A new approach to the construction of first-passage-time densities

A new method for constructing first-passage-time probability density functions is outlined. This rests on the possibility of constructing the transition p.d.f. of a new diffusion process in terms of a preassigned transition p.d.f. without making use of the classical space-time transformations of the Kolmogorov equation. A few examples are finally discusse

A horse, a horse, my kingdom for a horse. Saddle thrombosis of carotid bifurcation in acute stroke

Background: Saddle thrombosis is less frequently detected in carotid arteries than in peripheral arterial embolism. The clot and the distal vessel patency have to be promptly recognized in these cases, because if the carotid vessel is open distally, chances may arise for successful emergent surgical procedures to remove the thrombus. At conventional static imaging, mobile floating thrombi may be difficult to differentiate from thrombosis on carotid complicated lesions of atherosclerotic origin. High-resolution ultrasound (US), with its unique capability of real-time imaging, adds fundamental data for interpretation of the findings. Methods: Carotid ultrasound has been performed in acute stroke patients with high-resolution probes. Real-time clips are analyzed and imaging is presented. Results: Saddle carotid bifurcation thrombosis of cardiac origin has been identified in 2 patients with acute homolateral ischemic stroke, with prompt successful surgical removal in one case. Moreover, an example of a thrombus attached on the ruptured surface of a complicated atherosclerotic plaque in an acute symptomatic stroke patient that was successfully operated in emergency is presented. Conclusions: Early high-resolution ultrasound with real-time imaging can easily identify peculiar characteristics of carotid vulnerable diseases in acute stroke phase. Different clinical implications result from the early identification of these different conditions, modifying the therapeutical strategies. © 2012 Elsevier GmbH

Polychlorinated Biphenyls (PCBs) in the Environment: Occupational and Exposure Events, Effects on Human Health and Fertility

In the last decade or so, polychlorinated biphenyls (PCBs) garnered renewed attention in the scientific community due to new evidence pointing at their continued presence in the environment and workplaces and the potential human risks related to their presence. PCBs move from the environment to humans through different routes; the dominant pathway is the ingestion of contaminated foods (fish, seafood and dairy products), followed by inhalation (both indoor and outdoor air), and, to a lesser extent, dust ingestion and dermal contact. Numerous studies reported the environmental and occupational exposure to these pollutants, deriving from building materials (flame-retardants, plasticizers, paints, caulking compounds, sealants, fluorescent light ballasts, etc.) and electrical equipment. The highest PCBs contaminations were detected in e-waste recycling sites, suggesting the need for the implementation of remediation strategies of such polluted areas to safeguard the health of workers and local populations. Furthermore, a significant correlation between PCB exposure and increased blood PCB concentrations was observed in people working in PCB-contaminated workplaces. Several epidemiological studies suggest that environmental and occupational exposure to high concentrations of PCBs is associated with different health outcomes, such as neuropsychological and neurobehavioral deficits, dementia, immune system dysfunctions, cardiovascular diseases and cancer. In addition, recent studies indicate that PCBs bioaccumulation can reduce fertility, with harmful effects on the reproductive system that can be passed to offspring. In the near future, further studies are needed to assess the real effects of PCBs exposure at low concentrations for prolonged exposure in workplaces and specific indoor environments

Effects of cardiac resynchronization therapy on systemic inflammation and neurohormonal pathways in heart failure

Background: The effect of cardiac resynchronization therapy (CRT) on systemic inflammation and neurohormonal alterations associated with heart failure is not well characterized. Accordingly, we aimed to assess the long term effects of CRT on systemic inflammation and neurohormonal factors in heart failure patients. Methods and results: In 47 HF patients (NYHA III–IV) we evaluated, at baseline and after one year of CRT: TNF-α, TNF soluble receptors (sTNFR1 and sTNFR2), insulin-like growth factor-1α (IGF-1α), adiponectin, norepinephrine, pro-atrial natriuretic peptide (pro-ANP), N-terminal-pro-brain natriuretic peptide (NT-proBNP) and angiotensin II, NYHA functional class, quality of life (the Minnesota Living with Heart Failure questionnaire), a 6-minute walk test and an echocardiogram. Long-term CRT decreased activation of renin–angiotensin system (RAS) only in patients with reverse remodelling. It failed to prevent a decline in adiponectin levels, regardless of reverse remodelling. NT-proBNP remained unchanged in patients with reverse remodelling, whereas its levels increased in those without reverse remodelling. IGF-1α increased with CRT, whereas CRT had no effect on pro-ANP and inflammatory markers. Conclusions: Long-term CRT is associated with decreased RAS activation and stabilization of NT-proBNP in heart failure patients with reverse remodelling. Long-term CRT, with or without reverse remodelling, does not affect systemic inflammation and fails to prevent a decline in adiponectin

Genetic modulation of PINK1 differentially affects mitophagy compared with autophagy disclosing common mechanisms of genetic and environmental parkinsonism

