Direct Observation of Sub-Poissonian Temporal Statistics in a Continuous Free-Electron Beam with Subpicosecond Resolution.

We present a novel method to measure the arrival time statistics of continuous electron beams with subpicosecond resolution, based on the combination of an rf deflection cavity and fast single electron imaging. We observe Poissonian statistics within time bins from 100 to 2 ns and increasingly pronounced sub-Poissonian statistics as the time bin decreases from 2 ps to 340 fs. This 2D streak camera, in principle, enables femtosecond-level arrival time measurements, paving the way to observing Pauli blocking effects in electron beams and thus serving as an essential diagnostic tool toward degenerate electron beam sources for free-electron quantum optics.

Photodiode-based time zero determination for ultrafast electron microscopy.

Pump-probe experiments in ultrafast electron microscopy require temporal overlap between the pump and probe pulses. Accurate measurements of the time delay between them allows for the determination of the time zero, the moment in time where both pulses perfectly overlap. In this work, we present the use of a photodiode-based alignment method for these time zero measurements. The cheap and easy-to-use device consists of a photodiode in a sample holder and enables us to temporally align individual, single-electron pulses with femtosecond laser pulses. In a first device, a temporal resolution of 24 ps is obtained, limited by the photodiode design. Future work will utilize a smaller photodiode with a lower capacitance, which will increase the temporal resolution and add spatial resolution as well. This upgrade will bring the method toward the micrometer and picosecond spatiotemporal resolution.

Pain Intensity, coping and maternal satisfaction in Low-Risk labouring Women: A prospective descriptive correlational study.

OBJECTIVES: The primary aim of the study was to explore pain intensity (PI) and pain coping (PC) scores and the relationship between them. The secondary aim was to explore the correlation between PI and PC scores with labour progress, parity, labour acceleration, labour augmentation and maternal satisfaction. METHODS: A prospective descriptive correlational study was conducted in a maternity hospital in Northern Italy. The sample included 54 low-risk women in active labour at term of pregnancy. A data record sheet was used to collect the relevant variables and the Italian Birth Satisfaction Scale Revised (I-BSS-R) was administered to participants at least 24 h after birth. RESULTS: In the first labour stage, the average PI score was 6.99 (SD = 1.95) and the average PC score was 6.5 (SD = 2.22). During the second labour stage, the average PI score was 7.75 (SD = 1.74) and the average PC score was 4.97 (SD = 2.76). The average PI score trend increased with labour progress. The average PC score improved between 4 and 7 cm of cervical dilatation. A significant positive correlation between PI scores and oxytocin augmentation (p < 0.001) and labour progression (p < 0.001) was noted. A significant positive correlation between PC scores and oxytocin augmentation (p = 0.02) was also observed. No significant differences were found for maternal satisfaction in regard to PI and PC scores. CONCLUSION: coping in labour do not solely depend on PI but also on labour progress and oxytocin augmentation. Additional support to empower women to cope with pain may be required in case of labour augmentation.

The relation between the symbol digit modalities test, fatigue, depression, and anxiety symptoms in a Belgian MS cohort.

BACKGROUND: Multiple sclerosis (MS) is associated with high prevalence of cognitive impairment, ranging from 40 to 80%. The purpose of this single-center retrospective study was to examine the relation between cognitive function, as measured by Symbol Digit Modalities Test (SDMT), with fatigue, anxiety, and depression symptoms in a Belgian cohort of patients with MS. METHODS: Sociodemographic and clinical data were analyzed in 66 (F:40, M:26) Belgian patients with a diagnosis of MS. The cognitive function was assessed with the oral version of SDMT, depression and anxiety symptoms with the Hospital Anxiety and Depression scale (HAD), fatigue symptoms with the French valid version of the Fatigue Impact Scale in MS (EMIF-SEP), which is a scale composed of four dimensions (cognitive, physical, social, and psychological) allowing a multidimensional evaluation of fatigue. RESULTS: The multivariate linear regression analysis demonstrated that lower SDMT scores were associated with higher EDSS score and psychological dimension of fatigue symptoms. No association were found between SDMT and anxiety or depression symptoms. Conversely, higher depression and anxiety symptoms were associated with higher total fatigue symptoms, but lower physical dimension of fatigue symptoms. Higher anxiety symptoms were also independently associated with higher social dimension of fatigue symptoms. CONCLUSION: A complex relationship exists between cognitive performance, fatigue, and neuropsychiatric symptoms in Belgian people with MS. The level of disability and fatigue adversely affects the cognitive function in MS, whereas depression and anxiety seem to not have a significant effect. A more complex relationship exists between fatigue and neuropsychiatric symptoms, with a divergent interplay between the different dimensions of fatigue that supports the multidimensional approach to assessing fatigue in MS.

