Predictive Values of Transcutaneous Oxygen Tension for Above-the-ankle Amputation in Diabetic Patients with Critical Limb Ischemia

ObjectiveTo assess the values of transcutaneous oxygen tension (TcPO2) capable of predicting above-the-ankle amputation in diabetic patients diagnosed for critical limb ischemia (CLI) according to the criteria of the TransAtlantic Inter-Society Consensus.DesignRetrospective study.MethodsFrom January 1999 to December 2003, 564 diabetic patients were consecutively hospitalized for CLI in one limb. Revascularization with angioplasty or bypass graft was performed when possible and, if not possible, prostanoid therapy was used. In patients in whom therapies did not relieve the rest pain or the gangrene was extended above the Chopart joint, an above-the-ankle-amputation was performed. After treatment TcPO2 values were evaluated in all patients at the dorsum of the foot.ResultsFifty-five (9.8%) patients underwent an above-the-ankle amputation: 22 of 420 patients who underwent angioplasty, 17 of 117 patients who underwent bypass (14.5%) and 16 of 27 patients in whom revascularization was not possible. Post-treatment TcPO2, measured by a receiver operating characteristic (ROC) curve, showed a value 34mmHg as the best threshold for determining the need for revascularization, with an area under the curve of 0.89 (95%CI 0.85–0.94).Using logistic regression analysis the probability of above-the-ankle amputation for this threshold is 9.7% and reduces to 3% for TcPO2>40mmHg.ConclusionTcPO2 levels<34mmHg indicate the need for revascularization, while for values ≥ 34<40mmHg this need appears less pressing, although there remains a considerable probability of amputation. TcPO2 levels greater than 40mmHg suggest that revascularization is dependent on the severity of tissue loss and possible morbidity caused by the procedure

Regional citrate anticoagulation in CVVH: a new protocol combining citrate solution with a phosphate-containing replacement fluid

Regional citrate anticoagulation (RCA) is a valid anticoagulation method in continuous renal replacement therapies (CRRT) and different combination of citrate and CRRT solutions can affect acid-base balance. Regardless of the anticoagulation protocol, hypophosphatemia occurs frequently in CRRT. In this case report, we evaluated safety and effects on acid-base balance of a new RCA- continuous veno-venous hemofiltration (CVVH) protocol using an 18 mmol/L citrate solution combined with a phosphate-containing replacement fluid. In our center, RCA-CVVH is routinely performed with a 12 mmol/L citrate solution and a postdilution replacement fluid with bicarbonate (protocol A). In case of persistent acidosis, not related to citrate accumulation, bicarbonate infusion is scheduled. In order to optimize buffers balance, a new protocol has been designed using recently introduced solutions: 18 mmol/L citrate solution, phosphate-containing postdilution replacement fluid with bicarbonate (protocol B). In a cardiac surgery patient with acute kidney injury, acid-base status and electrolytes have been evaluated comparing protocol A (five circuits, 301 hours) vs. protocol B (two circuits, 97 hours): pH 7.39 ± 0.03 vs. 7.44 ± 0.03 (P < 0.0001), bicarbonate 22.3 ± 1.8 vs. 22.6 ± 1.4 mmol/L (NS), Base excess −2.8 ± 2.1 vs. −1.6 ± 1.2 (P = 0.007), phosphate 0.85 ± 0.2 vs. 1.3 ± 0.5 mmol/L (P = 0.027). Protocol A required bicarbonate and sodium phosphate infusion (8.9 ± 2.8 mmol/h and 5 g/day, respectively) while protocol B allowed to stop both supplementations. In comparison to protocol A, protocol B allowed to adequately control acid-base status without additional bicarbonate infusion and in absence of alkalosis, despite the use of a standard bicarbonate concentration replacement solution. Furthermore, the combination of a phosphate-containing replacement fluid appeared effective to prevent hypophosphatemia

Coarse Grained Density Functional Theories for Metallic Alloys: Generalized Coherent Potential Approximations and Charge Excess Functional Theory

