The quantitative measurements of fetal and placental growth performed in this study could be useful in setting up a database for comparison with human fetal ultrasounds. We speculate that, in the future, the chinchilla could be used as an animal model for the study of US in human pregnancy.

Hyper-activation of Aurora kinase a-polo-like kinase 1-FOXM1 axis promotes chronic myeloid leukemia resistance to tyrosine kinase inhibitors.

BACKGROUND: Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by the constitutive tyrosine kinase (TK) activity of the BCR-ABL1 fusion protein. Accordingly, TK inhibitors have drastically changed the disease prognosis. However, persistence of the transformed hematopoiesis even in patients who achieved a complete response to TK inhibitors and the disease relapse upon therapy discontinuation represent a major obstacle to CML cure. METHODS: Thiostrepton, Danusertib and Volasertib were used to investigate the effects of FOXM1, AKA and Plk1 inhibition in K562-S and K562-R cells. Apoptotic cell death was quantified by annexin V/propidium iodide staining and flow cytometry. Quantitative reverse transcription (RT)-PCR was used to assess BCR-ABL1, FOXM1, PLK1 and AURKA expression. Protein expression and activation was assessed by Western Blotting (WB). Clonogenic assay were performed to confirm K562-R resistance to Imatinib and to evaluate cells sensitivity to the different drugs. RESULTS: Here we proved that BCR-ABL1 TK-dependent hyper-activation of Aurora kinase A (AURKA)-Polo-like kinase 1 (PLK1)-FOXM1 axis is associated with the outcome of Imatinib (IM) resistance in an experimental model (K562 cell line) and bone marrow hematopoietic cells. Notably, such a biomolecular trait was detected in the putative leukemic stem cell (LSC) compartment characterized by a CD34+ phenotype. Constitutive phosphorylation of FOXM1 associated with BCR-ABL1 TK lets FOXM1 binding with ß-catenin enables ß-catenin nuclear import and recruitment to T cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription complex, hence supporting leukemic cell proliferation and survival. Lastly, the inhibition of single components of AURKA-PLK1-FOXM1 axis in response to specific drugs raises the expression of growth factor/DNA damage-inducible gene a (GADD45a), a strong inhibitor of AURKA and, as so, a critical component whose induction may mediate the eradication of leukemic clone. CONCLUSIONS: Our conclusion is that AURKA, PLK1 and FOXM1 inhibition may be considered as a promising therapeutic approach to cure CML.

Estimating bacteria diversity in different organs of nine species of mosquito by next generation sequencing.

BACKGROUND: Symbiosis in insects is accumulating significant amount of studies: the description of a wide array of mutualistic associations across the evolutionary history of insects suggests that resident microbiota acts as a driving force by affecting several aspects of hosts biology. Among arthropods, mosquito midgut microbiota has been largely investigated, providing crucial insights on the role and implications of host-symbiont relationships. However, limited amount of studies addressed their efforts on the investigation of microbiota colonizing salivary glands and reproductive tracts, crucial organs for pathogen invasion and vertical transmission of symbiotic microorganisms. Using 16S rRNA gene sequencing-based approach, we analysed the microbiota of gut, salivary glands and reproductive tracts of several mosquito species, representing some of the main vectors of diseases, aiming at describing the dynamics of bacterial communities within the individual. RESULTS: We identified a shared core microbiota between different mosquito species, although interesting inter- and intra-species differences were detected. Additionally, our results showed deep divergences between genera, underlining microbiota specificity and adaptation to their host. CONCLUSIONS: The comprehensive landscape of the bacterial microbiota components may ultimately provide crucial insights and novel targets for possible application of symbionts in innovative strategies for the control of vector borne diseases, globally named Symbiotic Control (SC), and suggesting that the holobiont of different mosquito species may significantly vary. Moreover, mosquito species are characterized by distinctive microbiota in different organs, likely reflecting different functions and/or adaptation processes.

Anticipatory postural responses prior to protective steps are not different in people with PD who do and do not freeze.

