Aflibercept, ranibizumab and bevacizumab upcoming biosimilars: a general overview.

Anti-vascular endothelial growth factors currently are the first-line treatment option for neovascular age-related macular degeneration (nAMD) and other retinal vascular disorders, and their clinical use is associated with high financial burden. Biosimilars are a type of biological product highly similar to referral biologic drugs; they are increasing competition among biologics and have the potential to reduce the overall expenditures on biologics. In this comprehensive literature review, the current investigational biosimilars acting on retinal diseases are discussed. The authors review the results of clinical studies and highlight ongoing trials. Several biosimilar candidates are under evaluation and the pipeline will rapidly change in the future, as soon as each patent expires. Clinicians have to know these new therapeutic agents, which might come in the mainstream clinical practice as a more cost-efficient option.

Birth by cesarean section and mood disorders among adolescents of a birth cohort study in northern Brazil.

The increasing number of cesarean sections worldwide has encouraged research on the long-term effects of this birth type on the offspring's mental health. The objective of this study was to investigate whether there is an association between birth by cesarean section and the development of mood disorders (depression and bipolar disorders) in adolescents. A cohort study was carried out with 1603 adolescents from 18 to 19 years old who participated in the third phase of a birth cohort study in São Luís, MA, in 2016. Information on birth type and weight, prematurity, mother's age and schooling, parity, marital status, and smoking behavior during pregnancy, were collected at birth. The study outcomes were depression, bipolar disorder, and "mood disorder" construct. A Directed Acyclic Graph (DAG) was developed to select the variables for minimal adjustment for confounding and collision bias. Associations were estimated through propensity score weighting using a two-step estimation model, and confounders for cesarean birth were used in the predictive model. There was no significant association in the relationship between birth type and depression (95%CI: -0.037 to 0.017; P=0.47), bipolar disorder (95%CI: -0.019 to 0.045; P=0.43), and mood disorder (95%CI: -0.033 to 0.042; P=0.80) in adolescents of both sexes. Birth by cesarean section was not associated with the development of mood disorders in adolescents.

Birth by cesarean section and mood disorders among adolescents of a birth cohort study in northern Brazil

The increasing number of cesarean sections worldwide has encouraged research on the long-term effects of this birth type on the offspring's mental health. The objective of this study was to investigate whether there is an association between birth by cesarean section and the development of mood disorders (depression and bipolar disorders) in adolescents. A cohort study was carried out with 1603 adolescents from 18 to 19 years old who participated in the third phase of a birth cohort study in São Luís, MA, in 2016. Information on birth type and weight, prematurity, mother's age and schooling, parity, marital status, and smoking behavior during pregnancy, were collected at birth. The study outcomes were depression, bipolar disorder, and "mood disorder" construct. A Directed Acyclic Graph (DAG) was developed to select the variables for minimal adjustment for confounding and collision bias. Associations were estimated through propensity score weighting using a two-step estimation model, and confounders for cesarean birth were used in the predictive model. There was no significant association in the relationship between birth type and depression (95%CI: -0.037 to 0.017; P=0.47), bipolar disorder (95%CI: -0.019 to 0.045; P=0.43), and mood disorder (95%CI: -0.033 to 0.042; P=0.80) in adolescents of both sexes. Birth by cesarean section was not associated with the development of mood disorders in adolescents.

Sub-Clinical Effects of Chronic Noise Exposure on Vestibular System.

AIM: to investigate the effect of chronic noise exposure on vestibular function of subjects without clinical evidence of vestibular disorders and with documented cochlear damage from noise. SUBJECTS AND METHODS: 25 patients with chronic noise-induced hearing loss (NIHL) and without vestibular complaints (group A) and 25 matched controls with sensorineural hearing loss without noise exposure (group B), underwent audiological and vestibular test including caloric and cervical vestibular-evoked myogenic potentials tests (cVEMPs). RESULTS: In subjects chronically exposed to noise, similarly to that of the auditory threshold, an increase in the evocation threshold of VEMPs has been documented, statistically significant (p<0,05) and independent of the performance of the auditory threshold. p1-n1 amplitude values showed a significant difference between group A and group B. No significant difference for p1-n1 latencies between the two groups was found. CONCLUSION: We have documented the possibility of vestibular lesion, along with cochlear damage, related to chronic acoustic trauma.

Pharmacological, Surgical and Diagnostic Innovations in Meniere's Disease: A Review.

PURPOSE: To investigate literature about pharmacological, surgical, and diagnostic innovations for Meniere's Disease (MD). SUMMARY: Meniere's disease is an inner ear disorder characterized by the presence of endolymphatic hydrops in the inner ear and symptomatology of recurrent and debilitating vertigo attacks, tinnitus, aural fullness, and fluctuating sensorineural hearing loss. Although many therapeutic options for MD have been proposed during years, no consensus has been reached by the scientific community. In the last decade, many therapeutic options have been proposed, as intratympanic steroid, intratympanic gentamicin, and intravenous glycerol. Recently, the role of the antisecretory factor in the diet of MD patients have been investigated. Surgery is recommended for intractable MD; some authors proposed new approaches including transcanal endoscopic infracochlear vestibular neurectomy, new marsupiliazation technique in sac surgery, and tenotomy of the stapedius and tensor tympani muscles.

Drug-Induced Sleep Endoscopy (DISE) with Simulation Bite to Predict the Success of Oral Appliance Therapy in Treating Obstructive Sleep Apnea/Hypopnea Syndrome (OSAHS).

STUDY OBJECTIVES: Oral appliances have gained their place in the treatment of obstructive sleep apnea (OSA) where custom-made titratable mandibular advancement devices (MAD) have become the oral appliance of choice. This study aimed to asses the value of the drug-induced sleep endoscopy (DISE) using a MAD in the prediction of treatment outcome for OSAHS. METHODS: This is a prospective, single-center cohort study that enrolled sixty-six consecutive patients with diagnosed OSA (5 events/h < apnea-hypopnea index (AHI) < 50 events/h) to be treated with a custom-made titratable MAD. The patients were evaluated polysomnographically with the MAD in situ after the adaptation and titration period of 3 months. The associations between findings during DISE and treatment outcome were assessed. RESULTS: The subjects showed a wide range of severity of OSAHS pre-treatment: median AHI was 43.10 with a range from 20.13 to 66.07. The simulation bite was associated with a significant increase in cross-sectional area at level of the velopharynx, tongue base and epiglottis. MAD treatment response in the studied population was 91%, with a mean AHI improving from 43.10 to 12.93. CONCLUSIONS: Drug-induced sleep endoscopy with simulation bite is an acceptably reproducible technique for determining the sites of obstruction in OSAHS subjects; it thus offers possibilities as a prognostic indicator for treatment with MAD.

When tumor doesn't read textbook. Third case of TTF1 and p40 co-expression in the same tumour cells in a non-small cell carcinoma. A potential new entity to consider?

INTRODUCTION: The 2011 WHO Classification for lung adenocarcinoma enlightened the need for a wise use of immunohistochemistry to preserve tissue for both diagnosis and molecular studies. The current recommendation is to use a panel comprising TTF1 and p40 to classify tumors with no clear squamous or glandular differentiation as many studies have showed the higher specificity of p40 over p63 as marker of squamous differentiation. However, the co-expression of both markers opens a new scenario with subsequent classification and potentially treatment issues. MATERIALS AND METHODS: We report a case of a non-small lung cell carcinoma (NSCLC) with coexistent expression of TTF1 and p40 in the same tumour cells. To our knowledge, this peculiar immunohistochemical profile is very rare, and thus a review of the clinical and molecular features including molecular variances of the tumour was performed. Review of the pertinent literature was also carried out. RESULTS: Two additional articles describing unusual cases of NSCLC with coexistent expression of TTF1 and p40 were found and compared to our case. Interestingly, they all carried out aberrant mutation in TP53 oncogene and were of advance stage. CONCLUSION: The positivity for both "squamous" and "adenocarcinomatous" markers and mutations of TP53 could be the expression of a not fully recognized variant of NSCLC with possible implications for classification, diagnosis and therapy.

Clogging in constructed wetlands: Indirect estimation of medium porosity by analysis of ground-penetrating radar images.