The class of the Generalized Coherent Potential Approximations (GCPA) to the Density Functional Theory (DFT) is introduced within the Multiple Scattering Theory formalism for dealing with, ordered or disordered, metallic alloys. All GCPA theories are based on a common ansatz for the kinetic part of the Hohenberg-Kohn functional and each theory of the class is specified by an external model concerning the potential reconstruction. The GCPA density functional consists of marginally coupled local contributions, does not depend on the details of the charge density and can be exactly rewritten as a function of the appropriate charge multipole moments associated with each lattice site. A general procedure based on the integration of the 'qV' laws is described that allows for the explicit construction the same function. The coarse grained nature of the GCPA density functional implies great computational advantages and is connected with the O(N) scalability of GCPA algorithms. Moreover, it is shown that a convenient truncated series expansion of the GCPA functional leads to the Charge Excess Functional (CEF) theory [E. Bruno, L. Zingales and Y. Wang, Phys. Rev. Lett. {\bf 91}, 166401 (2003)] which here is offered in a generalized version that includes multipolar interactions. CEF and the GCPA numerical results are compared with status of art LAPW full-potential density functional calculations for 62, bcc- and fcc-based, ordered CuZn alloys, in all the range of concentrations. These extensive tests show that the discrepancies between GCPA and CEF are always within the numerical accuracy of the calculations, both for the site charges and the total energies. Furthermore, GCPA and CEF very carefully reproduce the LAPW site charges and the total energy trends.Comment: 19 pages, 11 figure

Personalized Treatment Planning Automation in Prostate Cancer Radiation Oncology: A Comprehensive Dosimetric Study

Background: In radiation oncology, automation of treatment planning has reported the potential to improve plan quality and increase planning efficiency. We performed a comprehensive dosimetric evaluation of the new Personalized algorithm implemented in Pinnacle3 for full planning automation of VMAT prostate cancer treatments. Material and Methods: Thirteen low-risk prostate (without lymph-nodes irradiation) and 13 high-risk prostate (with lymph-nodes irradiation) treatments were retrospectively taken from our clinical database and re-optimized using two different automated engines implemented in the Pinnacle treatment system. These two automated engines, the currently used Autoplanning and the new Personalized are both template-based algorithms that use a wish-list to formulate the planning goals and an iterative approach able to mimic the planning procedure usually adopted by experienced planners. In addition, the new Personalized module integrates a new engine, the Feasibility module, able to generate an “a priori” DVH prediction of the achievability of planning goals. Comparison between clinically accepted manually generated (MP) and automated plans generated with both Autoplanning (AP) and Personalized engines (Pers) were performed using dose-volume histogram metrics and conformity indexes. Three different normal tissue complication probabilities (NTCPs) models were used for rectal toxicity evaluation. The planning efficiency and the accuracy of dose delivery were assessed for all plans. Results: For similar targets coverage, Pers plans reported a significant increase of dose conformity and less irradiation of healthy tissue, with significant dose reduction for rectum, bladder, and femurs. On average, Pers plans decreased rectal mean dose by 11.3 and 8.3 Gy for low-risk and high-risk cohorts, respectively. Similarly, the Pers plans decreased the bladder mean doses by 7.3 and 7.6 Gy for low-risk and high-risk cohorts, respectively. The integral dose was reduced by 11–16% with respect to MP plans. Overall planning times were dramatically reduced to about 7 and 15&nbsp;min for Pers plans. Despite the increased complexity, all plans passed the 3%/2 mm γ-analysis for dose verification. Conclusions: The Personalized engine provided an overall increase of plan quality, in terms of dose conformity and sparing of normal tissues for prostate cancer patients. The Feasibility “a priori” DVH prediction module provided OARs dose sparing well beyond the clinical objectives. The new Pinnacle Personalized algorithms outperformed the currently used Autoplanning ones as solution for treatment planning automation

Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung: Final analysis of the randomised phase 3 LUX-Lung 8 trial