The second most frequent cause of autosomal recessive Parkinson’s disease is represented by mutations in the PTEN-induced putative kinase1 (PINK1). The PINK1 protein mainly localizes to mitochondria which are considered the target organelles mainly affected in Parkinson’s disease. In fact, parkinsonism-inducing neurotoxins such as rotenone, MPTP and methamphetamine all damage mitochondria. Therefore, the ability to counteract mitochondrial toxicity and promoting mitochondrial renewal by mithophagy and mitochondrial biogenesis is critical to cure Parkinsonism. For instance the autophagy-dependent removal of altered mitochondria known as mitophagy is supposed to be key in conteracting mitochondrial toxicity. Interestingly mitochondrial PINK1 is known to interact with autophagy proteins such as beclin1 and the ubiquitin-ligase parkin. Therefore, in the present study we evaluated whether such an interaction produced downstream effects leading to autophagy activation. This was evaluated through the simultaneous analysis of co-localization of parkin and beclin1 with the autophagy initiator ubiquitin. These phenomena were analyzed both at mitochondrial level and throughout the cytosol by analyzing autophagy-like vacuoles and LC3-II positive structures. Interestingly, despite increased mitophagy PINK1 overexpression did not produce a general activation of the autophagy pathway. It is likely that such a selective fashion of autophagy activation only limited to mitochondrial removal could explain the relevance of PINK1 for Parkinson’s disease but not for other neurodegenerative, autophagy-related disorders. The present data were obtained through several experimental settings featuring PINK1 overexpression, mutation, deletion and silencing of the gene. The effects were analyzed in baseline conditions but were supplemented by experiments in the presence of methamphetamine used here both as a mitochondrial neurotoxin and an autophagy-dependent Parkinsonism inducing compound. Data revealed that PINK1 was critical for mitochondria and cell viability already in baseline conditions though such an effect was magnified upon methamphetamine exposure. The present findings while explaining the molecular interactions which are likely to induce PINK1-dependent genetic Parkinsonism, provide a further evidence on the critical role of genetic and environmental alterations in the genesis of Parkinson’s disease

Valutazione di Health Technology Assessment del sistema di sanificazione biologico a base di probiotici del genere Bacillus (PCHS)

Le infezioni correlate all’assistenza: priorità per la salute pubblica Epidemiologia delle infezioni correlate all’assistenza in Italia e loro impatto per la salute pubblica Sistemi di sanificazione attualmente disponibili in Italia Il Probiotic Cleaning Hygiene System (PCHS): caratteristiche della tecnologia, aspetti di efficacia e sicurezza Un sistema di sanificazione a base di probiotici per la riduzione delle infezioni correlate all’assistenza e la resistenza antimicrobica: analisi dell’impatto sul budget Impatto ambientale per la salute pubblica degli attuali sistemi di sanificazione di ambienti/superfici in setting assistenziale e comunitario e potenziali benefici dei nuovi sistemi innovativi Analisi delle principali raccomandazioni nazionali su sanificazione e disinfezione degli ambienti sanitari Valutazione etica dell’utilizzo del Probiotic Cleaning Hygiene System (PCHS) in Italia Elementi chiave per il processo decisional

High familial burden of cancer correlates with improved outcome from immunotherapy in patients with NSCLC independent of somatic DNA damage response gene status

Family history of cancer (FHC) is a hallmark of cancer risk and an independent predictor of outcome, albeit with uncertain biologic foundations. We previously showed that FHC-high patients experienced prolonged overall (OS) and progression-free survival (PFS) following PD-1/PD-L1 checkpoint inhibitors. To validate our findings in patients with NSCLC, we evaluated two multicenter cohorts of patients with metastatic NSCLC receiving either first-line pembrolizumab or chemotherapy. From each cohort, 607 patients were randomly case-control matched accounting for FHC, age, performance status, and disease burden. Compared to FHC-low/negative, FHC-high patients experienced longer OS (HR 0.67 [95% CI 0.46-0.95], p\u2009=\u20090.0281), PFS (HR 0.65 [95% CI 0.48-0.89]; p\u2009=\u20090.0074) and higher disease control rates (DCR, 86.4% vs 67.5%, p\u2009=\u20090.0096), within the pembrolizumab cohort. No significant associations were found between FHC and OS/PFS/DCR within the chemotherapy cohort. We explored the association between FHC and somatic DNA damage response (DDR) gene alterations as underlying mechanism to our findings in a parallel cohort of 118 NSCLC, 16.9% of whom were FHC-high. The prevalence of\u2009 65\u20091 somatic DDR gene mutation was 20% and 24.5% (p\u2009=\u20090.6684) in FHC-high vs. FHC-low/negative, with no differences in tumor mutational burden (6.0 vs. 7.6 Mut/Mb, p\u2009=\u20090.6018) and tumor cell PD-L1 expression. FHC-high status identifies NSCLC patients with improved outcomes from pembrolizumab but not chemotherapy, independent of somatic DDR gene status. Prospective studies evaluating FHC alongside germline genetic testing are warranted

PRISM (Polarized Radiation Imaging and Spectroscopy Mission): A White Paper on the Ultimate Polarimetric Spectro-Imaging of the Microwave and Far-Infrared Sky

PRISM (Polarized Radiation Imaging and Spectroscopy Mission) was proposed to ESA in response to the Call for White Papers for the definition of the L2 and L3 Missions in the ESA Science Programme. PRISM would have two instruments: (1) an imager with a 3.5m mirror (cooled to 4K for high performance in the far-infrared---that is, in the Wien part of the CMB blackbody spectrum), and (2) an Fourier Transform Spectrometer (FTS) somewhat like the COBE FIRAS instrument but over three orders of magnitude more sensitive. Highlights of the new science (beyond the obvious target of B-modes from gravity waves generated during inflation) made possible by these two instruments working in tandem include: (1) the ultimate galaxy cluster survey gathering 10e6 clusters extending to large redshift and measuring their peculiar velocities and temperatures (through the kSZ effect and relativistic corrections to the classic y-distortion spectrum, respectively) (2) a detailed investigation into the nature of the cosmic infrared background (CIB) consisting of at present unresolved dusty high-z galaxies, where most of the star formation in the universe took place, (3) searching for distortions from the perfect CMB blackbody spectrum, which will probe a large number of otherwise inaccessible effects (e.g., energy release through decaying dark matter, the primordial power spectrum on very small scales where measurements today are impossible due to erasure from Silk damping and contamination from non-linear cascading of power from larger length scales). These are but a few of the highlights of the new science that will be made possible with PRISM.Comment: 20 pages Late

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P < 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria