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Antonio M Fea,1 Andrea Ghilardi,1 Davide Bovone,1 Michele Reibaldi,1 Alessandro Rossi,1 Earl R Craven2 1Dipartimento di Scienze Oftalmologiche-Universita’ di Torino, Torino, Italy; 2Glaucoma Center of Excellence, The Johns Hopkins Wilmer Eye Institute, Baltimore, Maryland, USACorrespondence: Antonio M Fea, Tel +39 3495601674, Email antoniomfea@gmail.comAbstract: PRESERFLO™ MicroShunt is a new minimally invasive glaucoma surgical (MIGS) device, implanted with an ab externo approach, which drains the aqueous humor to the subconjunctival space. It has been designed as a safer and less invasive approach for treating medically uncontrolled primary open-angle glaucoma (POAG) patients. The classic way of MicroShunt implantation involves different key steps, which includes creating a small scleral pocket with a 1mm blade; passing a 25-gauge (25G) needle through the scleral pocket into the anterior chamber (AC); and subsequently flushing the stent with a 23-gauge (23G) thin-wall cannula. However, sliding the needle into the scleral pocket can create false passages, thus making the device’s threading more difficult. The purpose of the current paper is to propose a simplified implantation approach. Our method proposes to make the scleral tunnel by using directly the 25G needle and, at the limbus, this 25G needle is used to slightly depress the sclera and enter into the AC. The MicroShunt is subsequently assembled on a 23G cannula mounted on a 1mL syringe. The syringe can then be used to flush the device. Outflow can thus be confirmed immediately by seeing drops of aqueous humor leaking from the external opening of the stent. This new approach may have different potential advantages, such as better control of the site of entry, avoids wrong passages, reduces or eliminates the risk of aqueous humor sideway flow, facilitates a parallel path to the iris plane, and it is faster.Keywords: MIGS, open-angle glaucoma, Preserflo, MicroShunt, glaucoma surgery, subconjunctival filtration surgery

Estimates of the spectrum and frequency of pathogenic variants in Parkinsons disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinsons disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

Habituation and dishabituation are the most prevalent measures of infant cognitive functioning, and they have reliably been shown to predict later cognitive outcomes. Yet, the exact mechanisms underlying infant habituation and dishabituation are still unclear. To investigate them, we tested 106 8-month-old infants on a classic habituation task and a novel visual learning task. We used a hierarchical Bayesian model to identify individual differences in sustained attention, learning performance, processing speed and curiosity from the visual learning task. These factors were then related to habituation and dishabituation. We found that habituation time was related to individual differences in processing speed, while dishabituation was related to curiosity, but only for infants who did not habituate. These results offer novel insights in the mechanisms underlying habituation and serve as proof of concept for hierarchical models as an effective tool to measure individual differences in infant cognitive functioning.

Infants' bodies, brains, and environments are ever-changing. Although this continuous transformation is a fundamental feature of development, how infants actively adapt and learn amidst such volatility is still unknown. To address this, we devised a novel learning task in which the location of a reward was systematically altered, transitioning from stable to volatile periods. Through computational modelling, we inferred from the infants' gaze and pupil data the learning processes that enabled them to navigate these changing environments. We found that infants' tonic pupil size reflected trial-by-trial changes in the level of environmental volatility. Moreover, phasic changes in pupil size when observing the reward indicated that infants relied on the information about volatility to optimize their learning. This resulted in the successful performance of the task, as indicated by the pattern of anticipatory looks to the correct reward locations. Together, these results identify the active role that infants play in adapting to change.

Abstract Occurrence of resistance to olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) approved in ovarian carcinoma, has already been shown in clinical settings. Identifying combination treatments to sensitize tumor cells and/or overcome resistance to olaparib is critical. Polo-like kinase 1 (PLK1), a master regulator of mitosis, is also involved in the DNA damage response promoting homologous recombination (HR)-mediated DNA repair and in the recovery from the G2/M checkpoint. We hypothesized that PLK1 inhibition could sensitize tumor cells to PARP inhibition. Onvansertib, a highly selective PLK1 inhibitor, and olaparib were tested in vitro and in vivo in BRCA1 mutated and wild-type (wt) ovarian cancer models, including patient-derived xenografts (PDXs) resistant to olaparib. The combination of onvansertib and olaparib was additive or synergic in different ovarian cancer cell lines, causing a G2/M block of the cell cycle, DNA damage, and apoptosis, much more pronounced in cells treated with the two drugs as compared to controls and single agents treated cells. The combined treatment was well tolerated in vivo and resulted in tumor growth inhibition and a statistically increased survival in olaparib-resistant-BRCA1 mutated models. The combination was also active, although to a lesser extent, in BRCA1 wt PDXs. Pharmacodynamic analyses showed an increase in mitotic, apoptotic, and DNA damage markers in tumor samples derived from mice treated with the combination versus vehicle. We could demonstrate that in vitro onvansertib inhibited both HR and non-homologous end-joining repair pathways and in vivo induced a decrease in the number of RAD51 foci-positive tumor cells, supporting its ability to induce HR deficiency and favoring the activity of olaparib. Considering that the combination was well tolerated, these data support and foster the clinical evaluation of onvansertib with PARPis in ovarian cancer, particularly in the PARPis-resistant setting.

