Characteristics of Sexual Violence Against Adolescent Girls: A 10 Years' Retrospective Study of 731 Sexually Abused Adolescents.

Introduction: Sexual violence against young girls is a pervasive multifaceted phenomenon which embraces several different forced sexual acts, including attempted and/or completed rape, sexual coercion and harassment, and sexual contact with force or threat of force. The aim of this study is to evaluate the characteristics of sexual violence in adolescent girls, by a retrospective analysis of 731 consecutive cases of sexually abused girls. Materials and Methods: We analyzed demographic characteristics, risk factors for rape, and the eventual subsequent presence and type of ano-genital lesions. Results: We found that sexual violence with penetration was perpetrated in 591 (80%) cases. Vulnerability factors related with a major risk of rape were age >17 years old and consumption of alcohol and/or other drugs. About 196 (55%) victims had at a least one genital lesion. Conclusion: A prompt identification of red flags of sexual violence may help physicians in suspecting and managing cases of sexual assault in adolescent girls, even in the absence of typical lesions.

Risk Stratification in COVID-19 Pneumonia - Determining the Role of Lung Ultrasound.

LUS patterns of COVID-19 pneumonia have been described and shown to be characteristic. The aim of the study was to predict the prognosis of patients with COVID-19 pneumonia, using a score based on LUS findings. MATERIALS AND METHODS: An observational, retrospective study was conducted on patients admitted to Niguarda hospital with a diagnosis of COVID-19 pneumonia during the period of a month, from March 2nd to April 3rd 2020. Demographics, clinical, laboratory, and radiological findings were collected. LUS was performed in all patients. The chest was divided into 12 areas. The LUS report was drafted using a score from 0 to 3 with 0 corresponding to A pattern, 1 corresponding to well separated vertical artifacts (B lines), 2 corresponding to white lung and small consolidations, 3 corresponding to wide consolidations. The total score results from the sum of the scores for each area. The primary outcome was endotracheal intubation, no active further management, or death. The secondary outcome was discharge from the emergency room (ER). RESULTS: 255 patients were enrolled. 93.7 % had a positive LUS. ETI was performed in 43 patients, and 24 received a DNI order. The general mortality rate was 15.7 %. Male sex (OR 3.04, p = 0.014), cardiovascular disease and hypertension (OR 2.75, p = 0.006), P/F (OR 0.99, p < 0.001) and an LUS score > 20 (OR 2.52, p = 0.046) were independent risk factors associated with the primary outcome. Receiver operating characteristic (ROC) curve analysis for an LUS score > 20 was performed with an AUC of 0.837. Independent risk factors associated with the secondary outcome were age (OR 0.96, p = 0.073), BMI (OR 0.87, p = 0,13), P/F (OR 1.03, p < 0.001), and LUS score < 10 (OR 20.9, p = 0.006). ROC curve analysis was performed using an LUS score < 10 with an AUC 0.967. CONCLUSION: The extent of lung abnormalities evaluated by LUS score is a predictor of a worse outcome, ETI, or death. Moreover, the LUS score could be an additional tool for the safe discharge of patient from the ER.

Correlation between lung ultrasound and chest CT patterns with estimation of pulmonary burden in COVID-19 patients.

PURPOSE: The capability of lung ultrasound (LUS) to distinguish the different pulmonary patterns of COVID-19 and quantify the disease burden compared to chest CT is still unclear. METHODS: PCR-confirmed COVID-19 patients who underwent both LUS and chest CT at the Emergency Department were retrospectively analysed. In both modalities, twelve peripheral lung zones were identified and given a Severity Score basing on main lesion pattern. On CT scans the well-aerated lung volume (%WALV) was visually estimated. Per-patient and per-zone assessments of LUS classification performance taking CT findings as reference were performed, further revisioning the images in case of discordant results. Correlations between number of disease-positive lung zones, Severity Score and %WALV on both LUS and CT were assessed. The area under receiver operating characteristic curve (AUC) was calculated to determine LUS performance in detecting %WALV ≤ 70 %. RESULTS: The study included 219 COVID-19 patients with abnormal chest CT. LUS correctly identified as positive 217 (99 %) patients, but per-zone analysis showed sensitivity = 75 % and specificity = 66 %. The revision of the 121 (55 %) cases with positive LUS and negative CT revealed COVID-compatible lesions in 42 (38 %) CT scans. Number of disease-positive zones, Severity Score and %WALV between LUS and CT showed moderate correlations. The AUCs for LUS Severity Score and number of LUS-positive zones did not differ in detecting %WALV ≤ 70 %. CONCLUSION: LUS in COVID-19 is valuable for case identification but shows only moderate correlation with CT findings as for lesion patterns and severity quantification. The number of disease-positive lung zones in LUS alone was sufficient to discriminate relevant disease burden.

