p53 deficient breast cancer cells reprogram preadipocytes toward tumor-protective immunomodulatory cells.

The TP53 gene is mutated in approximately 30% of all breast cancer cases. Adipocytes and preadipocytes, which constitute a substantial fraction of the stroma of normal mammary tissue and breast tumors, undergo transcriptional, metabolic, and phenotypic reprogramming during breast cancer development and play an important role in tumor progression. We report here that p53 loss in breast cancer cells facilitates the reprogramming of preadipocytes, inducing them to acquire a unique transcriptional and metabolic program that combines impaired adipocytic differentiation with augmented cytokine expression. This, in turn, promotes the establishment of an inflammatory tumor microenvironment, including increased abundance of Ly6C+ and Ly6G+ myeloid cells and elevated expression of the immune checkpoint ligand PD-L1. We also describe a potential gain-of-function effect of common p53 missense mutations on the inflammatory reprogramming of preadipocytes. Altogether, our study implicates p53 deregulation in breast cancer cells as a driver of tumor-supportive adipose tissue reprogramming, expanding the network of non-cell autonomous mechanisms whereby p53 dysfunction may promote cancer. Further elucidation of the interplay between p53 and adipocytes within the tumor microenvironment may suggest effective therapeutic targets for the treatment of breast cancer patients.

Cross-talk between mutant p53 and p62/SQSTM1 augments cancer cell migration by promoting the degradation of cell adhesion proteins.

Missense mutations in the p53 tumor suppressor abound in human cancer. Common ("hotspot") mutations endow mutant p53 (mutp53) proteins with oncogenic gain of function (GOF), including enhanced cell migration and invasiveness, favoring cancer progression. GOF is usually attributed to transcriptional effects of mutp53. To elucidate transcription-independent effects of mutp53, we characterized the protein interactome of the p53R273H mutant in cells derived from pancreatic ductal adenocarcinoma (PDAC), where p53R273H is the most frequent p53 mutant. We now report that p53R273H, but not the p53R175H hotspot mutant, interacts with SQSTM1/p62 and promotes cancer cell migration and invasion in a p62-dependent manner. Mechanistically, the p53R273H-p62 axis drives the proteasomal degradation of several cell junction­associated proteins, including the gap junction protein Connexin 43, facilitating scattered cell migration. Concordantly, down-regulation of Connexin 43 augments PDAC cell migration, while its forced overexpression blunts the promigratory effect of the p53R273H-p62 axis. These findings define a mechanism of mutp53 GOF.

Procoagulant phenotype of virus-infected pericytes is associated with portal thrombosis and intrapulmonary vascular dilations in fatal COVID-19.

BACKGROUND & AIMS: Mechanisms and clinical impact of portal microthrombosis featuring severe COVID-19 are unknown. Intrapulmonary vascular dilation (IPVD)-related hypoxia has been described in severe liver diseases. We hypothesized that portal microthrombosis is associated with IPVD and fatal respiratory failure in COVID-19. METHODS: Ninety-three patients who died from COVID-19, were analysed for portal microvascular damage (histology), IPVD (histology and chest-computed tomography, CT), and hypoxemia (arterial blood gas). Seventeen patients who died from COVID-19-unrelated pneumonia served as controls. Vascular lesions and microthrombi were phenotyped for endothelial (vWF) and pericyte (αSMA/PDGFR-ß) markers, tissue factor (TF), viral spike-protein and nucleoprotein (SP, NP), fibrinogen, platelets (CD41a). Viral particles in vascular cells were assessed by transmission electron microscopy (TEM). Cultured pericytes were infected with SARS-CoV-2 to measure TF expression and tubulisation of human pulmonary microvascular endothelial cells (HPMEC) was assessed upon vWF treatment. RESULTS: IPVD was present in 16/66 COVID-19 patients with both liver and lung histology, with a younger age (62 vs 78yo), longer illness (25 vs 14 days), worsening hypoxemia (PaO2/FiO2 from 209 to 89), and more ventilatory support (63 vs 22%) compared to COVID-19/Non-IPVD. IPVD, absent in controls, were confirmed by chest-CT. COVID-19/IPVD liver histology showed portal microthrombosis in >82.5% of portal areas, with a thicker wall of αSMA/PDGFR-ß+/ SP+/NP+ pericytes compared with COVID-19/Non-IPVD. Thrombosed portal venules correlated with αSMA+ area, whereas infected SP+/NP+ pericytes expressed TF. SARS-CoV-2 viral particles were observed in portal pericytes. In-vitro SARS-CoV-2 infection of pericytes up-regulated TF and induced endothelial cells to overexpress vWF, which expanded HPMEC tubules. CONCLUSIONS: SARS-CoV-2 infection of liver pericytes elicits a local procoagulant response associated with extensive portal microthrombosis, IPVD and worsening respiratory failure in fatal COVID-19. IMPACT AND IMPLICATIONS: Vascular involvement of the liver represents a serious complication of COVID-19 infection that must be considered in the work-up of patients with long-lasting and progressively worsening respiratory failure, as it may associate with the development of intrapulmonary vascular dilations. This clinical picture is associated with a pro-coagulant phenotype of portal venule pericytes, which is induced by SARS-CoV-2 infection of pericytes. Both observations provide a model that may apply, at least in part, to other vascular disorders of the liver, featuring obliterative portal venopathy, similarly characterized at the clinical level by development of hypoxemia and at the histological level, by phlebosclerosis and reduced caliber of the portal vein branches in the absence of cirrhosis. Moreover, our findings bring light to an as yet overlooked player of thrombosis pathophysiology, i.e. pericytes, which may provide novel therapeutic tools to halt prothrombotic mechanisms.