In recent years, microalgae, particularly Euglena gracilis, have been candidates for the food/feed industry thanks to their nutritional and functional properties. However, the inclusion of E. gracilis in the diet of livestock animals is little studied, especially regarding its antioxidant activity. Furthermore, microalgae are known for their variability in nutritional quality and functional properties, mainly due to cultivation conditions. For this reason, the aim of the present work was to investigate the nutritional and functional aspects (total phenolic content TPC, Folin-Ciocalteu assay); antioxidant activity (ABTS and FRAP assays) of E. gracilis, grown in three different media, following chemical extraction (H2O:EtOH) and ex vivo digestion method. The microalgae growth media were characterised as follows: EgM (standard medium); ETX (standard medium + aminoacidic-extract); DOE-ETX (ETX + microelements). The results showed an interesting nutritional profile for all the microalgae analysed, although the values were modulated by media nutrients. Although EgM (6.94 ± 0.25 g/L) was characterised by a significant higher growth yield than ETX (5.75 ± 0.14 g/L) and DOE-ETX (4.72 ± 0.17 g/L), results also confirmed by the paramylon content (4.35 ± 0.13; 3.16 ± 0.08; 2.25 ± 0.05 g/L, respectively) (p

Abstract Background Suicide is one of the leading causes of death among young people and university students. Research has identified numerous socio-demographic, relational, and clinical factors as potential predictors of suicide risk, and machine learning techniques have emerged as promising ways to improve risk assessment. Objective This cross-sectional observational study aimed at identifying predictors and college student profiles associated with suicide risk through a machine learning approach. Methods A total of 3102 students were surveyed regarding potential suicide risk, socio-demographic characteristics, academic career, and physical/mental health and well-being. The classification tree technique and the multiple correspondence analysis were applied to define students’ profiles in terms of suicide risk and to detect the main predictors of such a risk. Results Among the participating students, 7% showed high potential suicide risk and 3.8% had a history of suicide attempts. Psychological distress and use of alcohol/substance were prominent predictors of suicide risk contributing to define the profile of high risk of suicide: students with significant psychological distress, and with medium/high-risk use of alcohol and psychoactive substances. Conversely, low psychological distress and low-risk use of alcohol and substances, together with religious practice, represented the profile of students with low risk of suicide. Conclusions Machine learning techniques could hold promise for assessing suicide risk in college students, potentially leading to the development of more effective prevention programs. These programs should address both risk and protective factors and be tailored to students’ needs and to the different categories of risk.

Abstract Bendamustine has been retrospectively shown to be an effective and safe lymphodepletion regimen prior to the anti-CD19 chimeric antigen receptor T cell (CART) products tisagenlecleucel and axicabtagene ciloleucel, as well as the anti-BCMA CART products idecabtagene vicleucel and ciltacabtagene autoleucel. However, bendamustine as lymphodepletion prior to lisocabtagene maraleucel (liso-cel), a 4-1BB co-stimulated, fixed CD4:CD8 ratio anti-CD19 CART product, has not been described yet. Thus, we studied a cohort of sequentially-treated patients with large B-cell lymphomas who received bendamustine lymphodepletion before liso-cel at the University of Pennsylvania between 5/2021 and 12/2023 (n = 31). Patients were evaluated for toxicities and responses. Of note, 7 patients (22.6%) would have dnot met the inclusion criteria for the registrational liso-cel clinical trials, mostly due to older age. Overall and complete response rates were 76.9% and 73.1%, respectively. At a median follow-up of 6.3 months, the 6-month progression-free and overall survival were 59.9% and 91.1%, respectively. Rates of cytokine-release syndrome (CRS) and neurotoxicity (ICANS) of any grade were 9.7% and 9.7%, respectively, with no grade ≥ 3 events. No infections were reported during the first 30 days following liso-cel infusion. Neutropenia ≥ grade 3 was observed in 29.0% of patients; thrombocytopenia ≥ grade 3 occurred in 9.7%. In conclusion, bendamustine lymphodepletion before liso-cel appears to be a strategy that can drive tumor responses while ensuring a mild toxicity profile.

Abstract Trauma scientists have raised the alarm about the devastating consequences of the Ukraine war on mental health. We examined how higher education students—as indirect victims—coped with this conflict and how they emotionally reacted during 2022. We involved 2314 students from 16 countries through an online survey. A structural equation model indicated significant relations between war-related worry about military and macroeconomics domains and two coping strategies (opposition, support giving), in turn significantly linked with six emotions. The model was strongly invariant across gender, study field, and geographic area. The most frequent emotions were anger and anxiety, followed by two future-centred emotions (hopelessness and hope). Emotions were more frequent for females and students of the countries geographically close to the war region. Our findings call for evidence-based policy recommendations to be implemented by institutions to combat the negative short and long-term psychological sequelae of being witnesses of armed conflicts.