BACKGROUND: Protective stepping after a loss of balance is related to falls. Anticipatory postural responses (APAs) prior to protective stepping can impact step performance, may be larger in people with PD, and have been suggested to be related to freezing of gait (FOG). However, whether people with PD and FOG (PD + FOG) exhibit larger APAs than people with PD and no FOG (PD-FOG) is unknown. RESEARCH QUESTION: Determine the impact of freezing status on APAs prior to protective steps, thus providing a better understanding of the link between FOG and APAs. METHODS: Twenty-eight people with PD (13 PD + FOG) were exposed to 50 support surface translations (25 forward, 25 backward, random order) resulting in protective steps. The size of medio-lateral weight shifts prior to the protective step (i.e. APAs), and the percentage of trials with an APA were calculated via force-plates. FOG status was assessed at the time of testing as well as 3.25(+/-0.43) years later. Participants without FOG at testing, but with FOG at follow-up were identified as "converters". RESULTS AND SIGNIFICANCE: For both forward and backward protective stepping, size and percentage trials with an APA were not statistically different between PD + FOG and PD-FOG, even after excluding converters from the PD-FOG group (p > 0.27 for all). No group by direction interactions were observed. These data suggest that, in mild to moderate PD, an inability to couple APAs with stepping, rather than an inappropriately sized APA, may be most related to freezing of gait.

Oral management of adult patients undergoing hematopoietic stem cell transplantation.

Chemotherapy and hematopoietic stem cell transplantation (HSCT) are the current treatments for patients with hematological diseases; they result in myelosuppression, and increase the susceptibility of patients to severe infections. The oral cavity is a potential site of complications in HSCT patients, because it is the entrance for agents that can cause systemic infections; it is one of the most frequent locations for side effects deriving from conditioning therapy. The importance of dental pre-chemotherapy and transplant prescription is often stressed, since both therapies depress the immune system and platelets, making each intervention at this stage a high risk. The aim of this article is to review the potential complications of HSCT, and to extrapolate from the scientific literature the treatments and timeframes in which dental therapies can be performed, avoiding important risks for patients.

Costs and Resource Use Associated with Alzheimer's Disease in Italy: Results from an Observational Study.

BACKGROUND: The GERAS II study aimed to assess societal costs and resource use associated with Alzheimer's disease (AD) for patients and their primary caregivers in Italy and Spain, stratified for different severity stages of AD at baseline. This report presents baseline results for Italy. DESIGN: GERAS II was a prospective, multicentre, observational study of routine care in AD. SETTING: Community-dwelling patients attending specialist secondary care centres (memory clinics/Alzheimer's Evaluation Units) and their primary informal caregivers were recruited into the study. PARTICIPANTS: Patients were aged ≥55 years, presented within the normal course of care, had a diagnosis of probable AD and a Mini-Mental State Examination (MMSE) score of ≤26. Patients and caregivers were stratified according to patient AD dementia severity at baseline: mild, MMSE score 21-26; moderate, MMSE score 15-20; or moderately severe/severe, MMSE score <15. MEASUREMENTS: Data collected for patients and caregivers included demographics/clinical characteristics; current medication; patient cognitive, functional and behavioural assessments; patient and caregiver health-related quality of life (HRQoL); and patient and caregiver resource use. The costs associated with the resources used were calculated. Costs were broken down into patient healthcare costs, patient social care costs and caregiver informal care costs. RESULTS: Of 198 patients enrolled from Italy, 29 (15%) had mild AD dementia, 80 (40%) had moderate AD dementia, and 89 (45%) had moderately severe/severe AD dementia. Patient and caregiver characteristics showed some differences between AD dementia severity groups; for example, a numerically higher proportion of patients with mild and moderately severe/severe AD dementia were taking memantine compared with those with moderate AD dementia. Patient functioning and behavioural and psychological symptoms worsened with increasing AD dementia severity (p<0.05 between groups for all measures). No significant difference between the disease severity groups was observed in patient HRQoL, and there was no clear pattern in resource use. However, all measures of caregiver time spent helping the patient differed significantly between groups (p<0.05) and were highest in patients with moderately severe/severe AD dementia. Mean (standard deviation) total monthly societal costs per patient (2013 values) were €1850 (1901), €1552 (1322) and €2728 (2184) for patients with mild, moderate and moderately severe/severe AD dementia, respectively (p<0.001 between groups). Caregiver informal care costs were the greatest contributor to total societal costs and amounted to €1370, €1223 and €2223 per patient per month for mild, moderate and moderately severe/severe AD dementia groups, respectively (p<0.001 between groups). CONCLUSION: Total Italian societal costs generally increased with increasing AD dementia severity. However, costs were slightly lower for moderate than for mild AD dementia, possibly reflecting the observed unusual trend of greater caregiver time and higher memantine use in patients with mild versus moderate AD dementia.

SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis.

The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM. Reduced or no SETD2 protein expression-and consequently, H3K36 trimethylation-was found in all cases and inversely correlated with disease aggressiveness. Proteasome inhibition rescued SETD2 expression and H3K36 trimethylation and resulted in marked accumulation of ubiquitinated SETD2 in SETD2-deficient patients but not in patients with near-normal SETD2 expression. Bortezomib and, to a lesser extent, AZD1775 alone or in combination with midostaurin induced apoptosis and reduced clonogenic growth of HMC-1 cells and of neoplastic mast cells from advanced SM patients. Our findings may have implications for prognostication of SM patients and for the development of improved treatment approaches in advanced SM.

Predictors of Asymptomatic Radiation-induced Abdominal Atherosclerosis.

AIMS: To identify predictors of asymptomatic radiation-induced abdominal atherosclerosis in patients treated with radiotherapy and evaluated by abdominal vascular ultrasonography. MATERIALS AND METHODS: Forty-two testicular classic seminoma patients (median age 34 years, range 16-56) undergoing radical inguinal orchiectomy were analysed. Twenty-six patients underwent post-surgery radiotherapy (median total dose 25 Gy, range 25-43), two of them also received chemotherapy (CHT) and 16 patients were treated with surgery alone or by surgery followed by CHT (control group). The presence of stenosis in an abdominal vessel and renal resistive index (RRI), evaluated by echo-colour Doppler (ECD), were considered as indicators of late vascular damage. Chi-square and Mann-Whitney tests were used to compare groups. For the radiotherapy group, near maximum (D2%) and mean dose (Dmean) metrics of critical structures (abdominal arteries and renal hila) were extracted from retrievable dose maps (18 of 26 radiotherapy patients). To evaluate clinical and dosimetric factors associated with vascular damage, univariate and multivariate analyses were carried out. The impact of dose to arteries, evaluated as separate subvolumes, was analysed comparing the stenotic arteries with normal ones by logistic regression. The area under the receiver operator characteristic curve (AUC) was used to evaluate the test accuracy. RESULTS: In the radiotherapy group there was a significantly different incidence of stenosis (31% versus 0%, P = 0.016) and a higher median average RRI (0.63 versus 0.60, P = 0.032) compared with the control group. The median time intervals between treatment and ECD were 64 months (range 12-120) and 48 months (range 12-168) in the radiotherapy and control groups (P = 0.399), respectively. A younger age at radiotherapy was the only clinical risk factor for stenosis (P = 0.006). Artery Dmean was significantly associated with stenosis (P = 0.008), with an odds ratio of 1.13 (95% confidence interval 1.01-1.26) and an AUC of 0.85 (95% confidence interval 0.77-0.91). Renal hilum D2% was correlated with RRI (Rs = 0.406, P = 0.02). CONCLUSIONS: Late vascular damage represents a potential effect of abdominal radiotherapy, even at a moderate dose. Younger age at irradiation, artery and renal hila dose metrics are associated with increased risk. Ultrasound-based follow-up may allow for non-invasive early detection of asymptomatic radiation-induced damage, helping to prevent severe vascular events.