Identification of the degree of porous medium clogging in constructed wetlands (CWs) is a complex procedure because bed obstruction is a phenomenon that occurs in the subsurface and involves several factors. Ideal methods must allow for subsurface analysis and be non-invasive, what is the case of ground penetrating radar (GPR or georadar) used for soil characterization. Thus, this work aimed to evaluate the use of GPR for clogging characterization of two full-scale horizontal subsurface flow constructed wetlands (HSSF-CWs), one unit planted with cattail (Typha latifolia) and the other unit with no vegetation. Both units received municipal sewage (50 p.e. each) previously treated in an anaerobic reactor, had been in operation for seven years (at the time the GPR was used) and showed signs of heavy clogging, leading to surface flow. In order to produce a standard for GPR image (created by the response of the reflected wave in the passage through different media) identification and association of colors with the environmental conditions inside the medium (cleaner or more obstructed condition), a clean granular rock filter (in operation for only one month), similar to the unplanted unit, was used. Equations developed for indirectly estimating the porosity, based on the RGB (red, green and blue) color scale, indicated that the methodology was in agreement with the visual conditions of surface flow occurrence in the HSSF-CW, showing to be a suitable non-invasive method to characterize the advancement of clogging in CWs.

Pleural chondroid metaplasia in a background of IgG4 plasma cell rich chronic inflammatory infiltrate: report of a rare case with review of literature.

Mesothelial reactive and degenerative changes secondary to inflammatory conditions, toxin exposure, neoplastic and non-neoplastic disease are often encountered in routine histopathology practice. Herein, we report a very rare case of pleural chronic inflammation with features suggestive for IgG4-related disease associated with the formation of a nest of mature, benign looking cartilage in the pleura of a middle age male patient. The review of the pertinent literature reveals that to date, only few cases of chondroid metaplasia or benign tumor (choristoma) are reported in mesothelium and only occasionally in this change is found in the pleura.

Serological survey on Leptospira infection in slaughtered swine in North-Central Italy.

Swine can act as asymptomatic carriers of some Leptospira serovars. In this study, 1194 sera from 61 farms located in five different Regions of North-West Italy were collected from slaughtered healthy pigs. Presence of antibody against four Leptospira serovars was evaluated. Overall, 52.5% of analysed farms presented at least one positive animal and 34.4% presented at least one positive swine with titre ⩾1:400. A percentage of 16.6% sera was positive and 5.9% samples presented a positive titre ⩾1:400. Tuscany and Lombardy showed the highest percentage of positive farms (64.3% and 54.6%, respectively) and sera (28.5% and 13.3%, respectively), probably due to environmental conditions and potential risk factors, which promote maintenance and spreading of Leptospira in these areas. The main represented serogroups were Australis (21.3% positive farms, 8.2% positive sera) and Pomona (18.0% positive farms, 8.1% positive sera). In swine, these serogroups are the most detected worldwide; however, our results seem to highlight a reemerging of serogroup Pomona in pigs in investigated areas. A low percentage of sera (0.6%) scored positive to Canicola, leaving an open question on the role of pigs in the epidemiology of this serovar. Higher antibody titres were detected for serogroups Australis and Pomona. Swine leptospirosis is probably underestimated in Italy and could represent a potential risk for animal and human health.

Cellular fibroma in the Douglas cavity, mimicking a malignant neoplasia: fibroma, fibrosarcoma or mitotically active cellular fibroma?

INTRODUCTION: Ovarian fibroma is a benign stromal tumour composed of spindle/ovoid fibroblastic cells producing collagen. Approximally 10% of fibromas are densely cellular with small amount of collagen. In these cases, if mild nuclear atypia is present, they are best addressed as cellular fibroma. However cellular fibroma may show a greater mitotic activity and therefore they should be referred as mitotically active cellular fibromas. Mostly benign, it is necessary to differentiate them from malignant tumours such as fibrosarcomas. METHODS: We report a case of an unusual presentation of mitotically active cellular fibroma, detected in the Douglas cavity of a young woman, with normal appearing ovaries and uterus, mimicking a malignant neoplasia clinically and on imaging. In fact abdominal mass may be associated with acute pain, resulting in clinical emergency, really difficult to distinguish from a frank malignancy, before surgical procedure. RESULTS: We described the clinical, radiological and pathological characteristics of our case and we make a comparison of what previously described in literature. DISCUSSION: The differential diagnosis among those entities is based on the microscopic features such as atypia and the number of mitoses. However, according to their dimensions, it may be necessary to generously sample these tumours and sometimes, to perform a panel of immunohistochemical markers, in order to make a correct diagnosis, establish the best treatment and the right follow-up. In fact, the prognosis is not certain, due to the possible recurrence, especially if not completely excised.

Transcranial brain photoplethysmography to study the venules of cerebral cortex in patients with multiple sclerosis.

