Robustness analysis of surface-guided DIBH left breast radiotherapy: personalized dosimetric effect of real intrafractional motion within the beam gating thresholds.

PURPOSE: The robustness of surface-guided (SG) deep-inspiration breath-hold (DIBH) radiotherapy (RT) for left breast cancer was evaluated by investigating any potential dosimetric effects due to the residual intrafractional motion allowed by the selected beam gating thresholds. The potential reduction of DIBH benefits in terms of organs at risk (OARs) sparing and target coverage was evaluated for conformational (3DCRT) and intensity-modulated radiation therapy (IMRT) techniques. METHODS: A total of 192 fractions of SGRT DIBH left breast 3DCRT treatment for 12 patients were analyzed. For each fraction, the average of the real-time displacement between the isocenter on the daily reference surface and on the live surface ("SGRT shift") during beam-on was evaluated and applied to the original plan isocenter. The dose distribution for the treatment beams with the new isocenter point was then calculated and the total plan dose distribution was obtained by summing the estimated perturbed dose for each fraction. Then, for each patient, the original plan and the perturbed one were compared by means of Wilcoxon test for target coverage and OAR dose-volume histogram (DVH) metrics. A global plan quality score was calculated to assess the overall plan robustness against intrafractional motion of both 3DCRT and IMRT techniques. RESULTS: Target coverage and OAR DVH metrics did not show significant variations between the original and the perturbed plan for the IMRT techniques. 3DCRT plans showed significant variations for the left descending coronary artery (LAD) and the humerus only. However, none of the dose metrics exceeded the mandatory dose constraints for any of the analyzed plans. The global plan quality analysis indicated that both 3DCRT and IMRT techniques were affected by the isocenter shifts in the same way and, generally, the residual isocenter shifts more likely tend to worsen the plan in all cases. CONCLUSION: The DIBH technique proved to be robust against residual intrafractional isocenter shifts allowed by the selected SGRT beam-hold thresholds. Small-volume OARs located near high dose gradients showed significant marginal deteriorations in the perturbed plans with the 3DCRT technique only. Global plan quality was mainly influenced by patient anatomy and treatment beam geometry rather than the technique adopted.

Choice of Frontline Tyrosine-Kinase Inhibitor and Early Events in Very Elderly Patients With Chronic Myeloid Leukemia in Chronic Phase: A "Campus CML" Study.

OBJECTIVES: The study aimed to evaluate the utilization of frontline TKI therapy in a large cohort of elderly CP-CML patients. METHODS: A retrospective analysis was conducted on 332 CP-CML patients aged 75 years or older among 1929 diagnosed from January 2012 to December 2019 followed at 36 participating Hematology Centers involved in the "Campus CML" project. RESULTS: Among the patients analyzed, 85.8% received imatinib (IM) while 14.2% received second-generation TKIs (2G-TKI), 59.5% dasatinib, and 40.5% nilotinib. Most patients initiated IM at standard dose (67.3%) while 32.7% at reduced dose. A similar trend was observed with 2G-TKIs. The cumulative incidence of permanent TKI discontinuation at 12 months was 28.4%, primarily due to primary resistance (10.1%) and extra-hematologic toxicity (9.5%), with no significant difference between IM and 2G-TKI groups. Following the introduction of generic IM in Italy in 2018, IM usage increased significantly compared with 2G-TKIs. CONCLUSIONS: IM was in our Centers the preferred frontline therapy for older CP-CML patients, with increasing utilization after the introduction of generic formulations. However, 2G-TKIs are still used in a substantial proportion of patients, suggesting individualized physician assessments regarding patient suitability and expectations. Further investigation is needed to assess efficacy and safety of reduced TKI doses in this patient population.

Surface-guided DIBH radiotherapy for left breast cancer: impact of different thresholds on intrafractional motion monitoring and DIBH stability.