Delayed and recurrent dimethyl fumarate induced-lymphopenia in patients with multiple sclerosis.

BACKGROUND: Early lymphopenia is a known side effect of dimethyl fumarate, a disease-modifying therapy for MS. However, the long-term effects on immune response and the impact on lymphocyte counts when another disease-modifying treatment is introduced, remain unknown. To better understand these specific aspects, we reviewed cases that develop prolonged grade 2 to 4 lymphopenia under dimethyl fumarate in Lausanne MS clinic. METHOD: Retrospective analysis of the 12 patients (10.1%) who discontinued dimethyl fumarate because of prolonged lymphopenia amongst the 119 patients treated with dimethyl fumarate. We reviewed their demographics, as well as their clinical, biological and MRI characteristics compared to the non-lymphopenic patients, during dimethyl fumarate therapy, and within a timeframe of up to 18 months after switching to another disease-modifying treatment. We also focused on lymphocyte subsets in a subgroup of patients. RESULTS: Compared to non-lymphopenic patients, lymphopenic patients were older at dimethyl fumarate initiation (51.4 yo vs 39.7, p = 0.0003) and the majority were male (p = 0.037). Three of them (25%) developed delayed lymphopenia, more than one year after treatment onset. Despite persistent lymphopenia, three patients experienced disease activity. Amongst the nine patients (75%) who were switched to another therapy, five (55.6%) presented recurrent lymphopenia, predominantly with a CD8+ T cell decrease. CONCLUSIONS: Dimethyl fumarate has a long-term impact on lymphocyte biology, even after its discontinuation, with a sustained reduction in CD8+ T cells that may increase opportunistic infection risk, and should be taken in consideration when switching therapies after dimethyl fumarate.

Midwifery students' perspectives of physical and virtual mobility activities including preferences for e-learning: A cross-sectional survey.

BACKGROUND: Contemporary higher education requires that all midwifery students have insight and understanding of global health practice and demonstrate intercultural sensitivity. However, the mobility models currently offered do not often fit the lives of large numbers of midwifery students. OBJECTIVES: To investigate midwifery students' international physical mobility activities and factors that affect mobility; to determine midwifery students' learning needs and preferences for related e-learning packages. DESIGN: Multi-centre, descriptive quantitative survey. SETTINGS: Four European Higher Education Institutions based in the United Kingdom, Estonia, Italy and the Netherlands offering an undergraduate midwifery programme. PARTICIPANTS: The sample included 205 midwifery students from Italy (n = 93), the Netherlands (n = 51); United Kingdom (n = 35) and Estonia (n = 26). METHODS: Data were collected in June-July 2020 through an online cross-sectional, bespoke questionnaire and analysed using summary statistical analysis. RESULTS: There is a high level of interest across a range of mobility opportunities, especially those of shorter duration. Barriers to mobility comprised finance, caring responsibilities, concerns about fitting mobility activities into the midwifery programme, negative impact on studies and language barriers. The most frequently identified facilitators of mobility included professional perspectives such as interest in other cultures and midwifery in other settings and an endorsement that mobility would add value to their development as a midwife. When engaging in virtual learning, the most preferred resources mentioned by the students were videos, video calls with peers, choice quiz and discussion forum. CONCLUSIONS: The barriers identified require new approaches to enable all midwifery students to benefit from transnational learning. The survey findings provide insights into midwifery students' perspectives from which a new mobility model can be developed.

Unexpected worsening of progressive multifocal leucoencephalopathy following COVID-19 pneumonia.

Progressive multifocal leucoencephalopathy is a serious side effect of natalizumab, a humanized monoclonal antibody approved for the treatment of multiple sclerosis. Here, we report a case of unexpected worsening of natalizumab-related progressive multifocal leucoencephalopathy following COVID-19. After natalizumab discontinuation, a slight neurological improvement was observed, but, two months later the patient was admitted to the hospital because of neurological deterioration and COVID-19 mild pneumonia. Except for SARS-CoV-2 infection, no other potential factors of neurological worsening were identified. Thus, we pose the hypothesis that SARS-CoV-2 was instrumental in the progressive multifocal leucoencephalopathy deterioration.