Background: LUX-Lung 8 was a randomised, controlled, phase 3 study comparing afatinib and erlotinib as second-line treatment of patients with advanced squamous cell carcinoma (SCC) of the lung. We report the final overall survival (OS) and safety analyses of LUX-Lung 8 and investigate the characteristics of patients who achieved long-term benefit (≥12 months’ treatment). Methods: LUX-Lung 8 (NCT01523587) enroled patients between March 2012 and January 2014 in 183 cancer centres located in 23 countries worldwide and this final analysis had a data cut-off of March 2018. Eligible patients had stage IIIB or IV lung SCC and had progressed after at least four cycles of platinum-based chemotherapy. Patients were randomly assigned (1:1) to receive afatinib (40 mg per day) or erlotinib (150 mg per day) until disease progression. Endpoints included OS and safety; a post-hoc analysis of patients with long-term benefit (≥12 months on treatment) was also conducted. Findings: 795 eligible patients were randomly assigned (398 to afatinib, 397 to erlotinib). OS was significantly prolonged with afatinib compared with erlotinib (median 7·8 months vs 6·8 months; hazard ratio 0·84; 95% CI 0·73–0·97; p = 0·0193). These findings were consistent with those of the primary analysis and were consistent across subgroups. Adverse events (AEs) were manageable with dose interruption and reduction, with similar AEs being experienced between both groups. Twenty-one (5·3%) patients receiving afatinib and 13 (3·3%) patients receiving erlotinib achieved long-term benefit; median OS was 34·6 months and 20·1 months, respectively. Amongst 132 afatinib-treated patients who underwent tumour genetic analysis, ERBB family mutations were more common in patients with long-term benefit than in the overall population (50% vs 21%). Interpretation: Afatinib is a treatment option for patients with SCC of the lung progressing on chemotherapy who are ineligible for immunotherapy, particularly those with ERBB family genetic aberrations. Afatinib has a predictable and manageable tolerability profile, and long-term treatment may be well tolerated

INSUFFICIENZA RENALE ACUTA NEL PAZIENTE OSPEDALIZZATO: STUDIO OSSERVAZIONALE

Abstract Congresso Nazionale Società Italiana di Nefrologia. L’insufficienza renale acuta (IRA) ha una prevalenza sempre più elevata (Hsu C et al., Kidney Int 2007, 72:208-12) e si associa a incremento della mortalità e dei tempi di degenza. Scopo. Studio prospettico osservazionale finalizzato alla valutazione della tipologia di IRA e dei principali “outcome” in pazienti ricoverati presso il nostro ospedale e giunti all’osservazione del nefrologo. Pazienti e metodi. Sono stati presi in considerazione pazienti che avevano sviluppato IRA definita secondo i criteri RIFLE. A tale scopo è stata utilizzata la scheda raccolta dati proposta per un registro IRA dal gruppo di studio “area critica” della Sezione ALaMMU della SIN. La scheda includeva le seguenti informazioni: esordio, eziopatogenesi, tipolo- gia, durata e decorso dell’IRA, fattori di comorbilità, presenza di MODS (Multiple Organ Dysfunction Syndrome), necessità e tipo di terapia sostitutiva, “outcome” (sopravvivenza, recupero funzione renale). Risultati. Negli ultimi 4 anni (2005-2009) sono stati osservati 274 pazienti (188 M, 86 F) con IRA. Età: 66.9±14.6 aa. IRA insorta durante il ricovero: 53.6% (n=147). IRA oligurica: 71.5% (n=196). IRA sovrapposta a IRC (classi K/DOQI 3-5): 63.5% (n=174). Fattori di co- morbilità: ipertensione arteriosa 71.9%, diabete mellito 41.2%, arteriopatia polidistrettua- le 27.7%, neoplasia 13.5%. Tipo di IRA: pre-renale 33.2% (n=91), renale 56.2% (n=154), post-renale 10.6% (n=29). IRA associata a MODS: 31% (n=85). Classe RIFLE: “R” 8.4% (n=23), “I” 6.2% (n=17), “F” 85.4% (n=234). Necessità di terapia sostitutiva (IHD o CRRT): 54% (n=148). Accesso vascolare: femorale (85.8%), giugulare interna (12.8%), succlavia (1.4%). Pazienti usciti dal follow-up: 4% (n=11). La mortalità è stata del 31.9% (n=84) ed è risultata significativamente più elevata nell’IRA oligurica (37.8% vs 12.8%, p 21 gg 12.3%. L’analisi multivariata ha evidenziato il significato prognostico sfavorevole dell’oliguria (OR 2.58, CI 1.15-5.8, p=0.021), della necessità di RRT (OR 4.2, CI 1.74-10, p<0.001) e della presenza di MODS (OR 4, CI 1.8-8.8, p<0.0001). Conclusioni. La prevalenza di IRA di grado grave e la numerosità relativa della popo- lazione di pazienti con IRA associata a MODS rappresentano una particolarità e allo stesso tempo, un limite dello studio. In relazione alla prevalenza di IRA insorta durante il ricovero, spesso sovrapposta a IRC, e alla percentuale non trascurabile di IRA prerenale, emerge la necessità di attuare misure preventive finalizzate a ridurre l’incidenza di cause iatrogene. In una percentuale elevata di pazienti si è assistito a recupero completo o parziale della funzione renale che si è verificato nella maggior parte dei casi entro 7 gg. Si conferma, infine, il significato prognostico sfavorevole dell’oliguria, della necessità di terapia sostitutiva e della presenza di MODS già riportato in letteratura

