Biogen (Italy)

Objectives: To analyze speech perception outcomes of a cohort of experienced adult cochlear implant (CI) users to explore whether there is a correlation with electrical dynamic range (EDR) parameters, and to describe speech intelligibility curve morphology according to the degree of CI performance. Methods: A bicentric retrospective observational study. Data were extracted from a cochlear implantation database from a total of 36 CI users implanted with Advanced Bionics devices. Results: Mean age at implantation was 56.61 years. In the majority of cases, hearing loss onset was more than 15 years before implantation (80.55%), and only 11.11% of cases preserved residual hearing. This resulted in a significant relationship between speech therapy and better speech recognition (p = 0.044). At the same time, no correlation was found between age, duration of deafness before implantation, and maximum speech perception achieved (p > 0.05). Mean speech audiometry curves displayed a roll-over phenomenon in poor performers and a plateau effect in average performers. In contrast, the mean curve of high performers exhibited a steeper morphology (p < 0.0001). Speech recognition threshold (SRT) and word recognition score (WRS) were predictors of speech audiogram curves (p = 0.006). No direct correlation was found between the mean T-level, M-level, dynamic range, and maximum recognition score, even after clustering electrodes by position along the cochlea (p > 0.05). Conclusions: EDR parameters did not emerge as independent predictors of speech recognition outcomes within this specific cohort. Speech therapy and rehabilitative efforts showed a significant relationship with improved performance, and speech audiogram curve morphology may offer a more specific clinical tool for assessing global CI performance. Further prospective studies with larger, more homogenous populations are required to validate these findings.

Heat stress (HS) in dairy cows disrupts homeostasis and thermoregulation, negatively affecting milk production, health status, and metabolism. Dietary supplementation with phytoextracts such as polyphenols may offer an effective dietary strategy by stimulating the immune system, reducing oxidative stress, and ultimately enhancing welfare, metabolic function, and milk performance. This study aimed to evaluate the effects of supplementing mid-lactating Fleckvieh cows with rumen-protected grape extract (Nor-Grape BP-O, Nor-Feed) on milk performance, rectal temperature (RT), behavior, immunometabolism, rumen fermentation, and innate immune response under naturally occurring HS conditions (temperature-humidity index >72). Thirty cows were balanced by days in milk, milk yield, and parity, and randomly assigned to receive either 470 mg/cow per day of Nor-Grape BP-O supplementation (NG-BPO, n = 15) or a control diet without supplementation (CTR, n = 15) and monitored for 35 d. Both groups were cooled daily using forced ventilation and fans. Temperature-humidity index, milk yield, heavy breathing (HB), rumination, and eating time were recorded daily. Milk, blood, and rumen fluid samples were collected at different time points, and RT was measured. The NG-BPO cows exhibited greater milk production, fat-corrected milk, energy-corrected milk, and yields of fat and protein, alongside lower SCC compared with CTR cows. The NG-BPO cows exhibited improved thermoregulatory responses, reflected by significantly lower RT and reduced HB. Supplementation with Nor-Grape BP-O lowered inflammatory status and enhanced innate immune responses, as indicated by higher plasma zinc and myeloperoxidase levels, lower haptoglobin concentrations, and increased phagocytic activity of neutrophils and monocytes compared with CTR cows. These findings were supported by higher levels of proinflammatory cytokines TNF-α and IL-1 β during peak HS periods, compared with CTR cows. In addition, the NG-BPO group had lower circulating platelet and eosinophil counts compared with the CTR group. In conclusion, supplementation with a low dose of rumen-protected dry grape extract-rich in low-molecular-weight polyphenols (oligomeric and monomeric flavanols, anthocyanins)-effectively supported milk production and quality in heat-stressed dairy cows. Moreover, supplementation improved thermotolerance during heat waves and enhanced innate immune functions while reducing inflammatory responses. These findings suggest Nor-Grape BP-O as an effective dietary strategy to mitigate the negative effects of HS by enhancing cow performance and welfare during periods of elevated environmental temperatures.

