Is the alpha-beta ratio of prostate cancer really low? A prospective, non-randomized trial comparing standard and hyperfractionated conformal radiation therapy.

BACKGROUND AND PURPOSE: The objectives of the current study were to compare genito-urinary (GU) and gastro-intestinal (GI) toxicities as well as biochemical control (bRFS) in prostate cancer, utilizing conventional (2.0 Gy daily) (STD) or hyperfractionated (HFX) conformal irradiation (CRT). HFX (1.2 Gy BID) was chosen as a radiobiological method to try to reduce long term sequelae without compromising local control. PATIENTS AND METHODS: Three-hundred-and-seventy consecutive patients (pts) entered this prospective, non-randomized trial in the period January 1993-January 2003; 209 were treated with STD and 161 with HFX CRT. All were evaluable for acute toxicity analysis, 179 (STD) and 151 pts (HFX) being evaluable for late sequelae and bRFS analyses. Pt characteristics were not statistically different in the two groups. CRT consisted of a 4-field technique for prostate and/or pelvic nodes and a 5-field boost with rectal shielding. Median doses were 74 and 79.2 Gy for STD and HFX patients respectively, the latter dose being isoeffective for tumour control assuming alpha/beta=10 (EQD(2)=73.9 Gy). Median follow-up was 29.4 months (25.2 mos for STD; 37.7 mos for HFX; P<0.01). The two regimens were compared in terms of acute and late GU and GI toxicities and 5-year bRFS by univariate and multivariate analyses. RESULTS: Acute grade> or =2 GU toxicity was higher in the STD group (48.6% versus 37.3% in HFX, P=0.03), while no significant difference was found for acute GI toxicity. Late grade> or =2 GU and GI toxicities were lower in the HFX group (5-year actuarial rate: GU: 10.1% versus 20.3%, P=0.05; GI: 6.0% versus 10.6%, P=0.18). Five-year bRFS were 70% (+/-13.8%, 95% CI) and 82.6% (+/-7.2%) for STD and HFX, respectively (P=0.44); a trend favouring HFX was found in the subgroup of pts who did not receive hormonal therapy (5-year bRFS: 85.9%+/-12.4% versus 63.9%+/-23.8%, P=0.15). Multivariate analysis revealed only risk groups and age statistically related to bRFS but not fractionation regimen. Using the Nahum-Chapman TLCP model and prostate parameter set, which includes hypoxia, the TLCPs are approximately equal for the two regimens, whereas assuming alpha/beta=1.5 and no hypoxia we obtain 73% for the STD group but only 36% for the HFX group. CONCLUSIONS: As expected from radiobiological considerations, HFX reduces GI and GU late toxicities. Concerning early bRFS, our clinical findings suggest that HFX is no less effective than STD when delivering an isoeffective (alpha/beta=10) dose. Despite the relatively short follow-up, this result appears to be inconsistent with a low alpha/beta ratio for prostate cancer.     

Early increase of plasma soluble VEGFR-2 is associated with clinical benefit from second-line treatment of paclitaxel and ramucirumab in advanced gastric cancer

Ramucirumab plus paclitaxel is considered the standard of care in the second-line treatment of gastric carcinoma (GC). The aim of this study was to evaluate plasma vascular endothelial growth factor-A (VEGF-A), VEGF-D, and circulating soluble VEGF receptor-2 (sVEGFR-2) as possible markers of resistance or response to ramucirumab administered with paclitaxel in pretreated metastatic GC patients. Plasma samples were collected at different time points (on days 1 and 15 of the first 3 cycles, at best radiologic response and at disease progression). VEGF-A, VEGF-D and sVEGFR-2 were analysed by ELISA. Correlations of biomarker baseline levels or dynamic changes with outcome measures were assessed. Progression-free survival (PFS) was the primary endpoint of the study. Forty-one patients were enrolled. VEGF-A and VEGF-D, but not sVEGFR-2, values significantly increased during treatment compared to baseline (P < 0.001). A positive correlation between VEGF-A and sVEGFR-2 at cycle 2 was found (P=0.045). At univariate analysis, higher baseline levels of VEGF-A were associated with worse OS (P=0.015). Early increase of sVEGFR-2 levels after the first treatment cycle was the only factor associated with longer PFS (6.6 vs. 3.6 months, P=0.049) and OS (18.6 vs. 5.2 months, P=0.008). Significance of sVEGFR-2 early increase was retained at multivariate analysis for OS (HR 0.32; 95% CI 0.12-0.91; P=0.032). The reported results confirmed the prognostic role of baseline VEGF-A and, with the limitations of the limited sample size and the lack of a control arm, suggested that the early increase of sVEGFR-2 after 1 cycle of treatment could be a potential predictive biomarker of benefit from second-line ramucirumab plus paclitaxel in GC.     