High throughput clogging free microfluidic particle filter by femtosecond laser micromachining.

In recent decades, driven by the needs of industry and medicine, researchers have been investigating how to remove carefully from the main flow microscopic particles or clusters of them. Among all the approaches proposed, crossflow filtration is one of the most attractive as it provides a non-destructive, label-free and in-flow sorting method. In general, the separation performance shows capture and separation efficiencies ranging from 70% up to 100%. However, the maximum flow rate achievable (µL/min) is still orders of magnitude away from those suitable for clinical or industrial applications mainly due to the low stiffness of the materials typically used. In this work, we propose an innovative hydrodynamic-crossflow hybrid filter geometry, buried in a fused silica substrate by means of the femtosecond laser irradiation followed by chemical etching technique. The material high stiffness combined with the accuracy of our manufacturing technique allows the 3D fabrication of non-deformable channels with higher aspect ratio posts, while keeping the overall device dimensions compact. The filter performance has been validated through experiments with both Newtonian (water-based solution of microbeads) and non-Newtonian fluids (blood), achieving separation efficiencies of up to 94% and large particles recovery rates of 100%, even at very high flow rates (mL/h).

Multidrug-resistant pathogens and ventilator-associated pneumonia in critically ill COVID-19 and non-COVID-19 patients: a prospective observational monocentric comparative study.

BACKGROUND: The COVID-19 pandemic has increased the incidence of ventilator-associated pneumonia (VAP) among critically ill patients. However, a comparison of VAP incidence in COVID-19 and non-COVID-19 cohorts, particularly in a context with a high prevalence of multidrug-resistant (MDR) organisms, is lacking. MATERIAL AND METHODS: We conducted a single-center, mixed prospective and retrospective cohort study comparing COVID-19 patients admitted to the intensive care unit (ICU) of the "Città della Salute e della Scienza" University Hospital in Turin, Italy, between March 2020 and December 2021 (COVID-19 group), with a historical cohort of ICU patients admitted between June 2016 and March 2018 (NON-COVID-19 group). The primary objective was to define the incidence of VAP in both cohorts. Secondary objectives were to evaluate the microbial cause, resistance patters, risk factors and impact on 28 days, ICU and in-hospital mortality, duration of ICU stay, and duration of hospitalization). RESULTS: We found a significantly higher incidence of VAP (51.9% - n = 125) among the 241 COVID-19 patients compared to that observed (31.2% - n = 78) among the 252 NON-COVID-19 patients. The median SOFA score was significantly lower in the COVID-19 group (9, Interquartile range, IQR: 7-11 vs. 10, IQR: 8-13, p < 0.001). The COVID-19 group had a higher prevalence of Gram-positive bacteria-related VAP (30% vs. 9%, p < 0.001), but no significant difference was observed in the prevalence of difficult-to-treat (DTR) or MDR bacteria. ICU and in-hospital mortality in the COVID-19 and NON-COVID-19 groups were 71% and 74%, vs. 33% and 43%, respectively. The presence of COVID-19 was significantly associated with an increased risk of 28-day all-cause hospital mortality (Hazard ratio, HR: 7.95, 95% Confidence Intervals, 95% CI: 3.10-20.36, p < 0.001). Tracheostomy and a shorter duration of mechanical ventilation were protective against 28-day mortality, while dialysis and a high SOFA score were associated with a higher risk of 28-day mortality. CONCLUSION: COVID-19 patients with VAP appear to have a significantly higher ICU and in-hospital mortality risk regardless of the presence of MDR and DTR pathogens. Tracheostomy and a shorter duration of mechanical ventilation appear to be associated with better outcomes.