Abstract Study question Can a seven-day long LH priming treatment preceding ovarian stimulation (OS) improve follicular responses, oocyte yields and ICSI/IVF outcomes of POSEIDON-4 patients? Summary answer A seven-day long LH priming can substantially increase pregnancy rates through specific benefits in different subgroups of POSEIDON-4 patients. What is known already The combination of advanced maternal age (AMA) with diminished ovarian reserve (DOR) has become one of the most relevant and complex topics in the field of reproductive medicine. AMA/DOR patients appear to be refractory to increased gonadotropin dose and may benefit from strategies specifically capable of increasing the population of FSH-responsive small follicles before the onset of ovarian stimulation (OS). Androgen mediated LH intra-ovarian activity stimulates early follicular development. Pre-treatment with LH has been suggested to improve ICSI/IVF outcomes in normal responders but has not been assessed in AMA/DOR patients, despite the prevalence and relevance of this population. Study design, size, duration Retrospective cohort study from 2022 to 2023, including 235 POSEIDON-4 patients stimulated with FSH+LH in a flexible antagonist protocol with oestradiol pre-treatment (n = 129) or with the same stimulatory treatment preceded by a seven-day LH priming (150 IU/day) combined with GnRH agonist downregulation (n = 106). Follicular responses, oocyte recovery and ICSI/IVF outcomes were compared between treatment-groups in overall POSEIDON-4 patients and in a subgroup of patients with AMH &amp;lt;0.75 ng/mL (n = 77/Control, n = 59/LH priming). Participants/materials, setting, methods All participants were POSEIDON-4 caucasian patients aged 35 to 44 years undergoing a single homologous ICSI/IVF cycle in our clinic. Outcomes in the form of percentages were compared with the Fisher’s exact test, whereas differences in continuous variables were assessed with the Wilcoxon sum rank test. A multivariate analysis was performed to control for the interference of unequal variations in maternal age, AMH, insemination method and presence of male subfertility. Main results and the role of chance Patients in different treatment groups did not differ (p &amp;gt; 0.05) regarding maternal age (39.2±2.5 vs. 39.3±2.5), basal FSH serum concentrations (11.0±4.6 vs. 10.1±4.3) and antral follicle count (6.3±3.0 vs. 6.4±3.3, for patients stimulated with and without LH priming, respectively), but patients treated with LH priming presented slightly lower AMH serum levels (0.56±0.3 vs. 0.63±0.3; p = 0.05). Nevertheless, patients treated with LH priming achieved a twice higher clinical pregnancy rate per cycle (19.8% vs. 9.3%; p = 0.02), accompanied by a 40% reduction in cycle cancellation (32.1% vs. 45.0%; p = 0.03) and increased production of viable embryos (transferred fresh + frozen) per cycle (1.22±1.09 vs. 0.94±1.07; p = 0.02) and per oocyte inseminated (48.3% vs. 38.5%; p = 0.01), but did not differ regarding follicular outputs or oocyte yield. The multivariate analysis indicated a robust association between LH priming and pregnancy achievement, independently of potential confounding variables (OR = 2.52; p = 0.02). A two-fold increase in pregnancy achievement was also observed in severely restricted POSEIDON 4 patients (AMH &amp;lt;0.75 ng/mL) subjected to the LH priming (p = 0.05), which in this case was accompanied by higher oocyte yields per cycle (3.3±2.8 vs. 2.2±2.0; p = 0.04) and per pick (3.9±2.6 vs. 2.3±2.0; p &amp;lt; 0.01). Limitations, reasons for caution This study is limited by its retrospective nature and the data may be potentially influenced by the use of different downregulation strategies in the treatment-groups, even if the literature indicates equivalent performance for these strategies in the population under analysis. Wider implications of the findings The present data strongly suggest that a seven-day LH priming preceding OS can markedly improve ICSI/IVF outcomes of POSEIDON-4 patients, while indicating that this strategy benefits in different ways subgroups of this increasingly prevalent patient category. These findings thus represent new valuable parameters for the progress of ovarian stimulation. Trial registration number NA