PURPOSE: To compare two left breast cancer patient cohorts (tangential vs. locoregional deep-inspiration breath-hold - DIBH treatment) with different predefined beam gating thresholds and to evaluate their impact on motion management and DIBH stability. METHODS: An SGRT-based clinical workflow was adopted for the DIBH treatment. Intrafractional monitoring was performed by tracking both the respiratory signal and the real-time displacement between the isocenter on the daily reference surface and on the live surface ("SGRT shift"). Beam gating tolerances were 5 mm/4 mm for the SGRT shifts and 5 mm/3 mm for the gating window amplitude for breast tangential and breast + lymph nodes locoregional treatments, respectively. A total of 24 patients, 12 treated with a tangential technique and 12 with a locoregional technique, were evaluated for a total number of 684 fractions. Statistical distributions of SGRT shift and respiratory signal for each treatment fraction, for each patient treatment, and for the two population samples were generated. RESULTS: Lateral cumulative distributions of SGRT shifts for both locoregional and tangential samples were consistent with a null shift, whereas longitudinal and vertical ones were slightly negative (mean values < 1 mm). The distribution of the percentage of beam on time with SGRT shift > 3 mm, > 4 mm, or > 5 mm was extended toward higher values for the tangential sample than for the locoregional sample. The variability in the DIBH respiration signal was significantly greater for the tangential sample. CONCLUSION: Different beam gating thresholds for surface-guided DIBH treatment of left breast cancer can impact motion management and DIBH stability by reducing the frequency of the maximum SGRT shift and increasing respiration signal stability when tighter thresholds are adopted.

Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study.

BACKGROUND: High-risk triple-negative breast cancers (TNBCs) are characterized by poor prognosis, rapid progression to metastatic stage and onset of resistance to chemotherapy, thus representing an area in need of new therapeutic approaches. Programmed death-ligand 1 (PD-L1) expression is an adaptive mechanism of tumour resistance to tumour-infiltrating lymphocytes, which in turn are needed for response to chemotherapy. Overall, available data support the concept that blockade of PD-L1/programmed cell death protein 1 checkpoint may improve efficacy of classical chemotherapy. PATIENTS AND METHODS: Two hundred and eighty patients with TNBC were enrolled in this multicentre study (NCT002620280) and randomized to neoadjuvant carboplatin area under the curve 2 and nab-paclitaxel 125 mg/m2 intravenously (i.v.) on days 1 and 8, without (n = 142) or with (n = 138) atezolizumab 1200 mg i.v. on day 1. Both regimens were given q3 weeks for eight cycles before surgery followed by four cycles of an adjuvant anthracycline regimen. The primary aim of the study was to compare event-free survival (EFS), and an important secondary aim was the rate of pathological complete response (pCR defined as the absence of invasive cells in breast and lymph nodes). The primary population for all efficacy endpoints is the intention-to-treat (ITT) population. RESULTS: The ITT analysis revealed that pCR rate after treatment with atezolizumab (48.6%) did not reach statistical significance compared to no atezolizumab [44.4%: odds ratio (OR) 1.18; 95% confidence interval 0.74-1.89; P = 0.48]. Treatment-related adverse events were similar with either regimen except for a significantly higher overall incidence of serious adverse events and liver transaminase abnormalities with atezolizumab. CONCLUSIONS: The addition of atezolizumab to nab-paclitaxel and carboplatin did not significantly increase the rate of pCR in women with TNBC. In multivariate analysis, the presence of PD-L1 expression was the most significant factor influencing the rate of pCR (OR 2.08). Continuing follow-up for the EFS is ongoing, and molecular studies are under way.

Family Pediatrician and Public Health collaboration, an alliance to increase vaccination coverage: an experience with MenB vaccination in Italy.

Background: Invasive Meningococcal Disease is a severe disease mainly affecting infants and young children. Most infections are caused by serogroups A, B, C, W, X, and Y. In the last 10 years, serogroup B has been the main cause of Invasive Meningococcal Disease in Europe. Recent data resulting from an observational study conducted in Italy show a significant reduction in the number of Invasive Meningococcal Disease cases due to Neisseria meningitidis B after the introduction of vaccine 4CMenB. Thus, the Naples Team of Federation of Italian Primary Care Pediatricians and the Public Health Department started an active collaboration focused on vaccination process management (named "Progetto Via") with the aim of increasing Meningococcal B vaccination coverage. Study design: Source of data is the regional platform "GE.VA.". Every Primary care Pediatrician uses daily to record vaccination activity. This platform is integrated with data entered by operators of the District/Vaccination Center. Methods: Time: January 2019 - December 2019. The Federation of Italian Primary Care Pediatricians/Naples organized a meeting to identify six coordinators. The pediatricians could choose to counsel in their own offices and send children to the vaccination center or to counsel and vaccinate directly in their own clinics. Results: A total of 78 pediatricians took part in the project: 46 did only counseling and 32 did both counseling and vaccination in their medical clinic. Data obtained show an overall average vaccination coverage growth of about 13% in the first 4 months of the survey, and a further growth of about 11% in the following seven months, with a total growth in the entire period of 24%. The pediatricians' counseling is essential to recover non-compliant subjects, considering both the relationship of trust with the families and the visits already scheduled as an ideal moment for vaccinations' status check. Conclusions: The project highlights how an effective collaboration between family pediatricians and the Local Health Authority becomes valuable in getting closer to reach the Ministerial goal of 95%. Vaccination coverage increased significantly when family pediatricians supported the activity of vaccine centers in distress in many regional situations. The trust relationship, the hourly availability and the capillary network of family pediatricians' clinics were key elements for the success of this project and were also recognized by parents.

Differences in training among prehospital emergency physicians in Germany.

Background: Germany has an interdisciplinary physician-based emergency medical service. Differences in training likely lead to different levels of expertise. Objectives: We assessed the number of manual procedures performed at the completion of training to determine level of experience of prehospital emergency physicians of different primary specialties. Materials and methods: Immediately after passing the board examination each examinee was asked to estimate the number of performed procedures for 26 manual skills. We compared the results with recommendations and data on learning manual skills. Results are presented as mean (standard deviation). Results: Endotracheal intubation via direct laryngoscopy was performed 1032 (739) times by anesthesiologists. Surgeons and internists performed 89 (89) and 77 (65) intubations, respectively. Intubation via video laryngoscopy was performed 79 (81) times by anesthesiologists, 11 (17) times by surgeons and 6 (11) times by internists. Surgeons had little experience in non-invasive ventilation, with 9 (19) performed procedures and had rarely used external pacemaker therapy or electrical cardioversion. In comparison, among all participants non-invasive ventilation was performed 152 (197) times, electrical cardioversion was performed 41 (103) times and an external pacemaker was used 6 (15) times. For other procedures the numbers did not markedly differ between the different specialties. Conclusion: The number of performed procedures markedly differed for some skills between different primary specialties. Recommendations regarding a procedural volume were not always met, suggesting missing expertise for some skills. A defined number of procedures should therefore be a formal requirement to be eligible for board certification in prehospital emergency medicine.

Focal lesions induce large-scale percolation of sleep-like intracerebral activity in awake humans.

Focal cortical lesions are known to result in large-scale functional alterations involving distant areas; however, little is known about the electrophysiological mechanisms underlying these network effects. Here, we addressed this issue by analysing the short and long distance intracranial effects of controlled structural lesions in humans. The changes in Stereo-Electroencephalographic (SEEG) activity after Radiofrequency-Thermocoagulation (RFTC) recorded in 21 epileptic subjects were assessed with respect to baseline resting wakefulness and sleep activity. In addition, Cortico-Cortical Evoked Potentials (CCEPs) recorded before the lesion were employed to interpret these changes with respect to individual long-range connectivity patterns. We found that small structural ablations lead to the generation and large-scale propagation of sleep-like slow waves within the awake brain. These slow waves match those recorded in the same subjects during sleep, are prevalent in perilesional areas, but can percolate up to distances of 60 mm through specific long-range connections, as predicted by CCEPs. Given the known impact of slow waves on information processing and cortical plasticity, demonstrating their intrusion and percolation within the awake brain add key elements to our understanding of network dysfunction after cortical injuries.