Estimation of Nanoporous Au Young’s Modulus from Serial Block Face-SEM 3D-Characterisation

Nanoporous Au has been subjected to serial block face-scanning electron microscopy (SBF-SEM) 3D-characterisation. Corresponding sections have been digitalized and used to evaluate the associated mechanical properties. Our investigation demonstrates that the sample is homogeneous and isotropic. The effective Young’s modulus estimated by an analytical multiscale approach agrees remarkably well with the values stated in the literature.     

The space-time profiles of sleep spindles and their coordination with slow oscillations on the electrode manifold

Sleep spindles are important for sleep quality and cognitive functions, with their coordination with slow oscillations (SOs) potentially organizing cross-region reactivation of memory traces. Here, we describe the organization of spindles on the electrode manifold and their relation to SOs. We analyzed the sleep night EEG of 34 subjects and detected spindles and SOs separately at each electrode. We compared spindle properties (frequency, duration, and amplitude) in slow wave sleep (SWS) and Stage 2 sleep (S2); and in spindles that coordinate with SOs or are uncoupled. We identified different topographical spindle types using clustering analysis that grouped together spindles co-detected across electrodes within a short delay (±300 ms). We then analyzed the properties of spindles of each type, and coordination to SOs. We found that SWS spindles are shorter than S2 spindles, and spindles at frontal electrodes have higher frequencies in S2 compared to SWS. Furthermore, S2 spindles closely following an SO (about 10% of all spindles) show faster frequency, shorter duration, and larger amplitude than uncoupled ones. Clustering identified Global, Local, Posterior, Frontal-Right and Left spindle types. At centro-parietal locations, Posterior spindles show faster frequencies compared to other types. Furthermore, the infrequent SO-spindle complexes are preferentially recruiting Global SO waves coupled with fast Posterior spindles. Our results suggest a non-uniform participation of spindles to complexes, especially evident in S2. This suggests the possibility that different mechanisms could initiate an SO-spindle complex compared to SOs and spindles separately. This has implications for understanding the role of SOs-spindle complexes in memory reactivation.     

Mental health,financial, and social outcomes among older adults with probable COVID-19 infection: A longitudinal cohort study

We investigated the immediate and longer-term impact (over 4-6 months) of probable COVID-19 infection on mental health, wellbeing, financial hardship, and social interactions among older people living in England. Data were analysed from 5146 older adults participating in the English Longitudinal Study of Ageing who provided data before the pandemic (2018-19) and at two COVID-19 assessments in 2020 (June-July and November-December). The associations of probable COVID-19 infection (first COVID-19 assessment) with depression, anxiety, poor quality of life (QoL), loneliness, financial hardship, and social contact with family/friends at the first and second COVID-19 assessments were tested using linear/logistic regression and were adjusted for pre-pandemic outcome measures. Participants with probable infection had higher levels of depression and anxiety, poorer QoL, and greater loneliness scores compared with those without probable infection at both the first (OR_depression = 1.62, P-value = 0.005; OR_anxiety = 1.59, P-value = 0.049; b_poorQoL = 1.34, P < 0.001; b_loneliness = 0.49, P < 0.001) and second (OR_depression = 1.56, P-value = 0.003; OR_anxiety = 1.55, P-value = 0.041; b_poorQoL = 1.38, P-value < 0.001; b_loneliness = 0.31, P-value = 0.024) COVID-19 assessments. Participants with probable infection also experienced greater financial difficulties than those without infection at the first assessment (OR = 1.50, P-value = 0.011). Probable COVID-19 infection is associated with longer-term deterioration of mental health and wellbeing and short-term increases in financial hardship among older adults. It is important to monitor the mental health of older people affected by COVID-19 and provide additional support to those in need.