Continuous stellate ganglion block for ventricular arrhythmias: case series, systematic review, and differences from thoracic epidural anaesthesia.

AIMS: Percutaneous stellate ganglion block (PSGB) through single-bolus injection and thoracic epidural anaesthesia (TEA) have been proposed for the acute management of refractory ventricular arrhythmias (VAs). However, data on continuous PSGB (C-PSGB) are scant. The aim of this study is to report our dual-centre experience with C-PSGB and to perform a systematic review on C-PSGB and TEA. METHODS AND RESULTS: Consecutive patients receiving C-PSGB at two centres were enrolled. The systematic literature review follows the latest Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Our case series (26 patients, 88% male, 60 ± 16 years, all with advanced structural heart disease, left ventricular ejection fraction 23 ± 11%, 32 C-PSGBs performed, with a median duration of 3 days) shows that C-PSGB is feasible and safe and leads to complete VAs suppression in 59% and to overall clinical benefit in 94% of cases. Overall, 61 patients received 68 C-PSGBs and 22 TEA, with complete VA suppression in 63% of C-PSGBs (61% of patients). Most TEA procedures (55%) were performed on intubated patients, as opposed to 28% of C-PSGBs (P = 0.02); 63% of cases were on full anticoagulation at C-PSGB, none at TEA (P < 0.001). Ropivacaine and lidocaine were the most used drugs for C-PSGB, and the available data support a starting dose of 12 and 100 mg/h, respectively. No major complications occurred, yet TEA discontinuation rate due to side effects was higher than C-PSGB (18 vs. 1%, P = 0.01). CONCLUSION: Continuous PSGB seems feasible, safe, and effective for the acute management of refractory VAs. The antiarrhythmic effect may be accomplished with less concerns for concomitant anticoagulation compared with TEA and with a lower side-effect related discontinuation rate.

A two-tiered high-flow nasal cannula approach does not increase intensive care utilization and hospital length of stay in bronchiolitis.

While concerns about high-flow nasal cannula oxygen (HFNC) overuse and associated increased use of hospital resources are rapidly spreading, a two-tiered approach in its use is recommended by recent bronchiolitis guidelines. However, data on its effects in practice have not been reported. We aimed to analyze the trends in use of HFNC, hospitalizations, length of stay (LOS), and intensive care unit (ICU) admissions for bronchiolitis in a tertiary care center using a two-tiered HFNC approach since its introduction in practice. We retrospectively included data of children < 12 months of age who presented to the Paediatric Emergency Department (PED) and were hospitalized for bronchiolitis at our institution in the epidemic season between October 1st and April 30th during the years 2012-2023 and compared the clinical data across the years. Of the 687 hospitalized children included, 79.9% required oxygen supplementation. Use of HFNC significantly increased since its implementation (from 25% in 2012-2013 to over 60% since 2019-2020, p < 0.0001) and was most frequently administered as rescue treatment (in 57.5% of patients). There was no increased trend in ICU admissions (between 1.5% and 10.0% of hospitalizations across seasons, p = 0.40), while LOS, after increasing between 2013 and 2016 (medians between 4.0 and 5.4 days), remained stable thereafter (medians between 3.8 and 4.3 days). CONCLUSIONS: The use of HFNC according to a two-tiered approach does not appear to be associated with an increase in ICU utilization or LOS. WHAT IS KNOWN: • Bronchiolitis is one of the most common reasons for hospitalization in infants. • Use high-flow nasal canulae oxygen (HFNC) has rapidly spread outside the intensive care unit (ICU) to treat infants with bronchiolitis, although increasing evidence has dampened the initial enthusiasm about their effectiveness. • Concerns nowadays are rising about HFNC overuse and associated increased use of hospital resources, including escalation of care to ICU. WHAT IS NEW: • A more selective use of HFNC according to a "two-tiered approach", intended as a second-line rescue treatment in non-severely ill children who fail standard oxygen therapy, is not associated with increased ICU and length of hospital stay.

Combined SERS-Raman screening of HER2-overexpressing or silenced breast cancer cell lines.