Improving dose delivery accuracy with EPID in vivo dosimetry: results from a multicenter study.

PURPOSE: To investigate critical aspects and effectiveness of in vivo dosimetry (IVD) tests obtained by an electronic portal imaging device (EPID) in a multicenter and multisystem context. MATERIALS AND METHODS: Eight centers with three commercial systems-SoftDiso (SD, Best Medical Italy, Chianciano, Italy), Dosimetry Check (DC, Math Resolution, LCC), and PerFRACTION (PF, Sun Nuclear Corporation, SNC, Melbourne, FL)-collected IVD results for a total of 2002 patients and 32,276 tests. Data are summarized for IVD software, radiotherapy technique, and anatomical site. Every center reported the number of patients and tests analyzed, and the percentage of tests outside of the tolerance level (OTL%). OTL% was categorized as being due to incorrect patient setup, incorrect use of immobilization devices, incorrect dose computation, anatomical variations, and unknown causes. RESULTS: The three systems use different approaches and customized alert indices, based on local protocols. For Volumetric Modulated Arc Therapy (VMAT) treatments OTL% mean values were up to 8.9% for SD, 18.0% for DC, and 16.0% for PF. Errors due to "anatomical variations" for head and neck were up to 9.0% for SD and DC and 8.0% for PF systems, while for abdomen and pelvis/prostate treatments were up to 9%, 17.0%, and 9.0% for SD, DC, and PF, respectively. The comparison among techniques gave 3% for Stereotactic Body Radiation Therapy, 7.0% (range 4.7-8.9%) for VMAT, 10.4% (range 7.0-12.2%) for Intensity Modulated Radiation Therapy, and 13.2% (range 8.8-21.0%) for 3D Conformal Radiation Therapy. CONCLUSION: The results obtained with different IVD software and among centers were consistent and showed an acceptable homogeneity. EPID IVD was effective in intercepting important errors.

Modeling radiative and non-radiative pathways at both the Franck-Condon and Herzberg-Teller approximation level.

Here, we present a concise model that can predict the photoluminescent properties of a given compound from first principles, both within and beyond the Franck-Condon approximation. The formalism required to compute fluorescence, Internal Conversion (IC), and Inter-System Crossing (ISC) is discussed. The IC mechanism, in particular, is a difficult pathway to compute due to difficulties associated with the computation of required bosonic configurations and non-adiabatic coupling elements. Here, we offer a discussion and breakdown on how to model these pathways at the Density Functional Theory (DFT) level with respect to its computational implementation, strengths, and current limitations. The model is then used to compute the photoluminescent quantum yield (PLQY) of a number of small but important compounds: anthracene, tetracene, pentacene, diketo-pyrrolo-pyrrole (DPP), and Perylene Diimide (PDI) within a polarizable continuum model. Rate constants for fluorescence, IC, and ISC compare well for the most part with respect to experiment, despite triplet energies being overestimated to a degree. The resulting PLQYs are promising with respect to the level of theory being DFT. While we obtained a positive result for PDI within the Franck-Condon limit, the other systems require a second order correction. Recomputing quantum yields with Herzberg-Teller terms yields PLQYs of 0.19, 0.08, 0.04, 0.70, and 0.99 for anthracene, tetracene, pentacene, DPP, and PDI, respectively. Based on these results, we are confident that the presented methodology is sound with respect to the level of quantum chemistry and presents an important stepping stone in the search for a tool to predict the properties of larger coupled systems.

Role of inflammasome activation in tumor immunity triggered by immune checkpoint blockers.

Immune checkpoint blockers improve the overall survival of a limited number of patients among different cancers. Identifying pathways that influence the immunological and clinical response to treatment is critical to improve the therapeutic efficacy and predict clinical responses. Recently, a key role has been assigned to innate immune mechanisms in checkpoint blockade-driven anti-tumor responses. However, inflammatory pathways can both improve and impair anti-tumor immunity. In this review, we discuss how different inflammatory pathways, particularly inflammasome activation, can influence the clinical outcome of immune checkpoint blockers. Inflammasome activation may reinforce anti-tumor immunity by boosting CD8+ T cell priming as well as by enhancing T helper type 17 (Th17) responses. In particular, we focus on the modulation of the cation channel transmembrane protein 176B (TMEM176B) and the ectonucleotidase CD39 as potential targets to unleash inflammasome activation leading to reinforced anti-tumor immunity and improved efficacy of immune checkpoint blockers. Future studies should be aimed at investigating the mechanisms and cell subsets involved in inflammasome-driven anti-tumor responses.