safety of nintedanib plus docetaxel in advanced non squamous nsclc nsnsclc patients the preliminary results of the seneca second line nintedanib in non small cell lung cancer trial

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Impact of RNA Editing on Functions of the Serotonin 2C Receptor in vivo

Transcripts encoding 5-HT2C receptors are modified posttranscriptionally by RNA editing, generating up to 24 protein isoforms. In recombinant cells, the fully edited isoform, 5-HT2C-VGV, exhibits blunted G-protein coupling and reduced constitutive activity. The present studies examine the signal transduction properties of 5-HT2C-VGV receptors in brain to determine the in vivo consequences of altered editing. Using mice solely expressing the 5-HT2C-VGV receptor (VGV/Y), we demonstrate reduced G-protein coupling efficiency and high-affinity agonist binding of brain 5-HT2C-VGV receptors. However, enhanced behavioral sensitivity to a 5-HT2C receptor agonist was also seen in mice expressing 5-HT2C-VGV receptors, an unexpected finding given the blunted G-protein coupling. In addition, mice expressing 5-HT2C-VGV receptors had greater sensitivity to a 5-HT2C inverse agonist/antagonist enhancement of dopamine turnover relative to wild-type mice. These behavioral and biochemical results are most likely explained by increases in 5-HT2C receptor binding sites in the brains of mice solely expressing 5-HT2C-VGV receptors. We conclude that 5-HT2C-VGV receptor signaling in brain is blunted, but this deficiency is masked by a marked increase in 5-HT2C receptor binding site density in mice solely expressing the VGV isoform. These findings suggest that RNA editing may regulate the density of 5-HT2C receptor binding sites in brain. We further caution that the pattern of 5-HT2C receptor RNA isoforms may not reflect the pattern of protein isoforms, and hence the inferred overall function of the receptor

Metabolic effects of dehydroepiandrosterone replacement therapy in postmenopausal women

OBJECTIVE: To investigate whether long-term treatment with dehydroepiandrosterone (DHEA) in postmenopausal women can modify insulin sensitivity and plasma lipid profile. DESIGN AND METHODS: Twenty healthy postmenopausal women with serum dehydroepiandrosterone sulfate (DHEA-S) concentrations <2.5 micromol/l were enrolled and randomly assigned to two different treatment groups: group 1 were treated with micronized DHEA, 25 mg/day at 0800 h for 12 months; group 2 were treated with an identical placebo tablet. At the beginning and at the end of the study, plasma lipid profile, glucose tolerance (oral glucose tolerance test) and insulin sensitivity (euglycemic hyperinsulinemic clamp: M index) were assessed. RESULTS: After 12 months, the group treated with DHEA showed a considerable improvement of insulin sensitivity (M index +29.55%, P=0.01) and lipid pattern (high-density lipoprotein cholesterol +11.61%, P=0.03; low-density lipoprotein cholesterol -11.07%, P=0.04; triglycerides -19.60%, P=0.03), but glucose tolerance did not change. No modifications were observed in the placebo group. CONCLUSIONS: Long-term treatment with DHEA ameliorates some metabolic parameters that are linked to increased cardiovascular risk and, consequently, this seems to be an interesting therapeutic tool in the management of the postmenopausal syndrome