BACKGROUND: Breast cancer (BC) is a heterogeneous neoplasm characterized by several subtypes. One of the most aggressive with high metastasis rates presents overexpression of the human epidermal growth factor receptor 2 (HER2). A quantitative evaluation of HER2 levels is essential for a correct diagnosis, selection of the most appropriate therapeutic strategy and monitoring the response to therapy. RESULTS: In this paper, we propose the synergistic use of SERS and Raman technologies for the identification of HER2 expressing cells and its accurate assessment. To this end, we selected SKBR3 and MDA-MB-468 breast cancer cell lines, which have the highest and lowest HER2 expression, respectively, and MCF10A, a non-tumorigenic cell line from normal breast epithelium for comparison. The combined approach provides a quantitative estimate of HER2 expression and visualization of its distribution on the membrane at single cell level, clearly identifying cancer cells. Moreover, it provides a more comprehensive picture of the investigated cells disclosing a metabolic signature represented by an elevated content of proteins and aromatic amino acids. We further support these data by silencing the HER2 gene in SKBR3 cells, using the RNA interference technology, generating stable clones further analysed with the same combined methodology. Significant changes in HER2 expression are detected at single cell level before and after HER2 silencing and the HER2 status correlates with variations of fatty acids and downstream signalling molecule contents in the context of the general metabolic rewiring occurring in cancer cells. Specifically, HER2 silencing does reduce the growth ability but not the lipid metabolism that, instead, increases, suggesting that higher fatty acids biosynthesis and metabolism can occur independently of the proliferating potential tied to HER2 overexpression. CONCLUSIONS: Our results clearly demonstrate the efficacy of the combined SERS and Raman approach to definitely pose a correct diagnosis, further supported by the data obtained by the HER2 gene silencing. Furthermore, they pave the way to a new approach to monitor the efficacy of pharmacologic treatments with the aim to tailor personalized therapies and optimize patients' outcome.

Trends in research grant applications and outcomes among medical students in the United Kingdom: a national self-reported cross-sectional survey.

BACKGROUND: Research funding disparities contribute to clinical academic workforce inequalities. Hence, our study explores the association between student demographics and research grant application rates and outcomes among UK medical students. METHODS: This is a national multicentre cross-sectional survey of UK medical students in the 2020-21 academic year. Multiple zero-inflated negative binomial regression and generalized linear model (binomial distribution; logit link) were utilized to investigate the association between student demographics, number of grant applications submitted, and successful grant applications (yes or no). P-values less than a Bonferroni-corrected significance level of 0.05/36 = 0.0014 were considered to be statistically significant. RESULTS: A total of 1528 students participated from 36 medical schools. One hundred fifty-one respondents (9.9%) had applied for research grants. Black students submitted applications 2.90 times more often than white students [Incident rate ratio (IRR): 2.90, 95% confidence interval (CI): 1.37-6.16], with no ethnic disparity in the odds of successful applications. Gender did not influence application rates significantly (P = .248), but women were 4.61 times more likely to secure a grant than men [odds ratio: 4.61, 95% CI: 2.04-10.4]. Being a PubMed-indexed author was associated with increased grant application submission rates [IRR: 3.61, 95% CI: 2.20- 5.92] while conducting more research was associated with greater odds of securing a grant [odds ratio: 1.42, 95% CI: 1.17- 1.73]. CONCLUSION: Although black students submitted more applications, ethnicity did not influence success rates. Gender did not influence application rates, but women were more successful. These findings underscore the need for strategies supporting women and underrepresented students for continued academic achievement after graduation. KEY MESSAGES: What is already known on this topic Research funding for post-PhD researchers is believed to be a major driver of gender and ethnic inequalities in the clinical academic workforce.Students who receive research grants are more likely to receive postgraduate research grants.What this study adds Black students applied for more research grants than white students, but there were no ethnic differences in the odds of securing a grant.There were no gender differences in the research grant application rates. However, female students had greater odds of securing research grants compared to male students.How this study might affect research, practice or policy Medical schools should incorporate grant writing skills into the undergraduate research curriculum. Also, to sustain women's academic success post medical school, the NIHR and affiliates should provide research award extensions and childcare support for women when required.

Application of Raman spectroscopy to the evaluation of F-actin changes in sea urchin eggs at fertilization.