Rate of tree carbon accumulation increases continuously with tree size.

Forests are major components of the global carbon cycle, providing substantial feedback to atmospheric greenhouse gas concentrations. Our ability to understand and predict changes in the forest carbon cycle--particularly net primary productivity and carbon storage--increasingly relies on models that represent biological processes across several scales of biological organization, from tree leaves to forest stands. Yet, despite advances in our understanding of productivity at the scales of leaves and stands, no consensus exists about the nature of productivity at the scale of the individual tree, in part because we lack a broad empirical assessment of whether rates of absolute tree mass growth (and thus carbon accumulation) decrease, remain constant, or increase as trees increase in size and age. Here we present a global analysis of 403 tropical and temperate tree species, showing that for most species mass growth rate increases continuously with tree size. Thus, large, old trees do not act simply as senescent carbon reservoirs but actively fix large amounts of carbon compared to smaller trees; at the extreme, a single big tree can add the same amount of carbon to the forest within a year as is contained in an entire mid-sized tree. The apparent paradoxes of individual tree growth increasing with tree size despite declining leaf-level and stand-level productivity can be explained, respectively, by increases in a tree's total leaf area that outpace declines in productivity per unit of leaf area and, among other factors, age-related reductions in population density. Our results resolve conflicting assumptions about the nature of tree growth, inform efforts to undertand and model forest carbon dynamics, and have additional implications for theories of resource allocation and plant senescence.

Mercury Accumulation and Effects in the Brain of the Atlantic Sharpnose Shark (Rhizoprionodon terraenovae).

Few published studies have examined whether the elevated concentrations of the nonessential toxic metal mercury (Hg) often observed in shark muscle also occur in the shark brain or whether Hg accumulation affects shark neurophysiology. Therefore, this study examined accumulation and distribution of Hg in the shark brain, as well as effects of Hg on oxidative stress in the shark central nervous system, with particular focus on the Atlantic sharpnose shark (Rhizoprionodon terraenovae). Sharks were collected along the southeastern U.S. coast throughout most of this species' U.S. geographical range. Total Hg (THg) concentrations were measured in and compared between shark muscle and brain, whereas known biomarkers of Hg-induced neurological effects, including glutathione depletion, lipid peroxidation, and concentrations of a protein marker of glial cell damage (S100b), were measured in shark cerebrospinal fluid. Brain THg concentrations were correlated with muscle THg levels but were significantly lower and did not exceed most published thresholds for neurological effects, suggesting limited potential for detrimental responses. Biomarker concentrations supported this premise, because these data were not correlated with brain THg levels. Hg speciation also was examined. Unlike muscle, methylmercury (MeHg) did not comprise a high percentage of THg in the brain, suggesting that differential uptake or loss of organic and inorganic Hg and/or demethylation of MeHg may occur in this organ. Although Hg accumulation in the shark brain generally fell below toxicity thresholds, higher THg levels were measured in the shark forebrain compared with the midbrain and hindbrain. Therefore, there is potential for selective effects on certain aspects of shark neurophysiology if brain Hg accumulation is increased.

VGF function in depression and antidepressant efficacy.