OBJECTIVE: To evaluate the utility of a transcranial brain photoplethysmography parameter as a potential marker for patients with multiple sclerosis. METHODS: We investigated 38 patients affected by multiple sclerosis, according to the revised McDonald criteria (12 males and 26 females, mean age 41.1 ± 8.5 years, Expanded Disability Status Scale mean value 2.6 ± 2.1) and compared them with 20 age- and sex-matched healthy controls. By means of transcranial brain photoplethysmography, a safe and non-invasive technology, we measured the increase in cerebral blood volume during compression for 10 s of the internal jugular veins of both sides in sitting position. RESULTS: The cerebral blood volume increase was significantly smaller in the multiple sclerosis patients (left frontal cortex: -58%, p < 0.0001; right frontal cortex: -59%, p < 0.0001) compared with the controls. CONCLUSIONS: Our study reveals that a minor increase in cerebral blood volume on the frontal cortex of both sides in sitting position is associated with a diagnosis of multiple sclerosis and might be a new marker.

The increased distensibility of the wall of cerebral arterial network may play a role in the pathogenic mechanism of migraine headache.

The aim was to evaluate whether patients with episodic migraine with (MA+) and without aura (MA-), during the interictal period of migraine would have an altered distensibility of the wall of cerebral arterial network and whether it would play a role in migraine headache. To evaluate the distensibility of the wall of cerebral arterial network, we measured the time-delay in milliseconds (ms) between the R-wave of an electrocardiogram and the arterial pulse wave of cerebral microcirculation (R-APWCMtd) on the frontal cortex detected by near-infrared spectroscopy (NIRS) in 10 patients with MA+ (age 39.5 ± 12.2 years), in 10 with MA- (age 40.3 ± 10.2 years), according to ICHD-3 criteria 2012, during the interictal period of migraine, and in 15 age-, sex- and height-matched healthy control subjects. The patients with migraine had a significantly longer R-APWCMtd than the control subjects F = 13.4, p < 0.001: MA+:+38.3 ms; MA-:+34.7 ms indicating an increased distensibility of the wall of cerebral arterial network. In multiple regression analysis, R-APWCMtd was significantly associated with migraine (R (2) = 0.50, p < 0.0001) but not with age, gender, height, migraine attack frequency and disease duration. The increased distensibility leads to an increased flow pulsatility into intracranial dural meningeal vessels that may lead to a mechanical stimulation of the nociceptors that innervate the dural vasculature. This condition may play a role in promoting the sensitization of trigeminovascular afferents and sterile inflammation within the dura mater that are fundamental to the pathogenesis of migraine headache.

New brain reperfusion rehabilitation therapy improves cognitive impairment in mild Alzheimer's disease: a prospective, controlled, open-label 12-month study with NIRS correlates.

BACKGROUND AND AIMS: A large body of evidence indicates that cerebral hypoperfusion is one of the earliest signs in the development of Alzheimer's disease (AD). The aim of our study was to evaluate whether the brain reperfusion rehabilitation therapy (BRRT) would improve verbal memory and learning and/or global cognitive impairment in mild AD. METHODS: Using a prospective, controlled, open-label 12-month study, we enrolled 15 patients with mild AD, who underwent BRRT program (BRRT group), and 10 age-sex-matched mild AD patients, who received no treatment (control group). At baseline (T0), and at the end of the 3 months (T3), 6 months (T6) and 12 months (T12) participants from both groups were given an evaluation, using Mini-Mental State Examination (MMSE) and Rey Auditory Verbal Learning Test (RAVLT). In both groups by using near-infrared spectroscopy, at T0 and T12, we measured tissue oxygen saturation (TOI) on temporal-parietal and frontal cortex of both sides. RESULTS: Ten patients from the BRRT group and 10 from the control group completed the 12-month follow-up. At the end of rehabilitation protocol, a significant improvement of MMSE and RAVLT was observed in the BRRT group as compared to control group. At T12 compared to T0, a significant improvement of TOI on frontal cortex of both sides was observed in the BRRT group as compared to control group. CONCLUSION: BRRT improves verbal memory-learning and global cognitive impairment which are associated with increased TOI values on frontal cortex of both sides.

Ascertainment bias in dementias: a secondary to tertiary centre analysis in Central Italy and conceptual review.