Abstract Study question Does the incidence of DUC1 in IVF/ICSI cycles vary with the maternal profile and insemination method? Summary answer The incidence of DUC1 cycles is higher in patients with a more favourable prognosis. DUC1 embryos are more frequent in ICSI than in IVF cycles. What is known already The emergence of Time-Lapse Microscopy (TLM) has enabled a dynamic and thorough evaluation of in vitro embryo development, unveiling the occurrence of morphological phenomena unobserved with static observation, such as direct unequal cleavage (DUC), which is associated with a drastically reduced competence to implant. The incidence of DUC-1 (DUC immediately after syngamy) has been reported to vary from 8.3% to 26%, but the reasons underlying its occurrence and variability are unknown. There is evidence that the maternal profile and insemination method can impact embryo developmental competence, but whether they impact the incidence of DUC is also unknown. Study design, size, duration The study includes 2920 first IVF/ICSI cycles (2018 to 2022) providing 12492 embryos. Cycles presenting male infertility were excluded from the analysis. The percentages of DUC1 embryos in relation to total embryos and of cycles providing at least one DUC1 embryo in relation to total cycles were compared between AMA (advanced maternal age; ≥35) and pre-AMA (&amp;lt;35) cycles. Patient/cycle characteristics were compared between cycles with and without DUC1 occurrence in AMA and pre-AMA cycles, separately. Participants/materials, setting, methods Ovarian stimulation was induced with rFSH or with a combination of FSH and LH using classic antagonist or short agonist protocols. Oocytes were inseminated with either IVF or ICSI standard methodology. Embryo culture was performed in an integrated embryo culture Time-lapse System (EmbryoScope; Vitrolife). Differences between percentages were assessed by the Fisher’s exact test, while differences between continuous variables were assessed with the Wilcoxon sum rank test. Main results and the role of chance The percentage of DUC1 embryos in relation to total embryos did not vary between pre-AMA (5.4%) and AMA (5.2%; p &amp;gt; 0.05) cycles. Alternatively, the incidence of cycles providing at least one DUC1 embryo was higher in pre-AMA (21.7%) as compared with AMA patients (16.0%; p &amp;lt; 0.0001). In both pre-AMA and AMA cycles, DUC1 occurrence was associated with higher oocyte yield (13.5±7.7 vs. 10.6±6.7 and 11.0±6.3 vs. 7.5±5.5, respectively; p &amp;lt; 0.0001), higher AMH serum levels (4.4±4.7 vs. 3.4±3.2 and 3.0±3.6 vs. 2.1±2.1ng/mL, respectively; p &amp;lt; 0.004) and lower basal FSH serum levels (7.0±2.1 vs. 7.6±2.9 and 7.8±3.3 vs. 8.5±3.4mU/mL, respectively; p &amp;lt; 0.0001). Overall, the percentage of DUC1 embryos was higher in ICSI (5.6%) as compared to IVF (4.4%, p &amp;lt; 0.01) cycles. However, when the data was stratified by maternal age, DUC1 incidence was significantly higher in ICSI vs. IVF in AMA (5.6 vs 4.0%; p = 0.002) but not in pre-AMA (5.7 vs 5.0%; p = 0.19). All 21 DUC1 embryos transferred during the study failed to implant. Limitations, reasons for caution Our study is limited by its retrospective nature. The present conclusions must be confirmed in other patient populations with different race/genetics and habits. Wider implications of the findings The occurrence of cycles providing DUC1 embryos is paradoxically associated with a more favourable patient prognosis, and the percentage of DUC1 embryos is higher in ICSI as compared to IVF cycles in AMA patients. Our findings represent new valuable clues for the clarification of DUC1 underlying causes. Trial registration number NA