Brain-derived neurotrophic factor (BDNF) is a critical effector of depression-like behaviors and antidepressant responses. Here, we show that VGF (non-acronymic), which is robustly regulated by BDNF/TrkB signaling, is downregulated in hippocampus (male/female) and upregulated in nucleus accumbens (NAc) (male) in depressed human subjects and in mice subjected to chronic social defeat stress (CSDS). Adeno-associated virus (AAV)-Cre-mediated Vgf ablation in floxed VGF mice, in dorsal hippocampus (dHc) or NAc, led to pro-depressant or antidepressant behaviors, respectively, while dHc- or NAc-AAV-VGF overexpression induced opposite outcomes. Mice with reduced VGF levels in the germ line (Vgf+/-) or in dHc (AAV-Cre-injected floxed mice) showed increased susceptibility to CSDS and impaired responses to ketamine treatment in the forced swim test. Floxed mice with conditional pan-neuronal (Synapsin-Cre) but not those with forebrain (αCaMKII-Cre) Vgf ablation displayed increased susceptibility to subthreshold social defeat stress, suggesting that neuronal VGF, expressed in part in inhibitory interneurons, regulates depression-like behavior. Acute antibody-mediated sequestration of VGF-derived C-terminal peptides AQEE-30 and TLQP-62 in dHc induced pro-depressant effects. Conversely, dHc TLQP-62 infusion had rapid antidepressant efficacy, which was reduced in BDNF floxed mice injected in dHc with AAV-Cre, and in NBQX- and rapamycin-pretreated wild-type mice, these compounds blocking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) signaling, respectively. VGF is therefore a critical modulator of depression-like behaviors in dHc and NAc. In hippocampus, the antidepressant response to ketamine is associated with rapid VGF translation, is impaired by reduced VGF expression, and as previously reported, requires coincident, rapid BDNF translation and release.

Inhibition of Eph/ephrin interaction with the small molecule UniPR500 improves glucose tolerance in healthy and insulin-resistant mice.

Eph/ephrin interactions and their bidirectional signaling are integral part of the complex communication system between ß-cells, essential for glucose homeostasis. Indeed, Eph/ephrin system was shown to be directly involved in the glucose-stimulated insulin secretion (GSIS) process occurring in the pancreatic islets. Here we tested the Eph antagonist UniPR500 as GSIS enhancer. UniPR500 was validated as EphA5-ephrin-A5 inhibitor in vitro and its efficacy as GSIS enhancer was assessed on EndoC-ßH1 cells. The selectivity of UniPR500 was evaluated by testing this compound on a panel of well-known molecular targets responsible for the regulation of glucose homeostasis. Plasmatic levels of UniPR500 were measured by HPLC/MS approach after oral administration. Finally, UniPR500 was tested as hypoglycemic agent in healthy mice, in a non-genetic mouse model of insulin resistance (IR) and in a non-genetic mouse model of type 1 diabetes (T1D). The compound is an orally bioavailable and selective Eph antagonist, able to increase GSIS from EndoC-ßH1 cells. When tested in vivo UniPR500 showed to improve glucose tolerance in healthy and IR mice. As expected by a GSIS enhancer acting on healthy ß-cells, UniPR500 was ineffective when tested on a non-genetic mouse model of type 1 diabetes, where pancreatic function was severely compromised. In conclusion our findings suggest that Eph targeting is a new and valuable pharmacological strategy in the search of new hypoglycemic agents.

Vacancy induced formation of nanoporous silicon, carbon and silicon carbide.

Nanoporous semiconductors are used in a range of applications from sensing and gas separation, to photovoltaics, rechargeable batteries, energetic materials and micro electro mechanical systems. In most cases porosity occurs in conjunction with the competing process of amorphisation, creating a complicated material that responds differently to strain and density changes, depending on the composition. In this paper we use simple computational workflow involving Monte Carlo simulation, numerical characterisation and statistical analysis to explore the development of amorphous and nanoporous carbon, silicon and silicon carbide. We show that amorphous regions in Si and SiC form in advance of nanopores, and are essential in stabilising the nanopores once developed. Carbon prefers a porous structure at lower strains than amorphisation and exhibits a bimodal change in the structure which correlates with the change in C-C bond angles from tetrahedral sp3-like bonds to hexagonal sp2-like bonds as the strain increases. These results highlight how both of these processes can be analysed simultaneously using reliable interatomic forcefields or density functionals, provided sufficient samples are included to support the statistics.