Abstract The small muscle protein, X-linked (SMPX) gene encodes a cytoskeleton-associated protein, highly expressed in the inner ear hair cells (HCs), possibly regulating auditory function. In the last decade, several mutations in SMPX have been associated with X-chromosomal progressive non syndromic hearing loss in humans and, in line with this, Smpx-deficient animal models, namely zebrafish and mouse, showed significant impairment of inner ear HCs development, maintenance, and functioning. In this work, we uncovered smpx expression in the neuromast mechanosensory HCs of both Anterior and Posterior Lateral Line (ALL and PLL, respectively) of zebrafish larvae and focused our attention on the PLL. Smpx was subcellularly localized throughout the cytoplasm of the HCs, as well as in their primary cilium. Loss-of-function experiments, via both morpholino-mediated gene knockdown and CRISPR/Cas9 F0 gene knockout, revealed that the lack of Smpx led to fewer properly differentiated and functional neuromasts, as well as to a smaller PLL primordium (PLLp), the latter also Smpx-positive. In addition, the kinocilia of Smpx-deficient neuromast HCs appeared structurally and numerically altered. Such phenotypes were associated with a significant reduction in the mechanotransduction activity of the neuromast HCs, in line with their positivity for Smpx. In summary, this work highlights the importance of Smpx in lateral line development and, specifically, in proper HCs differentiation and/or maintenance, and in the mechanotransduction process carried out by the neuromast HCs. Because lateral line HCs are both functionally and structurally analogous to the cochlear HCs, the neuromasts might represent an invaluable—and easily accessible—tool to dissect the role of Smpx in HCs development/functioning and shed light on the underlying mechanisms involved in hearing loss.

Objective: Monoclonal antibodies (mAbs) against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) reduced Coronavirus Disease 2019 (COVID-19) hospitalizations in people at risk of clinical worsening. Real-world descriptions are limited. Methods: CONDIVIDIAMO, a two-year multicenter observational study, consecutively enrolled SARS-CoV-2 outpatients with ≥1 risk factor for COVID-19 progression receiving mAbs. Demographic data, underlying medical condition, type of mAbs combination received, duration of symptoms before mAbs administration, COVID-19 vaccination history, were collected upon enrolment and centrally recorded. Data on outcomes (hospitalizations, reasons of hospitalization, deaths) were prospectively collected. The primary endpoint was the rate of hospitalization or death in a 28-day follow-up, whichever occurred first; subjects were censored at the day of last follow-up or up to 28 days. The Kaplan-Meier method was used to estimate the incidence rate curve in time. The Cox regression model was used to assess potential risk factors for unfavorable outcome. Results were shown as hazard ratio (HR) along with the corresponding 95 % Confidence Interval (95%CI). Results: Among 1534 subjects (median [interquartile range, IQR] age 66.5 [52.4–74.9] years, 693 [45.2 %] women), 632 (41.2 %) received bamlanivimab ± etesevimab, 209 (13.6 %) casirivimab/imdevimab, 586 (38.2 %) sotrovimab, 107 (7.0 %) tixagevimab/cilgavimab. After 28-day follow-up, 87/1534 (5.6 %, 95%CI: 4.4%–6.8 %) met the primary outcome (85 hospitalizations, 2 deaths). Hospitalizations for COVID-19 (52, 3.4 %) occurred earlier than for other reasons (33, 2.1 %), after a median (IQR) of 3.5 (1–7) versus 8 (3–15) days (p = 0.006) from mAbs administration.In a multivariable Cox regression model, factors independently associated with increased hospitalization risk were age (hazard ratio [HR] 1.02, 95%CI 1.00–1.03, p = 0.021), immunodeficiency (HR 1.78, 95%CI 1.11–2.85, p = 0.017), pre-Omicron calendar period (HR 1.66, 95%CI 1.02–2.69, p = 0.041). Conclusions: MAbs real-world data over a 2-year changing pandemic landscape showed the feasibility of the intervention, although the hospitalization rate was not negligible. Immunosuppressed subjects remain more at risk of clinical worsening.

Abstract Pain control after deep brain stimulation (DBS) in Parkinson’s disease (PD) remains unclear. Following six months, subthalamic (STN)-DBS reduced sensory complaints related to parkinsonism and bodily discomfort, increasing central beta-endorphin level. Pallidal GPi-DBS decreased bodily discomfort and beta-endorphin levels. Unexplained pain by other conditions and bodily discomfort were negatively correlated with beta-endorphin levels. Thus, DBS regulates central opioids, and prioritizing STN is important for PD patients with significant sensory complications.