Clinical characteristics and respiratory support of 310 COVID-19 patients, diagnosed at the emergency room: a single-center retrospective study.

An ongoing outbreak of pneumonia associated with severe acute respiratory coronavirus 2 (SARS-CoV-2) occurred at the end of February 2020 in Lombardy, Italy. We analyzed data from a retrospective, single-center case series of 310 consecutive patients, with confirmed SARS-CoV-2 infection, admitted to the emergency room. We aimed to describe the clinical course, treatment and outcome of a cohort of patients with COVID-19 pneumonia, with special attention to oxygen delivery and ventilator support. Throughout the study period, 310 consecutive patients, with confirmed SARS-CoV-2 infection, attended the Emergency Room (ER), of these, 34 were discharged home directly from the ER. Of the remaining 276 patients, the overall mortality was 30.4%: 7 patients died in the ER and 77 during hospitalization. With respect to oxygen delivery: 22 patients did not need any oxygen support (8.0%), 151 patients were treated with oxygen only (54.7%), and 49 (17.8%) were intubated. 90 patients (32.6%) were treated with CPAP (Continuous Positive Airway Pressure) or NIV (Non Invasive Ventilation); in this group, 27 patients had a Do Not Intubate (DNI) order and were treated with CPAP/NIV as an upper threshold therapy, showing high mortality rate (88.9%). Among the 63 patients treated with CPAP/NIV without DNI, NIV failure occurred in 36 patients (57.1%), with mortality rate of 47.2%. Twenty-seven (27) patients were treated with CPAP/NIV without needing mechanical ventilation and 26 were discharged alive (96.3%). The study documents the poor prognosis of patients with severe respiratory failure, although a considerable minority of patients treated with CPAP/NIV had a positive outcome.

Connected: Recommendations and Techniques in Order to Employ Internet Tools for the Enhancement of Online Therapeutic Relationships. Experiences from Italy.

The article explores the different types of therapeutic relationship that can evolve both on- and offline, thanks to the use of tools, such as software and applications, which enable therapists and patients contact outside of the traditional setting. Given the premise that it is practically impossible today to maintain a relationship without the use of internet and telephones, it becomes necessary to question the ways in which the online space can become a useful extension of the therapeutic setting. The authors, starting from a consideration regarding the specificity of the online therapeutic relationship, analyze the best ways to use text and email messaging with patients. Furthermore, specific interactions via group chats are presented, for example, to coordinate a therapeutic team involving several professionals. Further, video chat settings are discussed through a clinical case presentation. Lastly, the therapist's management of social networks is debated, underscoring the importance for the therapists that his or her online identity be consistent with the offline image which patients are introduced to in the traditional setting of the therapy room.

Conformational targeting of intracellular Aß oligomers demonstrates their pathological oligomerization inside the endoplasmic reticulum.

Aß oligomers (AßOs) are crucially involved in Alzheimer's Disease (AD). However, the lack of selective approaches for targeting these polymorphic Aß assemblies represents a major hurdle in understanding their biosynthesis, traffic and actions in living cells. Here, we established a subcellularly localized conformational-selective interference (CSI) approach, based on the expression of a recombinant antibody fragment against AßOs in the endoplasmic reticulum (ER). By CSI, we can control extra- and intracellular pools of AßOs produced in an AD-relevant cell model, without interfering with the maturation and processing of the Aß precursor protein. The anti-AßOs intrabody selectively intercepts critical AßO conformers in the ER, modulating their assembly and controlling their actions in pathways of cellular homeostasis and synaptic signalling. Our results demonstrate that intracellular Aß undergoes pathological oligomerization through critical conformations formed inside the ER. This establishes intracellular AßOs as key targets for AD treatment and presents CSI as a potential targeting strategy.

Estimating the age of the most common Italian GRN mutation: walking back to Canossa times.