BACKGROUND AND AIMS: Ascertainment bias (AB) indicates a bias of an evaluation centre in estimating the prevalence/incidence of a disease due to the specific expertise of the centre. The aim of our study was to evaluate classification of different types of dementia in new cases appearing in secondary and tertiary centres, in order to evidence possible occurrence of AB in the various (secondary to tertiary) dementia centres. METHODS: To assess the mechanism of AB, the rates of new cases of the different forms of dementia reported by different centres were compared. The centres involved in the study were 11 hospital-based centres including a tertiary centre, located in the University Department of Clinical Neurology. The tertiary centre is endowed with state-of-the-art diagnostic facilities and its scientific production is prominently focused on dementia with Lewy bodies (DLB) thus suggesting the possible occurrence of a bias. Four main categories of dementia were identified: Alzheimer's disease (AD), DLB, fronto-temporal dementia (FTD), vascular dementia (VaD), with other forms in a category apart. The classification rate of new cases of dementia in the tertiary centre was compared with rates reported by secondary centres and rates of recoding were calculated during a follow-up of 2 years. RESULTS: The study classified 2,042 newly diagnosed cases of dementia in a population of 1,370,000 inhabitants of which 315,000 were older than 65. AD was categorized in 48-52 % of cases, DLB in 25-28 %, FTD in 2-4 % and VaD in 17-28 %. During the 2-year follow-up the diagnosis was re-classified in 40 patients (3 %). The rate of recoding was 5 % in the tertiary centre, 2-8 % in referrals from secondary to tertiary centre, 2-10 % in recodings performed in secondary centres and addressed to tertiary centre. Recoding or percentages of new cases of AD or DLB were not different in the comparison between secondary or between secondary and tertiary centres. FTD and VaD were instead significantly recoded. CONCLUSION: The results of the study suggest that in a homogeneous area, AB is not interfering with diagnosis of AD or DLB.

A new near-infrared spectroscopy parameter as marker for patients with migraine.

Due to the lack of markers for migraine, diagnosis relies entirely on symptomatology. The aim is to evaluate the utility of a new near-infrared spectroscopy parameter as potential marker for patients with episodic migraine with (MA+) and without aura (MA-) during the interictal period of migraine. We studied 10 patients with MA+ (age 39.5 ± 12.2 years) and 10 with MA- (age 40.3 ± 10.2 years), according to ICHD-II criteria 2004, during the interictal period of migraine and 15 age and sex matched healthy control subjects. The cases and controls were free from vascular risk factors and migraine prophylactic medications. At rest in all the participants, the time delay in millisecond (ms), between the R-wave of an electrocardiogram and the arterial pulse wave of cerebral microcirculation detected by transcranial near-infrared Spectroscopy (R-APWCMtd) on the frontal cortex of both side, was determined. The patients with migraine had a significantly longer R-APWCMtd than the control subjects: the patients with MA+: +38.3 ms, p < 0.0002; the patients with MA-: +34.7 ms, p < 0.0002, and there was no significant difference between MA+ and MA-, p = 0.71. We used receiver-operator characteristic (ROC) curve to assess the diagnostic potential of the R-APWCMtd measurement for diagnosis of migraine; we found an ROC area of 0.92, p < 0.0001, sensitivity 77.8 %, specificity 100 % and cutoff of 242 ms. Our study seems to indicate that the longer R-APWCMtd is independently associated with a diagnosis of migraine, and may be considered a new marker for migraine, especially in patients with MA+.

Tissue oxygen saturation and pulsatility index as markers for amnestic mild cognitive impairment: NIRS and TCD study.

OBJECTIVE: To evaluate the utility of near-infrared spectroscopy (NIRS) and transcranial Doppler (TCD) parameters as potential markers for amnestic mild cognitive impairment (aMCI). METHODS: By means of NIRS and TCD, noninvasive and inexpensive technologies, we studied 21 patients with aMCI (10 M and 11 F, 70.2 ± 7.3 years) and 10 age matched healthy controls. RESULTS: By means of NIRS, we found a significant mean decrease of tissue oxygen saturation of cortex microcirculation (TOI), - 27%, p < 0.0005, on the temporal-parietal cortex of both side compared to the controls. By means of TCD, we found a significant mean increase of pulsatility index (PI), p < 0.0007, of middle cerebral artery (MCA) of both side compared to the controls. Cerebrovascular risk factors were present in 81% of the aMCI patients. CONCLUSIONS: Our study reveals that the TOI reduction on the temporal-parietal cortex of both side and the increase of PI in both MCA are associated with a clinical diagnosis of aMCI patients. SIGNIFICANCE: The reduction of TOI may be considered a new marker for aMCI, especially when combined with the increase of PI in MCA.