The actin filaments on the surface of echinoderm oocytes and eggs readily undergo massive reorganization during meiotic maturation and fertilization. In sea urchin eggs, the actin cytoskeletal response to the fertilizing sperm is fast enough to accompany Ca2+ signals and to guide sperm's entry into the egg. Although recent work using live cell imaging technology confirmed changes in the actin polymerization status in fertilized eggs, as was previously shown using light and electron microscopy, it failed to provide experimental evidence of F-actin depolymerization a few seconds after insemination, which is concurrent with the sperm-induced Ca2+ release. In the present study, we applied Raman microspectroscopy to tackle this issue by examining the spectral profiles of the egg's subplasmalemmal regions before and after treating the eggs with actin drugs or fertilizing sperm. At both early (15 s) and late (15 min) time points after fertilization, specific peak shifts in the Raman spectra revealed change in the actin structure, and Raman imaging detected the cytoskeletal changes corresponding to the F-actin reorganization visualized with LifeAct-GFP in confocal microscopy. Our observation suggests that the application of Raman spectroscopy, which does not require microinjection of fluorescent probes and exogenous gene expression, may serve as an alternative or even advantageous method in disclosing rapid subtle changes in the subplasmalemmal actin cytoskeleton that are difficult to resolve.

Metabolic Silencing via Methionine-Based Amino Acid Restriction in Head and Neck Cancer.

In recent years, various forms of caloric restriction (CR) and amino acid or protein restriction (AAR or PR) have shown not only success in preventing age-associated diseases, such as type II diabetes and cardiovascular diseases, but also potential for cancer therapy. These strategies not only reprogram metabolism to low-energy metabolism (LEM), which is disadvantageous for neoplastic cells, but also significantly inhibit proliferation. Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumour types, with over 600,000 new cases diagnosed annually worldwide. With a 5-year survival rate of approximately 55%, the poor prognosis has not improved despite extensive research and new adjuvant therapies. Therefore, for the first time, we analysed the potential of methionine restriction (MetR) in selected HNSCC cell lines. We investigated the influence of MetR on cell proliferation and vitality, the compensation for MetR by homocysteine, the gene regulation of different amino acid transporters, and the influence of cisplatin on cell proliferation in different HNSCC cell lines.

Effect of short-term, high-dose probiotic supplementation on cognition, related brain functions and BDNF in patients with depression: a secondary analysis of a randomized controlled trial.

BACKGROUND: In major depressive disorder (MDD), cognitive dysfunctions strongly contribute to functional impairments but are barely addressed in current therapies. Novel treatment strategies addressing cognitive symptoms in depression are needed. As the gut microbiota-brain axis is linked to depression and cognition, we investigated the effect of a 4-week high-dose probiotic supplementation on cognitive symptoms in depression. METHODS: This randomized controlled trial included 60 patients with MDD, of whom 43 entered modified intention-to-treat analysis. A probiotic supplement or indistinguishable placebo containing maltose was administered over 31 days in addition to treatment as usual for depression. Participant scores on the Verbal Learning Memory Test (VLMT), Corsi Block Tapping Test, and both Trail Making Test versions as well as brain-derived neurotrophic factor levels were assessed at 3 different time points: before, immediately after and 4 weeks after intervention. Additionally, brain activation changes during working memory processing were investigated before and immediately after intervention. RESULTS: We found a significantly improved immediate recall in the VLMT in the probiotic group immediately after intervention, and a trend for a time × group interaction considering all time points. Furthermore, we found a time × group interaction in hippocampus activation during working memory processing, revealing a remediated hippocampus function in the probiotic group. Other measures did not reveal significant changes. LIMITATIONS: The modest sample size resulting from our exclusion of low-compliant cases should be considered. CONCLUSION: Additional probiotic supplementation enhances verbal episodic memory and affects neural mechanisms underlying impaired cognition in MDD. The present findings support the importance of the gut microbiota-brain axis in MDD and emphasize the potential of microbiota-related regimens to treat cognitive symptoms in depression. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier NCT02957591.

Impact of occupational asthma on health and employment status: a long-term follow-up study.

OBJECTIVES: The aim of this study was to assess the predictors of a favourable prognosis of occupational asthma (OA) and the employment status of patients with OA at least 2 years after diagnosis. METHODS: We collected data from 204 patients who had a diagnosis of OA confirmed by a positive specific inhalation challenge. We defined OA remission as meeting the following three criteria: no asthma symptoms, no antiasthma therapy for the last year and having normal lung function at the end of follow-up. A logistic regression analysis was performed to estimate the effects of the covariates. RESULTS: At 10.6±7.8-year follow-up, 60 of 204 possible patients participated in the study, and among them 17 showed OA remission. When compared with the 43 patients with persistent OA, these patients exhibited at diagnosis younger age (p=0.0039), shorter duration of symptomatic exposure (p=0.0512), better lung function expressed by higher forced vital capacity (FVC%) predicted (p=0.0164), forced expiratory volume in 1 s (FEV1) % predicted (p=0.0066) and FEV1/FVC% (p=0.0132), and less bronchial hyper-responsiveness (p=0.0118). Nevertheless, in the multivariable model, no variables were significantly associated with OA remission. At follow-up, three individuals have retired; among the remaining 57 workers, 91.2% were still employed and 43.8% of them had continued working in the same factory after ceasing exposure to the causative agent. CONCLUSIONS: This monocentric study did not identify a strong predictor of OA remission, but documented a high employment rate and a good job preservation over a long timeframe after diagnosis of OA mainly induced by low molecular weight agents.