Abstract Study question Does paternal age intensify the negative effects of cryopreservation on sperm quality? Summary answer Paternal age exacerbates the adverse impact of cryopreservation on sperm quality. What is known already Despite mounting evidence indicating age-related declines in sperm quality, the impact of APA on male fertility remains unclear. APA raises questions about DNA fragmentation and mitochondrial activity, a robust indicator of sperm functionality. While sperm cryopreservation is extensively employed in fertility preservation and assisted reproductive technology (ART), its potentially detrimental effects on cells compartments, including mitochondria, persist. The mechanisms of APA on sperm susceptibility to cryopreservation-induced cellular damage still need to be addressed. Study design, size, duration This prospective multicentric study, conducted between January and October 2023, comprised 200 men. Only normozoospermic samples were included in the research (n = 81). Then, based on their age, the participants were categorised into two groups: ages ≤35 (non-APA, n = 40) and ages ≥42 (APA, n = 41). The cohorts were stratified into distinct subgroups, encompassing both fresh and frozen/thawed specimens of APA and non-APA sperm, and subjected to evaluations encompassing mitochondrial functionality, acrosomal reaction, DNA fragmentation and Tyrosine phosphorylation. Participants/materials, setting, methods Semen samples were collected after 2-7 days abstinence and analysed according to WHO 2021 guidelines. Acrosomal status was determined using FITC-conjugate PSA. DNA fragmentation was examined with the Halosperm kit. Mitochondrial functionality was gauged using MitoTracker Red CMXRos through the percentage of stained cells and fluorescence intensity and PCR for mitochondrial DNA copy number (mtDNAcn). Tyrosine phosphorylation was assessed through immunofluorescence and Western Blotting. Main results and the role of chance Non-APA group exhibited significantly superior fresh semen characteristics. DNA fragmentation was notably elevated in fresh semen from APA group, reaching 21.7%, compared to 15.4% non-APA individuals. After cryopreservation, the DNA fragmentation index further increased in men over 42 years to 26.7%. Mitochondrial functionality analysis indicated a significant decrease in staining intensity in cryopreserved sperm, notably in the APA group, with mean fluorescence intensity decreasing from 3.35±1.5 to 1.8±0.5. In contrast, the non-APA group experienced a drop from 3.33±1.6 to 2.53±1.6. Additionally, in the APA group, a significant increase in mtDNAcn was observed in both fresh and frozen/thawed sperm compared to the younger counterparts, indicative of poor mitochondrial quality. Cryopreservation negatively impacted acrosome integrity in both age groups, with a significant decrease observed in unreacted acrosomes from 71.5% to 57.7% in the non-APA group and from 75% to 63% in the APA group. Furthermore, exploration of capacitation-like changes, like tyrosine phosphorylation, demonstrated a significant decrease with age and a negative impact of cryopreservation on tyrosine phosphorylation in sperm from young males. Limitations, reasons for caution Main limitations are the small number of examined samples and the inclusion of only normozoospermic patients. Therefore, future investigations are needed to provide a more comprehensive understanding of the impact of paternal age on cryopreservation-induced stress in human spermatozoa. Wider implications of the findings Our research sheds light on the influence of paternal age on sperm cryopreservation, revealing higher vulnerability of mitochondria and elevated DNA fragmentation in APA. These findings should be considered when advising older men on choosing cryopreservation techniques in assisted reproductive treatments. Trial registration number Not applicable

Abstract Background and Aims Radical cystectomy (RC) represents the first line surgical treatment for muscle-invasive bladder cancer (MIBC). RC is a complex surgical procedure characterized by significant morbidity and mortality. The incidence of significant complications following RC is a well-recognized issue however still paucity of data exists regarding postoperative renal function. Aim of the study was to evaluate the incidence of acute kidney injury (AKI) and Acute kidney disease (AKD) after RC, evaluating the impact of surgery (open or robotic one), comorbidities (hypertension, diabetes, CAD) and previous oncological treatments (chemotherapy, immunotherapy and radiotherapy). Method We collected a consecutive cohort of 839 patients who underwent RC for MIBC in a single tertiary institution between 2010 and 2022. All clinical variables and comorbidities were reported pre and after surgery. Serum creatinine with subsequently eGFR using CKD-EPI formula were collected at baseline pre-operative and in the acute setting at 24h, 48, 72h, 6 days for the AKI onset, and after 9,12,15,18,21,24,27,30,45, 60, 75, 90 days for the AKD establishment. We compared the incidence of AKI and AKD upon the two different surgical approaches for RC :the open and robotic one. Fisher's exact test; Wilcoxon rank sum test; Pearson's Chi-squared test were used for the statistical analysys. Results General characteristics of patients included in the study are summarized in Table 1. Surprisingly, a very high rate of both AKI (30%) and AKD (50%) was reported in the total cohort of patients, with an augmented incidence in the robotic surgery (p &amp;lt; 0.001). Moreover, stage II and III of both AKI and AKD affected a non-negligible percentage of patients, requiring advanced nephrological medical treatments and prolonged hospitalization (Table 1). The multivariate analysis showed that age, blood hypertension and BMI represent the major risk factors to develop both AKI and AKD (Table 3 and Figure 1). Conclusion AKI and AKD are very frequent and insidious side effects in the RC for MIBC. Therefore, a personalized nephrological counseling both in the pre and post -surgery asset is mandatory to reduce morbidity and mortality.