Timing of hospital admission in labour: latent versus active phase, mode of birth and intrapartum interventions. A correlational study.

BACKGROUND: Hospitalization of women in latent labour often leads to a cascade of unnecessary intrapartum interventions, to avoid potential disadvantages the recommendation should be to stay at home to improve women's experience and perinatal outcomes. AIM: The primary aim of this study was to investigate the association between hospital admission diagnosis (latent vs active phase) and mode of birth. The secondary aim was to explore the relationship between hospital admission diagnosis, intrapartum intervention rates and maternal/neonatal outcomes. METHODS: A correlational study was conducted in a large Italian maternity hospital. Data from January 2013 to December 2014 were collected from the hospital electronic records. 1.446 records of low risk women were selected. These were dichotomized into two groups based on admission diagnosis: 'latent phase' or 'active phase' of labour. FINDINGS: 52.7% of women were admitted in active labour and 47.3% in the latent phase. Women in the latent phase group were more likely to experience a caesarean section or an instrumental birth, artificial rupture of membranes, oxytocin augmentation and epidural analgesia. Admission in the latent phase was associated with higher intrapartum interventions, which were statistically correlated to the mode of birth. CONCLUSIONS: Women admitted in the latent phase were more likely to experience intrapartum interventions, which increase the probability of caesarean section. Maternity services should be organized around women and families needs, providing early labour support, to enable women to feel reassured facilitating their admission in labour to avoid the cascade of intrapartum interventions which increases the risk of caesarean section.

miR-205 regulates basement membrane deposition in human prostate: implications for cancer development.

The basement membrane (BM) is a layer of specialized extracellular matrix that surrounds normal prostate glands and preserves tissue integrity. Lack or discontinuity of the BM is a prerequisite for tumor cell invasion into interstitial spaces, thus favoring metastasis. Therefore, BM maintenance represents a barrier against cancer development and progression. In the study, we show that miR-205 participates in a network involving ΔNp63α, which is essential for maintenance of the BM in prostate epithelium. At the molecular level, ΔNp63α is able to enhance miR-205 transcription by binding to its promoter, whereas the microRNA can post-transcriptionally limit the amount of ΔNp63α protein, mostly by affecting ΔNp63α proteasomal degradation rather than through a canonical miRNA/target interaction. Functionally, miR-205 is able to control the deposition of laminin-332 and its receptor integrin-ß4. Hence, pathological loss of miR-205, as widely observed in prostate cancer, may favor tumorigenesis by creating discontinuities in the BM. Here we demonstrate that therapeutic replacement of miR-205 in prostate cancer (PCa) cells can restore BM deposition and 3D organization into normal-like acinar structures, thus hampering cancer progression.

Simultaneous ultrasound and microwave new reactor: detailed description and energetic considerations.

A new reactor in which microwaves (MW), delivered by a coaxial dipole antenna, and ultrasound (US), delivered by a metallic horn, can be simultaneously used in a liquid to perform different types of processes, widely referenced in literature, is presented in detail. Calibrations of thermal energy delivered to two liquids having very different dipolar moments (i.e. water and cyclohexane) using MW and US, both separately and simultaneously, are performed by employing the traditional calorimetric method. The main results are: (i) MW and US used simultaneously increase the thermal energy delivered to the two liquids with respect to their separate use, but differently using water or cyclohexane, and (ii) the total power absorbed by polar or non polar liquids is very different, both using MW and US.

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes.