Respiratory syncytial virus: can we still believe that after pandemic bronchiolitis is not a critical issue for public health?

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among infants and young children, resulting in annual epidemics worldwide. Since the beginning of the COVID-19 pandemic, non-pharmacological interventions were applied, interfering with the circulation of most respiratory viruses, including RSV. The aim of this study is to analyze the RSV infection trend among hospitalized infants during the actual epidemic season (2022-2023) in comparison with the last pre-pandemic season (2018-2019), in order to outline whether significant differences emerge due to COVID-19 pandemia. We retrospectively reviewed medical data on infants hospitalized at the Bambino Gesù Children's Hospital with diagnosis of bronchiolitis in the current epidemic season and in the last pre-pandemic season, 2018-2019. RSV remains the main etiological agent of bronchiolitis in terms of frequency and severity of infections in the ongoing epidemic season. The first RSV case of the 2022-2023 season was detected at week 42 vs week 47 in the 2018-2019 season. The length of epidemic season was of 17 weeks in 2022-2023 vs 18 weeks in 2018-2019. Comparing the two seasons, age at admission was significantly higher in the current season (median age 2022-2023 65 days vs median age 2018-2019 58 days), but the disease severity was similar.       Conclusions: The 2022-2023 bronchiolitis season in Italy started earlier than the usual pre-pandemic seasons but seasonality pattern may be going back to the pre-pandemic one. This season was not more severe than the previous ones. The impact of RSV disease on health care systems and costs remains a critical issue. What is Known: • RSV is one of the major leading causes of hospitalization among children aged less than 3 months. SarsCOV2 pandemic interfered with the seasonal circulation of most respiratory viruses, Including RSV. What is New: • The 2022-2023 bronchiolitis season in Italy started and peaked earlier than the usual pre-pandemic seasons but seasonality pattern may be realigning to the pre-pandemic one. The impact of RSV disease on health care systems and costs is concerning.

Electrophysiological and neuropsychological assessment of cognition in spinocerebellar ataxia type 1 patients: a pilot study.

BACKGROUND: Event-related potentials (ERPs) reflect cognitive processing: negative early components (N100, N200) are involved in the sensory and perceptual processing of a stimulus, whereas late positive component P300 requires conscious attention. Both neuropsychological and affective disorders are present in patients with spinocerebellar ataxia type 1 (SCA1), but the underlying mechanisms need further clarification. MATERIALS AND METHODS: In this pilot study, we assessed cognitive processing by recording auditory ERPs in 16 consecutive SCA1 patients and 16 healthy controls (HC) matched for age and sex. Motor and nonmotor symptoms were evaluated using the Scale for the Assessment and Rating of Ataxia (SARA) and an extensive neuropsychological battery. ERPs were recorded using an oddball paradigm, and peak latency and amplitude of N100, N200, and P300 were measured in the averaged responses to target tones. RESULTS: We found in SCA1 significantly increased latencies of N200 and P300 (p=0.033, p=0.007) and decreased amplitudes of N100 and P300 (p=0.024, p=0.038) compared with HC. Furthermore, P300 latency had the highest AUC in the discrimination of SCA1 in ROC analysis. The expansion of trinucleotide repeats correlated with P300 latency (r=-0.607, p=0.048), whereas both P300 and N100 amplitudes correlated with the severity of motor symptoms (r=-0.692, p=0.003; r=-0.621; p=0.010). Significant correlations between P300 latency and the scores of Emotion Attribution Task (r=-0.633, p=0.027), as well as between N200 latency and the scores of Frontal Assessment Battery and Stroop test (r=-0.520, p=0.047; r=0.538, p=0.039), were observed. CONCLUSIONS: This research provides for the first time an extensive characterization of ERPs as useful electrophysiological markers to identify early cognitive dysfunction in SCA1.