Mutations in the progranulin gene (GRN) were first implicated in frontotemporal lobar degeneration in 2006. The GRN p.Leu271LeufsX10 mutation is one of the most common GRN mutations worldwide. To gain further insight into the origin of this mutation in Italy, we performed a haplotype sharing analysis (32 families, residents of Lombardy) and refined the GRN p.Leu271LeufsX10 mutation dating. We showed that almost all families (30/32) can be traced to a single founder. We further estimated the age of this mutation using different methods and population growth rates both for Italy and Lombardy. Using DMLE, we dated the origin of this mutation to the Middle Ages, at the turn of the first millennium (phased families only, Italy: 39 and Lombardy: 32 generations ago; all families Italy: 45 and Lombardy 38 generations ago). Mutation dating was slightly postdated using Estiage (phased families only: 15 generations ago; all families: 20 generation ago). From a translational perspective, targeting mutation carriers offers a unique model to test disease-modifying drugs in clinical trials.

Distinct cerebrospinal fluid amyloid-beta peptide signatures in cognitive decline associated with Alzheimer's disease and schizophrenia.

Mild alterations in cognitive function are present in normal aging and severe cognitive alterations are a hallmark of Alzheimer's disease (AD). Cognitive deficits are prevalent in patients with schizophrenia (SCZ) and worsen with old age. We recently reported that elderly SCZ patients show reduced levels of amyloid-beta (Aß)1-42 in cerebrospinal fluid (CSF). To further clarify the role of Aß in cognitive decline, we analyzed the whole panel of CSF Aß isoforms in elderly SCZ patients as well as in sporadic AD using SELDI TOF MS. The immunoproteomic study revealed, in all analyzed CSF samples, the presence of 15 different Aß peptides. In CSF from SCZ, we detected an overall strong reduction of almost all Aß species while in sporadic AD Aß1-42 was the only peptide reduced. A significant independent association between Aß1-40 levels and global cognition was found in SCZ. In addition, in SCZ patients, duration of therapy was positively associated with soluble amyloid precursor protein alpha levels, the total amount of CSF Aß and the most abundant Aß1-40 isoform. These data suggests a dysmetabolism of amyloid precursor protein in older SCZ patients. Thus, the quite comparable reduction of CSF Aß1-42 in AD and in elderly SCZ patients reflects different pathophysiological dynamics in ageing brain.

Losing protein in the brain: the case of progranulin.

It is well known that progranulin protein is involved in wound repair, inflammation, and tumor formation. The wedding between progranulin and brain was celebrated in 2006 with the involvement of progranulin gene (GRN) in Frontotemporal lobar degeneration (FTLD), the most common form of early-onset dementia: up to date, 75 mutations have been detected in FTLD patients as well as in patients with widely variable clinical phenotypes. All pathogenic GRN mutations identified thus far cause the disease through a uniform mechanism, i.e. loss of functional progranulin or haploinsufficiency. Studies on GRN knockout mice suggest that progranulin-related neurodegenerative diseases may result from lifetime depletion of neurotrophic support together with cumulative damage in association with dysregulated inflammation, thus highlighting possible new molecular targets for GRN-related FTLD treatment. Recently, the dosage of plasma progranulin has been proposed as a useful tool for a quick and inexpensive large-scale screening of affected and unaffected carriers of GRN mutations. Before it is systematically translated into clinical practice and, more importantly, included into diagnostic criteria for dementias, further standardization of plasma progranulin test and harmonization of its use are required. Once a specific treatment becomes available for these pathologies, this test - being applicable on large scale - will represent an important step towards personalized healthcare. This article is part of a Special Issue entitled: Brain Integration.

Optimal plasma progranulin cutoff value for predicting null progranulin mutations in neurodegenerative diseases: a multicenter Italian study.

BACKGROUND: Recently, attention was drawn to a role for progranulin in the central nervous system with the identification of mutations in the progranulin gene (GRN) as an important cause of frontotemporal lobar degeneration. GRN mutations are associated with a strong reduction of circulating progranulin and widely variable clinical phenotypes: thus, the dosage of plasma progranulin is a useful tool for a quick and inexpensive large-scale screening of carriers of GRN mutations. OBJECTIVE: To establish the best cutoff threshold for normal versus abnormal levels of plasma progranulin. METHODS: 309 cognitively healthy controls (25-87 years of age), 72 affected and unaffected GRN+ null mutation carriers (24-86 years of age), 3 affected GRN missense mutation carriers, 342 patients with neurodegenerative diseases and 293 subjects with mild cognitive impairment were enrolled at the Memory Clinic, IRCCS S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy, and at the Alzheimer Unit, Ospedale Maggiore Policlinico and IRCCS Istituto Neurologico C. Besta, Milan, Italy. Plasma progranulin levels were measured using an ELISA kit (AdipoGen Inc., Seoul, Korea). RESULTS: Plasma progranulin did not correlate with age, gender or body mass index. We established a new plasma progranulin protein cutoff level of 61.55 ng/ml that identifies, with a specificity of 99.6% and a sensitivity of 95.8%, null mutation carriers among subjects attending to a memory clinic. Affected and unaffected GRN null mutation carriers did not differ in terms of circulating progranulin protein (p = 0.686). A significant disease anticipation was observed in GRN+ subjects with the lowest progranulin levels. CONCLUSION: We propose a new plasma progranulin protein cutoff level useful for clinical practice.