The coronavirus disease 2019 (COVID-19) pandemic has affected several aspects of people’s lives, including physical and mental health, employment and financial security, social connections, and access to healthcare (1). Despite a large body of research documenting the adverse psychosocial effects of the pandemic and its containment measures across the population, little is currently known regarding the impact that contracting COVID-19 itself may have on the individual’s mental health, personal finances, and social relationships.Several longitudinal studies have reported increases in depression, anxiety, and general psychological distress in the adult population during the COVID-19 pandemic compared with prepandemic levels (2, 3). People who have contracted COVID-19 might be particularly vulnerable to the psychological impact of the pandemic. Indeed, initial evidence suggests that the experience of COVID-19 symptoms is associated not only with adverse physical consequences, but also with long-term effects on mental health (4, 5). Various mechanisms could underlie the psychological effects of COVID-19 infection, including the potential neurotropic properties of the virus (6, 7); the presence of elevated proinflammatory cytokines (e.g., interleukin-6) in patients with severe COVID-19 symptoms (8), which are implicated in the development of psychiatric disorders such as depression (9); and the exposure to prolonged periods of social isolation and physical inactivity in people affected by COVID-19 (10), which in turn can increase mental distress and feelings of loneliness. Compounded by the widespread psychosocial effects of the pandemic across the population, these factors might further exacerbate the risk of mental health problems among individuals recovering from COVID-19 infection.Data from previous coronavirus epidemics demonstrate the potential psychiatric consequences of the virus in both the acute and postacute phases of the illness (11). Further, studies across different countries have found that individuals reporting COVID-19 symptoms and patients recovering from acute COVID-19 illness exhibit increased levels of anxiety, depression, suicidal ideation, loneliness, and poor quality of life (QoL) compared with healthy people (5, 12–19). Studies using data from electronic health records in the United States have also shown that COVID-19 patients with no previous psychiatric history are at increased risk of first-time diagnosis of psychiatric disorders compared with those affected by other health events (e.g., influenza) or healthy controls (20, 21). However, most studies to date are limited by small, nonrepresentative samples and short follow-up periods, and they lack longitudinal data on the participants’ mental health before COVID-19, as well as data on confounding factors. Since individuals with preexisting mental disorders seem particularly susceptible to COVID-19 infection (20, 22), it is unclear the extent to which reverse causality and confounding bias might contribute to the association between COVID-19 infection and psychological distress. In addition, studies involving electronic health records or clinical samples may not capture individuals with moderate COVID-19 symptoms and those with less severe mental health problems who do not present to health services.Longitudinal cohort studies are well suited to study the immediate and longer-term psychosocial consequences of COVID-19 infection in the general population, as they include comprehensive information on mental health before the infection and other confounding factors (e.g., sex, age, socioeconomic position). Results from the United Kingdom suggest that people with probable COVID-19 symptoms experience greater psychological distress up to 7 months following the start of the infection (23). In contrast, an online study in the United States found evidence only for short-term psychological effects that diminish as the symptoms subside (24). Notably, these studies have only focused on general psychological distress; therefore, the impact of COVID-19 infection on specific mental health and wellbeing outcomes (e.g., depression, anxiety, loneliness, and QoL) in the general population is unclear.Numerous studies have also highlighted the financial impact of the pandemic—including job losses, pay cuts, reductions in household income, fluctuations in stock markets and wealth held in risky assets, and widespread financial worries (25–27)—as well as its adverse consequences for various domains of social relationships, including social networks, social support, and social interaction (28, 29). However, these studies relate to the whole population rather than to people with COVID-19 infection. Empirical evidence regarding the impact that COVID-19 infection may have on a person’s financial situation and social relationships is limited. For instance, cross-sectional results suggest that adults who have experienced COVID-19 are more likely to report that their social relationships, work, and household finances have been adversely affected by the pandemic, compared with those who have not had COVID-19 (30). However, this analysis did not account for preexisting trends in social connections and economic outcomes, and it was unable to disentangle short-term versus longer-term psychosocial consequences of the infection.Older adults are at increased risk of social isolation and serious illness following COVID-19 infection (31), and they also are particularly vulnerable to the effects of chronic stress on the brain (32). A recent analysis of data from the English Longitudinal Study of Aging (ELSA) also demonstrates that the mental health and wellbeing of the older population deteriorated significantly as the pandemic progressed in 2020, compared with prepandemic levels (33). Given these factors, older people might be disproportionally affected by the psychosocial effects of COVID-19 infection. However, little research on COVID-19 has involved older adults who are also often unable to access online surveys (34). In addition, care-seeking behaviors changed considerably in the early stages of the pandemic, with large numbers of older adults with care needs not actively contacting health services and not seeking help (35). Therefore, older adults’ experiences of COVID-19 might be underrepresented in earlier studies.In the present analysis, we investigated the immediate and longer-term impact (over 4 to 6 months) of probable COVID-19 infection on mental health (i.e., depression and anxiety), wellbeing (i.e., QoL and loneliness), financial hardship, and social interactions in a large, representative sample of older adults from ELSA. In addition, we assessed whether the psychosocial impact of probable COVID-19 infection might vary across different sociodemographic groups. All outcomes were assessed before the pandemic began (i.e., 2018/2019) and on two occasions during the pandemic, which enabled us to test both short-term and longer-term associations. The data were collected online and by telephone interview to ensure coverage of those without internet access.     