Dienogest alone or dienogest combined with estrogens in the treatment of ovarian endometriomas, that is the question. A retrospective cohort study.

PURPOSE: to compare the effects of Dienogest 2 mg (D) alone or combined with estrogens (D + ethinylestradiol 0.03 mg, D + EE; D + estradiol valerate 1-3 mg, D + EV) in terms of symptoms and endometriotic lesions variations. METHODS: This retrospective study included symptomatic patients in reproductive age with ultrasound diagnosis of ovarian endometriomas. Medical therapy for at least 12 months with D, D + EE or D + EV was required. Women were evaluated at baseline visit (V1) and after 6 (V2) and 12 months (V3) of therapy. RESULTS: 297 patients were enrolled (156 in the D group, 58 in the D + EE group, 83 in the D + EV group). Medical treatment leaded to a significant reduction in size of endometriomas after 12 months, with no differences between the three groups. When comparing D and D + EE/D + EV groups, a significant decrease of dysmenorrhea was detected in the D group than in D + EE/D + EV group. Conversely, the reduction of dysuria was more significative in the D + EE/D + EV groups rather than in the D group. Regarding tolerability, treatment associated side effects were reported by 16.2% patients. The most frequent one was uterine bleeding/spotting, significantly higher in the D + EV group. CONCLUSION: Dienogest alone or associated with estrogens (EE/EV) seems to be equally effective in reducing endometriotic lesions mean diameter. The reduction of dysmenorrhea was more significative when D was administered alone, while dysuria seems to improve more when D is associated with estrogens.

Structured histopathology and laboratory evidence in nasal polyposis with different pathogenesis.

PURPOSE: Non-steroidal anti-inflammatory drugs-exacerbated respiratory disease (NERD), intrinsic asthma, eosinophilic granulomatosis with polyangiitis (EGPA) and odontogenic sinusitis may be associated with nasal polyps. The aim of the study was to compare circulating inflammatory cells and structural histopathology of these groups of nasal polyposis. METHODS: We retrospectively evaluated 71 patients with nasal polyps stratified according to the above-mentioned pathogenesis. All patients underwent preoperative laboratory investigations and primary endoscopic sinus surgery. Surgical specimens were submitted to structured histopathological evaluation. RESULTS: The median tissue eosinophil count (cells/HPF) was significantly different between the considered groups of nasal polyposis (p=0.0004). The median of NERD sub-cohort was significantly higher than intrinsic asthma (p=0.0030), odontogenic CRS (p=0.0001) and EGPA ones (p=0.0094). Eosinophilic aggregates positive rate was significantly higher in NERD sub-cohort than in odontogenic CRS (p=0.0072), EGPA (p=0.0497) and asthma (p=0.0188) ones. EGPA sub-cohort had a higher neutrophil infiltrate positive rate than NERD (p=0.0105) and intrinsic asthma ones (p=0.0040). Odontogenic CRS sub-cohort had a higher neutrophil infiltrate positive rate than NERD (p=0.0140) and asthma ones (p=0.0096). EGPA sub-cohort had a higher presence of fibrosis than NERD (p=0.0237) and odontogenic CRS sub-cohort (p=0.0107). Odontogenic sub-cohort had a lower sub-epithelial edema positive rate than NERD (p=0.0028) and asthma (p=0.0149) ones. CONCLUSIONS: Structural histopathology may identify nasal polyps histotypes with different morphological patterns. The identified histopathological features can facilitate the recognition of rational therapeutic and follow-up approaches that consider the tissue modifications associated with the response to drugs and surgery.

Predictors of self-reported research productivity amongst medical students in the United Kingdom: a national cross-sectional survey.