Cerebrospinal fluid biomarkers in Progranulin mutations carriers.

Cerebrospinal fluid (CSF) biomarkers (Aß1₋42, total tau, P-181 tau) are currently used to support a clinical diagnosis of Alzheimer's disease (AD). The CSF profile in frontotemporal lobar degeneration (FTLD) caused by Progranulin (GRN) mutation is unknown. We assessed CSF biomarkers in 145 AD, 140 FTLD (20 GRN positive, 120 GRN negative) patients, and 38 controls. Taking into account the reference values used in clinical practice, GRN mutation carriers and controls did not differ significantly for any biomarker, whereas GRN negative FTLD patients had higher tau levels than controls (p < 0.001) and patients carrying GRN Thr272fs mutation (p = 0.033, Chi-Square test). Comparing CSF biomarkers mean values among groups, total tau was significantly increased in GRN negative FTLD and in mutation carriers compared with controls (p < 0.001). P-181 tau CSF was increased in AD patients and in GRN negative FTLD compared with controls (p < 0.001), but not in 17 patients carrying the Thr272fs mutation. 88.2% of mutation carriers had normal CSF tau, despite the neurodegenerative nature of FTLD. Our results suggest that GRN mutation carriers have normal or borderline CSF biomarkers. In patients with an AD-like phenotype but normal or borderline CSF biomarkers, a diagnosis of FTLD-U caused by GRN mutations should be considered.

A window into the heterogeneity of human cerebrospinal fluid Aß peptides.

The initiating event in Alzheimer's disease (AD) is an imbalance in the production and clearance of amyloid beta (Aß) peptides leading to the formation of neurotoxic brain Aß assemblies. Cerebrospinal Fluid (CSF), which is a continuum of the brain, is an obvious source of markers reflecting central neuropathologic features of brain diseases. In this review, we provide an overview and update on our current understanding of the pathobiology of human CSF Aß peptides. Specifically, we focused our attention on the heterogeneity of the CSF Aß world discussing (1) basic research studies and what has been translated to clinical practice, (2) monomers and other soluble circulating Aß assemblies, and (3) communication modes for Aß peptides and their microenvironment targets. Finally, we suggest that Aß peptides as well as other key signals in the central nervous system (CNS), mainly involved in learning and hence plasticity, may have a double-edged sword action on neuron survival and function.

Cerebrospinal fluid biomarkers for Alzheimer's disease: the present and the future.

Alzheimer's disease (AD) is the major cause of dementia in the elderly. The biochemical changes that precede AD may be present up to 20 years before the clinical manifestation of the disease. The translational development of AD biomarkers may be theoretically achieved via two different strategies: the first strategy can be defined as 'knowledge-based' (deductive method), while the second one is a hypothesis-generating 'unbiased' approach (inductive strategy). The 'knowledge-based' approach relies on a direct understanding of the neuropathological processes that underlie the development of AD. In contrast, the 'unbiased' approach involves the use of modern techniques including proteomics and bioinformatics that allow unbiased investigations of numerous putative markers that may be informative with regard to AD. Cerebrospinal fluid (CSF) dosage of neuropathological AD-associated proteins has already been incorporated into the neurochemical diagnosis of AD, attesting the relevance of translational research. In the last few years, biomarker discovery research has successfully utilized genomics and proteomics for the identification of several promising molecular markers for AD. In the present article, we discuss the present state of the art and the future challenges in the search of CSF biomarkers for AD.

Cystatin C is released in association with exosomes: a new tool of neuronal communication which is unbalanced in Alzheimer's disease.