[Perioperative infusion therapy in children : Are infusion sets with precision flow regulators suitable for pediatric anesthesia?] / Perioperative Infusionstherapie im Kindesalter : Eignen sich Infusionssysteme mit Laufratenbeschränkung für die Kinderanästhesie?

BACKGROUND: Infusion sets with precision flow regulators are frequently used in children undergoing surgery in order to control the perioperative administration of fluids. There are no data about the safety and accuracy of these infusion sets. A study was therefore conducted to compare adjusted and actual flow rates of three different infusion sets with precision flow regulators under standardized conditions. METHODS: The study evaluated three different infusion sets with precision flow regulators each at two different static levels. The actual flow rates of 5 infusions were recorded each time for adjusted flow rates of 50 ml/h, 100 ml/h, 150 ml/h, 200 ml/h and 250 ml/h over 1 h. Statistical analysis was performed with Excel (Excel, Microsoft Corporation, Redmond, WA, USA) and SOFA (Paton-Simpson and Associates Ltd., USA). The results are presented as means (standard deviation). RESULTS: For the adjusted flow rates of 50, 100, 150, 200 and 250 ml/h, actual flow rates were 107 (5.3), 174.8 (6.5), 255.8 (10.2), 312.4 (15.7) and 362.6 (20.2) ml/h for the Frekadrop® infusion set at a static level of 128 cm and 83.8 (4.4), 147.8 (5.5), 197 (12.4), 257.2 (4.97) and 311.6 (17.9) ml/h at a static level of 100 cm, respectively. For the Exadrop® infusion set actual flow rates were 88.6 (6.9), 131.2 (14.1), 224.4 (14.1), 296.6 (27.6) and 330.4 (22.4) ml/h at a static level of 128 cm and 54 (4), 82.4 (10.2), 138.8 (15.7), 209.4 (36.8) and 249 (12) ml/h at a static level of 76 cm, respectively. For the D-Flo infusion set actual flow rates were 95.6 (2.8), 167.6 (29), 217.8 (9.9), 281.6 (10.6) and 396.8 (37.5) ml/h at a static level of 128 cm and 69.2 (4.4), 110.2 (12.6), 169.2 (6), 205.2 (14) and 243 (15.9) ml/h at a static level of 80 cm, respectively. CONCLUSION: The actual flow rates differed considerably from the adjusted flow rates in the evaluated infusion sets. The flow rates substantially depended on the static level of the infusion. First and foremost, regulation of the administered infusion volume does not seem to be reliable when using an infusion set with a precision flow regulator.

Experience and psychological impact of anal cancer screening in gay, bisexual and other men who have sex with men: a qualitative study.

OBJECTIVE: Human papillomavirus-related anal cancer rates are increasing and are particularly high in gay, bisexual and other men who have sex with men (GBM/MSM), especially HIV-positive individuals. Although screening programs for high-risk populations have been advocated, concerns about possible adverse psychological consequences exist. This study aimed to investigate GBM/MSM's experience, understanding and emotional response to screening techniques for anal cancer to determine how best to minimise psychological distress in future programs. METHODS: In-depth qualitative face-to-face interviews were conducted with 21 GBM/MSM participating in the "Study of the Prevention of Anal Cancer" in Sydney, Australia, between June 2013 and June 2014. Nonrandom, purposive sampling was used to ensure heterogeneity with respect to HIV status and screening test results. Framework analysis method was used to organise the data and identify emerging themes. RESULTS: Knowledge about anal cancer, human papillomavirus and the link between them was limited. Abnormal screening results affected participants' sense of well-being and were associated with anxiety and concern about developing anal cancer. HIV-negative men receiving abnormal results showed higher levels of distress compared to their HIV-positive counterparts. Consultations with general practitioners about abnormal results had an important role in increasing participants' understanding and in moderating their anxiety. CONCLUSION: Anal cancer screening should be accompanied by health education around anal cancer, its aetiology and the meaning of associated test results. Simple and effective communication strategies should be encouraged. Collaboration with general practitioners could assist the process of education and reporting test results.