Simple SummarySmall-cell lung cancer (SCLC) is the most aggressive form of lung cancer, is mostly associated with smoking and has a low survival rate. Among the different alterations in genes identified in SCLC, those related to the MYC family have emerged as highly relevant, alterations MYCN particularly define an aggressive and immunotherapy resistant SCLC subgroup. Due to its highly restricted expression in normal cells, MYCN is an ideal target for precision medicine, though it is difficult to target with traditional approaches. We propose an innovative approach to target MYCN in SCLC by an MYCN-specific expression inhibition at the level of gene transcription through an antigene oligonucleotide (BGA002). BGA002 exerted a potent and specific MYCN silencing in MYCN-expressing SCLC, leading to reversion of specific pathways and induction of cell death. Moreover, systemic administration of BGA002 inhibited tumor progression and significantly increased survival in SCLC mouse models, while also overcoming multidrug resistance.Small-cell lung cancer (SCLC) is the most aggressive lung cancer type, and is associated with smoking, low survival rate due to high vascularization, metastasis and drug resistance. Alterations in MYC family members are biomarkers of poor prognosis for a large number of SCLC. In particular, MYCN alterations define SCLC cases with immunotherapy failure. MYCN has a highly restricted pattern of expression in normal cells and is an ideal target for cancer therapy but is undruggable by traditional approaches. We propose an innovative approach to MYCN inhibition by an MYCN-specific antigene—PNA oligonucleotide (BGA002)—as a new precision medicine for MYCN-related SCLC. We found that BGA002 profoundly and specifically inhibited MYCN expression in SCLC cells, leading to cell-growth inhibition and apoptosis, while also overcoming multidrug resistance. These effects are driven by mTOR pathway block in concomitance with autophagy reactivation, thus avoiding the side effects of targeting mTOR in healthy cells. Moreover, we identified an MYCN-related SCLC gene signature comprehending CNTFR, DLX5 and TNFAIP3, that was reverted by BGA002. Finally, systemic treatment with BGA002 significantly increased survival in MYCN-amplified SCLC mouse models, including in a multidrug-resistant model in which tumor vascularization was also eliminated. These findings warrant the clinical testing of BGA002 in MYCN-related SCLC.

Urinary incontinence (UI) is a widespread condition affecting about 200 million people worldwide, with women affected more often than men and prevalence increasing with age. UI is a significant health problem that negatively impacts affected women’s well-being, sociality, and productivity. Therefore, seeking medical advice is highly recommended since valid treatment options exist. However, a definitive solution to the problem is not always possible. In these cases, absorbent containment products can help women deal with the persistent symptoms of incontinence, minimising the effects on the quality of life. High-quality products are paramount to avoid or reduce the onset of irritating skin phenomena, which can sometimes lead to more serious consequences, such as skin infections. Cotton is a natural fibre characterised by softness and hypoallergenic properties that has already shown its ability to improve skin health when used as a component of pads and other absorbent containment products. The aim of this work was to assess the safety and efficacy of a new organic cotton pull-on absorbent product in reducing skin erythema and oedema in women suffering from moderate to heavy urinary incontinence. In-vitro and clinical studies were performed. Results showed that the tested product effectively reduces skin erythema and oedema caused by the conventional use of synthetic pull-on absorbent products. Moreover, good compliance with the use was demonstrated compared to a non-cotton competitor device available on the market. In conclusion, the organic cotton absorbent device tested has improved the quality of life of women suffering from moderate to heavy urinary incontinence.

This document illustrates the results of the work of two interdisciplinary and multistakeholder panels (researchers, public institutions, and industry representatives) on drug territorialization and digitalization, organized as part of a residential seminar held on 30 September and 1st October 2021. Arising from some considerations about the demand for health and the provisions of the National Recovery and Resilience Plan (PNRR), the discussion touched various aspects of managing the transition from current to future management models. The importance of identifying criteria for prioritizing interventions in the area emerged: different methods of drug delivery, scientific information and measurement, re-evaluation of pathologies that can be managed in this area. Finally, the role of digitization within this change was explored. The opinions provided by the experts move towards making the most of the opportunities arising from PNRR, in terms of investments in healthcare and data application, with a view to improve health system efficiency, patient care and related outcomes.