BACKGROUND: The number of academic clinicians in the UK is declining and there are demographic inequalities in the clinical-academic workforce. Increased research productivity by medical students is believed to reduce future attrition in the clinical-academic workforce. Thus, this study investigated the association between student demographics and research productivity amongst UK medical students. METHODS: This is a national multicentre cross-sectional study of UK medical students in the 2020/21 academic year. We appointed one student representative per medical school, and they disseminated a 42-item online questionnaire over nine weeks, through departmental emails and social media advertisements. The outcome measures were: (i) publications (yes/no) (ii) number of publications (iii) number of first-authored publications (iv) abstract presentation (yes/no). We utilised multiple logistic and zero-inflated Poisson regression analyses to test for associations between the outcome measures and predictor variables at a 5% significance level. RESULTS: There are 41 medical schools in the UK. We received 1573 responses from 36 UK medical schools. We failed to recruit student representatives from three newly formed medical schools, whilst two medical schools prohibited us from sending the survey to their students. Women had lower odds of having a publication (OR: 0.53, 95% CI: 0.33-0.85) and on average had fewer first-author publications than men (IRR: 0.57, 95% CI: 0.37-0.89). Compared to white students, mixed-ethnicity students had greater odds of having a publication (OR: 3.06, 95% CI: 1.67-5.59), an abstract presentation (OR: 2.12, 95% CI: 1.37-3.26), and on average had a greater number of publications (IRR: 1.87, 95% CI: 1.02-3.43). On average, students who attended independent UK secondary schools had a higher rate of first-author publications compared to those that attended state secondary schools (IRR: 1.97, 95% CI: 1.23-3.15). CONCLUSION: Our data suggest that there are gender, ethnic and socioeconomic inequalities in research productivity among UK medical students. To tackle this, and potentially improve diversity in clinical academia, we recommend that medical schools should facilitate targeted high quality research mentorship, funding and training, especially for under-represented-in-medicine students.

Sperm DNA Fragmentation and Sperm-Borne miRNAs: Molecular Biomarkers of Embryo Development?

The evaluation of morpho-functional sperm characteristics alone is not enough to explain infertility or to predict the outcome of Assisted Reproductive Technologies (ART): more sensitive diagnostic tools are needed in clinical practice. The aim of the present study was to analyze Sperm DNA Fragmentation (SDF) and sperm-borne miR-34c-5p and miR-449b-5p levels in men of couples undergoing ART, in order to investigate any correlations with fertilization rate, embryo quality and development. Male partners (n = 106) were recruited. Semen analysis, SDF evaluation and molecular profiling analysis of miR-34c-5p and miR-449b-5p (in 38 subjects) were performed. Sperm DNA Fragmentation evaluation- a positive correlation between SDF post sperm selection and the percentage of low-quality embryos and a negative correlation with viable embryo were found. SDF > 2.9% increased the risk of obtaining a non-viable embryo by almost 4-fold. Sperm miRNAs profile­we found an association with both miRNAs and sperm concentration, while miR-449b-5p is positively associated with SDF. Moreover, the two miRNAs are positively correlated. Higher levels of miR-34c-5p compared to miR-449b-5p increases by 14-fold the probability of obtaining viable embryos. This study shows that SDF, sperm miR-34c-5p, and miR-449b-5p have a promising role as biomarkers of semen quality and ART outcome.

Dignity and time perspective: A pilot explorative study in cancer patients.

OBJECTIVES: This study investigated the possible correlation between emotional distress linked to dignity and dysfunctional temporal orientations in the oncological context. METHODS: We conducted an exploratory study between December 2020 and February 2021, referring to a sample of 107 patients in active treatment for solid tumors belonging to the Oncology Department of the Fondazione Poliambulanza (Brescia, Italy). We administered two self-report questionnaires: the Patient Dignity Inventory (PDI-IT) (Italian version, Grassi L, Costantini A, Caruso R, et al. (2017) Dignity and psychosocial-related variables in advanced and nonadvanced cancer patients by using the patient dignity inventory-Italian version. Journal of Pain and Symptom Management 53(2), 279-287), as a measure of perceived level of dignity, and the Italian version of the Zimbardo Time Perspective Inventory scale (ZTPI) (Zimbardo PG and Boyd JN (2009) Il paradosso del tempo. La nuova psicologia del tempo che cambierà la tua vita. Milano: Mondadori), as a measure of the experiential dimensions of time, such as past, present, and future. RESULTS: From the PDI-IT emerged that our sample reported high levels of physical and psychological distress. Furthermore, we founded higher distress in patients under 55 years (p = 0.04) and lower distress in retired patients (p = 0.01). The ZTPI showed in our patients prevailing orientations to the past-positive (39.3%) and the future (37.4%). We noticed a gender difference: men were mainly oriented to the future while women to the past-positive. Moreover, married subjects reported a prevalent orientation to past-positive and the future. Finally, data analysis found moderate positive correlation between the "Negative Past" dimension of ZTPI and high levels of physical (r = 0.203, p = 0.03) and psychological distress (r = 236, p = 0.01). SIGNIFICANCE OF RESULTS: In our experience in oncology, dignity and time perspective play a central role as indicators of the quality of care. Our study shows the importance of a treatment path that integrates the constructs of Dignity and Time Perspective to favor a better psychological adaptation.