Exploring MALDI-TOF MS approach for a rapid identification of Mycobacterium avium ssp. paratuberculosis field isolates.

AIMS: The aim of the study was to explore the suitability of matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) for a rapid and correct identification of Mycobacterium avium ssp. paratuberculosis (MAP) field isolates. METHODS AND RESULTS: MALDI-TOF MS approach is becoming one of the most popular tests for the identification of intact bacterial cells which has been shown to be fast and reliable. For this purpose, 36 MAP field isolates were analysed through MALDI-TOF MS and the spectra compared with two different databases: one provided by the vendor of the system employed (Biotyper ver. 3·0; Bruker Daltonics) and a homemade database containing spectra from both tuberculous and nontuberculous Mycobacteria. Moreover, principal component analysis procedure was employed to confirm the ability of MALDI-TOF MS to discriminate between very closely related subspecies. Our results suggest MAP can be differentiated from other Mycobacterium species, both when the species are very close (M. intracellulare) and when belonging to different subspecies (M. avium ssp. avium and M. avium ssp. silvaticum). CONCLUSIONS: The procedure applied is fast, easy to perform, and achieves an earlier accurate species identification of MAP and nontuberculous Mycobacteria in comparison to other procedures. SIGNIFICANCE AND IMPACT OF THE STUDY: The gold standard test for the diagnosis of paratuberculosis is still isolation of MAP by cultural methods, but additional assays, such as qPCR and subculturing for determination of mycobactin dependency are required to confirm its identification. We have provided here evidence pertaining to the usefulness of MALDI-TOF MS approach for a rapid identification of this mycobacterium among other members of M. avium complex.

Standardisation of minimal residual disease in multiple myeloma.

The assessment of the effectiveness of chemotherapy in oncology cannot disregard the concept of minimal residual disease (MRD). In fact, the efforts of numerous scientific groups all over the world are currently focusing on this issue, with the sole purpose of defining sensitive, effective assessment criteria that are, above all, able to give acceptable, easily repeatable results worldwide. Regarding this issue, especially with the advent of new drugs, multiple myeloma is one of the haematologic malignancies for which a consensus has not yet been reached. In this review, we analyse various techniques that have been used to improve the sensitivity of response, aimed at reducing the cut-off values previously allowed, as well as serological values like serum-free light chain, or immunophenotypic tools on bone marrow or peripheral blood, like multi-parameter flow cytometry, or molecular ones such as allele-specific oligonucleotide (ASO)-qPCR and next-generation/high-throughput sequencing technologies (NGS). Moreover, our discussion makes a brief reference to promising techniques, such as mass spectrometry for identifying Ig light chain (LC) in peripheral blood, and the assessment of gene expression profile not only in defining prognostic risk at the diagnosis but also as a tool for evaluation of response.

Mutation spectrum of the MTM1 gene in XLMTM patients: 10 years of experience in prenatal and postnatal diagnosis.

X-linked myotubular myopathy (XLMTM) is a congenital neuromuscular disorder defined by severe hypotonia, respiratory failure and histopathologic changes in muscle biopsy. The objective of this report is to inform about our experience of genetic analysis on a group of 25 unrelated XLMTM patients, clinically diagnosed by several Italian and European Medical Institutes from 2006 to 2015. The molecular strategy used for genotyping involved Sanger sequencing of coding and intron/exon regions and the Multiplex Ligation Probe Amplification method. A total of 13 different point variants (6 nonsense, 5 missense, 1 splicing and 1 small deletion) were found in 15 patients (60%). Three were new missense variants: c.185G>T p.(Arg62Ile), c.719T>A p.(Val240Glu), and c.1262G>T p.(Arg421Leu). No large duplications/deletions have been identified. We performed carrier testing of at-risk female relatives. Only one mutation was de novo. Successively, we offered XLMTM prenatal testing for seven pregnancies in five unrelated families. In this context, the aim to propose an effective molecular diagnostic service is to confirm clinical XLMTM diagnosis, to monitor the cause-disease mutation segregation in the family and to offer genetic counseling to have correct information regarding offspring risks and the prenatal testing.