Genetic experiments established that p63 is crucial for the development and maintenance of pluri-stratified epithelia and KLF4 for the barrier function of the skin. KLF4 is one of the factors that reprogram differentiated cells to iPS. We investigated the relationship between p63 and KLF4 using RNA interference, overexpression, chromatin immunoprecipitation and transient transfections with reporter constructs. We find that p63 directly represses KLF4 in normal keratinocytes (KCs) by binding to upstream promoter sites. Unlike p63, KLF4 levels are high in the upper layers of human skin and increase upon differentiation of KCs in vitro. In HaCaT KCs, which harbor two mutant alleles of p53, inactivation of p63 and of mutant p53 leads to KLF4 repression. p63 and p53 mutants are bound to sites in the KLF4 core promoter. Importantly, expression of the H179Y and R282Q p53 mutants in primary KCs is sufficient to activate endogenous KLF4. Finally, immunohistochemical analysis of tissue arrays confirms increased coexpression of KLF4 and mutant p53 in squamous cell carcinomas. Our data indicate that suppression of KLF4 is part of the growth-promoting strategy of p63 in the lower layers of normal epidermis, and that tumor-predisposing p53 mutations hijack p63 to a different location on the promoter, turning it into an activator of this reprogramming factor.

Intradialytic changes of plasma amino acid levels: effect of hemodiafiltration with endogenous reinfusion versus acetate-free biofiltration.

During hemodialysis, amino acids (AA) are lost in the ultrafiltrate with consequent modification of their plasma profile. The aim of this cross-sectional study was to evaluate intradialytic changes of plasma AA levels during a single session of hemodiafiltration with endogenous reinfusion (HFR) versus acetate-free biofiltration (AFB). 48 patients chronically treated with HFR or AFB were matched 1:1 for age, gender, Kt/V and diabetes. Blood samples were collected at the beginning and the end of dialysis. Baseline plasma levels (µmol/l) of total AA (3,176 ± 722), essential AA (889 ± 221), and branched chain AA (459 ± 140) levels in HFR were similar to those in AFB (3,399 ± 621, 938 ± 277, and 463 ± 71, respectively). Plasma intradialytic AA levels did not change in HFR, while in AFB there was a reduction by about 25%. In conclusion, as compared with AFB, HFR has a sparing effect on AA loss due to the lack of adsorption by cartridge and to their complete reinfusion in blood.

The p63 target HBP1 is required for skin differentiation and stratification.

Genetic experiments established that p63 is crucial for the development and maintenance of pluristratified epithelia. In the RNA interference (RNAi) screening for targets of p63 in keratinocytes, we identified the transcription factor, High Mobility Group (HMG) box protein 1 (HBP1). HBP1 is an HMG-containing repressor transiently induced during differentiation of several cell lineages. We investigated the relationship between the two factors: using RNAi, overexpression, chromatin immunoprecipitations and transient transfections with reporter constructs, we established that HBP1 is directly repressed by p63. This was further confirmed in vivo by evaluating expression in p63 knockout mice and in transgenics expressing p63 in basal keratinocytes. Consistent with these findings, expression of HBP1 increases upon differentiation of primary keratinocytes and HaCaT cells in culture, and it is higher in the upper layers of human skin. Inactivation of HBP1 by RNAi prevents differentiation of keratinocytes and stratification of organotypic skin cultures. Finally, we analyzed the keratinocyte transcriptomes after HBP1 RNAi; in addition to repression of growth-promoting genes, unexpected activation of differentiation genes was uncovered, coexisting with repression of other genes involved in epithelial cornification. Our data indicate that suppression of HBP1 is part of the growth-promoting strategy of p63 in the lower layers of epidermis and that HBP1 temporally coordinates expression of genes involved in stratification, leading to the formation of the skin barrier.

[Treatment of HCV-associated cryoglobulinemic glomerulonephritis]. / Terapia della glomerulonefrite secondaria a crioglobulinemia HCV-correlata.

HCV-related membranoproliferative glomerulonephritis is the most common cause of hepatitis C-associated renal disease. Its treatment is still under debate and based on scant experimental evidence. The recommended therapeutic strategy depends on the severity of the kidney disease. The first-line treatment for patients with mild to moderate clinical and histological kidney damage is antiviral therapy with pegylated interferon alpha and ribavirin for 48 weeks combined with symptomatic treatment (diuretics, angiotensin converting enzyme inhibitors and angiotensin receptor blockers). In case of severe renal involvement (nephrotic syndrome, nephritic syndrome and/or progressive renal failure, high activity score of glomerulonephritis on light microscopy), the initial treatment may consist of sequential administration of immunosuppressive therapies (plasmapheresis, corticosteroids and cyclophosphamide) and antiviral agents, although no definitive data are yet available from the literature. B-cell depleting agents such as rituximab may be an alternative to conventional therapy in refractory or intolerant patients. Large randomized and controlled clinical trials are needed to establish guidelines for the treatment of HCV-related cryoglobulinemic glomerulonephritis.