Assessment of Angiogenesis and Cell Survivability of an Inkjet Bioprinted Biological Implant in an Animal Model

The rapidly growing field of tissue engineering hopes to soon address the shortage of transplantable tissues, allowing for precise control and fabrication that could be made for each specific patient. The protocols currently in place to print large-scale tissues have yet to address the main challenge of nutritional deficiencies in the central areas of the engineered tissue, causing necrosis deep within and rendering it ineffective. Bioprinted microvasculature has been proposed to encourage angiogenesis and facilitate the mobility of oxygen and nutrients throughout the engineered tissue. An implant made via an inkjet printing process containing human microvascular endothelial cells was placed in both B17-SCID and NSG-SGM3 animal models to determine the rate of angiogenesis and degree of cell survival. The implantable tissues were made using a combination of alginate and gelatin type B; all implants were printed via previously published procedures using a modified HP inkjet printer. Histopathological results show a dramatic increase in the average microvasculature formation for mice that received the printed constructs within the implant area when compared to the manual and control implants, indicating inkjet bioprinting technology can be effectively used for vascularization of engineered tissues.     

Visual stimulation and frequency of focal neurological symptoms engage distinctive neurocognitive resources in migraine with aura patients: a study of resting-state functional networks

IntroductionSeveral functional neuroimaging studies on healthy controls and patients with migraine with aura have shown that the activation of functional networks during visual stimulation is not restricted to the striate system, but also includes several extrastriate networks.MethodsBefore and after 4 min of visual stimulation with a checkerboard pattern, we collected functional MRI in 21 migraine with aura (MwA) patients and 18 healthy subjects (HS). For each recording session, we identified independent resting-state networks in each group and correlated network connection strength changes with clinical disease features.ResultsBefore visual stimulation, we found reduced connectivity between the default mode network and the left dorsal attention system (DAS) in MwA patients compared to HS. In HS, visual stimulation increases functional connectivity between the independent components of the bilateral DAS and the executive control network (ECN). In MwA, visual stimulation significantly improved functional connectivity between the independent component pairs salience network and DAS, and between DAS and ECN. The ECN Z-scores after visual stimulation were negatively related to the monthly frequency of aura.ConclusionsIn individuals with MwA, 4 min of visual stimulation had stronger cognitive impact than in healthy people. A higher frequency of aura may lead to a diminished ability to obtain cognitive resources to cope with transitory but important events like aura-related focal neurological symptoms.