It has recently become clear that proteins associated with neurodegenerative disorders can be selectively incorporated into intraluminal vesicles of multivesicular bodies and subsequently released within exosomes. Multiple lines of research support a neuroprotective role for cystatin C in Alzheimer's disease (AD). Herein we demonstrate that cystatin C, a protein targeted to the classical secretory pathway by its signal peptide sequence, is also secreted by mouse primary neurons in association with exosomes. Immunoproteomic analysis using SELDI-TOF MS revealed the presence in exosomes of at least 9 different cystatin C glycoforms. Moreover, the over-expression of familial AD-associated presenilin 2 mutations (PS2 M239I and PS2 T122R) resulted in reduced levels of all cystatin C forms (native and glycosylated) and of amyloid-ß precursor protein (APP) metabolites within exosomes. A better understanding of the mechanisms involved in exosomal processing and release may have important implications for the fight against AD and other neurodegenerative diseases.

Optimization protocol for amyloid-ß peptides detection in human cerebrospinal fluid using SELDI TOF MS.

PURPOSE: The aim of the present work was to set up an optimized protocol for human cerebrospinal fluid amyloid-ß (Aß) profiling. EXPERIMENTAL DESIGN: We devised an immunoproteomic assay that employs monoclonal antibodies (mAbs) on Preactivated Surface (PS20) chip array followed by SELDI TOF MS. A comparison of a number of factors was performed, and the impact of these differences was noted. Each variable was tested using in parallel two different mAbs, 6E10 and 4G8. In addition, we tested whether the combined use of these two mAbs could improve the capture of N and C-terminally truncated Aß peptides and then the quality of spectra. RESULTS: The best results were obtained using a mixture of Aß mAbs (0.125 µg/µL 6E10+4G8): 15 Aß peptides (including 3 N-terminally truncated forms) were detected. CONCLUSIONS AND CLINICAL RELEVANCE: This approach has many potential advantages in speed, sensitivity and economy of reagents and could be helpful in order to define the role played by specific Aß truncated forms in cognitive decline.

Plasma cystatin C and risk of developing Alzheimer's disease in subjects with mild cognitive impairment.

Recent years have witnessed an increasing interest in mild cognitive impairment (MCI), particularly as a possible prodromal stage of Alzheimer's disease (AD). Experimental and clinical data have suggested that cystatin C (CysC) is protective against the development of AD. In this study, we sought to cross-sectionally and longitudinally investigate the changes in plasma CysC levels in patients with MCI and whether the levels of this molecule might serve as a biochemical predictor of cognitive decline in this patient group. Cross-sectional analysis of baseline data showed a borderline significant difference in plasma CysC levels among the three study groups (Controls, n=63; AD, n=63; MCI, n=59) (p =0.032) that disappeared after post hoc analysis. Plasma CysC levels did not differ at baseline (t1) and at follow-up (t2) both in MCI patients that converted to AD (n= 32) and those that did not convert (n=27). However, a significant independent association between CysC at t1 and CysC at t2 was found in non-converters but not in converters MCI subjects. Moreover, when disease onset was evaluated in patients groups stratified on the basis of their CysC plasma levels, a significant anticipation of the conversion to dementia in MCI subjects with CysC levels below the median (CysC < 1067 ng/ml) (p =0.0011) was observed. Altogether, this work adds to the growing body of literature suggesting that CysC modulates the clinical expression of cognitive decline, and opens a new area of investigation of CysC as a therapeutic target for neurodegenerative disorders.

Novel T719P AbetaPP mutation unbalances the relative proportion of amyloid-beta peptides.

A novel missense mutation (T719P) in the amyloid-beta protein precursor (AbetaPP) gene was discovered in a 46-year old patient affected by early onset familial Alzheimer's disease. Using surface enhanced laser desorption/ionization mass spectrometry (SELDI-TOF MS), we determined mass profiles of amyloid-beta peptides (Abeta) in cerebrospinal fluid (CSF) of the AbetaPP mutated patient, healthy control subjects (n = 10), and of two subjects carrying mutations in presenilins genes (PS) (i.e., PS1 P117L and PS2 T122R): seven different C-terminally and three N-terminally truncated Abeta peptides were found in CSF. The investigated AbetaPP as well as PS mutations were associated with an overall reduction of Abeta species, except for Abeta(10-40). Interestingly, the AbetaPP T719P mutation unbalanced the relative proportion of Abeta peptides with a reduction of Abeta(1-40) and Abeta(1-42) paralleled by an increase of Abeta(1-38) and Abeta(10-40). Despite the specific neuropeptidomic phenotype associated with the AbetaPP T719P mutation, the enrichment in Abeta(10-40) paralleled by depletion of Abeta(1-42) seems to be a common theme in familial AD. The AbetaPP T719P mutation is of particular interest because it is the only mutation located in close proximity to the AbetaPP epsilon-cleavage site.