[Resistant hypertension in non-dialysis chronic kidney disease]. / Ipertensione resistente nella malattia renale cronica non-dialitica.

Resistant hypertension is defined as blood pressure that remains above the target of <140/90 mm Hg in the general population and <130/80 mm Hg in people with diabetes mellitus or chronic kidney disease (CKD) in spite of the use of at least three full-dose antihypertensive drugs including a diuretic, or as blood pressure that reaches the target by means of four or more drugs. Hypertension is a frequent complication in CKD and a determining factor in the progression of renal damage, especially in proteinuric and diabetic patients, as well as contributing to a high cardiovascular risk. Clinical practice guidelines recommend blood pressure levels below 130/80 mm Hg in all CKD patients, but the target is reached in only a small proportion (10-20%), both in nephrology and non-nephrology settings. The resistance to antihypertensive treatment may be considered one of the causes of the poor achievement of blood pressure targets in CKD patients.

[Erythropoiesis-stimulating agents in chronic kidney disease: which route of administration?]. / Agenti stimolanti l'eritropoiesi nell'insufficienza renale cronica: quale via di somministrazione?

In the last twenty years, erythropoiesis-stimulating agents (ESAs) have improved the management of renal anemia, with significant amelioration of quality of life in patients on hemodialysis. ESAs can be administered both intravenously and subcutaneously. In predialysis chronic kidney disease and in peritoneal dialysis, the administration route is necessarily subcutaneous. In hemodialysis the intravenous route was initially preferred because of the presence of ready vascular access for drug administration. Subsequent studies have demonstrated that the subcutaneous route allowed the achievement of optimal levels of hemoglobin with a reduction of mean administered dose, number of injections, and costs. A few years ago, the finding of a higher risk of pure red cell aplasia associated with subcutaneous administration of epoetin reopened the debate about the route of administration. We here review the studies on the preferable route of administration of epoetin and darbepoetin- alpha, in terms of efficacy and safety, and take a look at future perspectives.

p63 regulates the caspase-8-FLIP apoptotic pathway in epidermis.

The transcription factor p63, member of the p53 family, is crucial for epithelial development. An RNAi screening identified the apoptotic gene Procaspase-8 as a target activated by p63. The caspase-8 inhibitor FLIP is also under p63 control. We analysed and detailed the direct transactivation through the use of RNAi, reporter assays, ChIPs, western blots, confocal studies in HaCat, as well as in primary human keratinocytes. The direct DeltaNp63 regulation of these targets was confirmed in vivo using transgenic DeltaNp63 mice under the K5 promoter, as compared with p63 knockout mice, and in vitro in normal human primary keratinocytes following UV irradiation. Lowering the steady state of p63 protein levels changes the relative ratio of FLIP isoforms, causing the activation of the expressed, inactive Procaspase-8, into the active isoform thus triggering the proapoptotic cascade. Therefore, p63 fine-tunes the Procaspase-8-FLIP pro- and antiapoptotic pathway in keratinocytes.

[Diagnostic role of ambulatory blood pressure monitoring in non-dialysis CKD patients]. / Monitoraggio della pressione arteriosa per 24 ore: indicazioni e utilità nella IRC pre-dialitica.

In chronic kidney disease, blood pressure control is a major aim of therapy to slow down renal disease progression and reduce the cardiovascular risk. Ambulatory blood pressure monitoring is a valid tool to define the prognosis and indicated therapy for hypertension. It allows to detect blood pressure patterns such as the white-coat effect, resulting in a better definition of the cardiovascular risk profile. Description of the circadian pressure rhythm, moreover, may reveal the presence of physiological nocturnal loss (dipping status). Recently, it has been demonstrated that a non-dipping status is associated with a higher risk of end-stage renal disease and more rapid progression of kidney disease independent of blood pressure control. Furthermore, longitudinal studies have demonstrated that a non-dipping status is associated with increased cardiovascular morbidity and mortality in the general population and in hypertensive patients. We have less information on this issue in chronic kidney disease. In this high-risk subgroup of hypertensive patients, it remains ill-defined whether ambulatory blood pressure monitoring predicts cardiovascular outcomes better than in-office measurement.