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Background: Hypophonia is a prevailing problem in people with multiple sclerosis (PwMS). However, evidence supporting the effectiveness of voice rehabilitation is lacking., Objective: The aim of this study was to identify the most effective method to reduce hypophonia., Methods: In this randomized controlled trial, 44 PwMS were randomized to intensive and high-effort voice treatment groups, the LSVT-LOUD ® , and conventional treatment group. Subjects received 16 treatments (4 sessions/week) lasting 45 minutes. The primary outcome was voice intensity (dB) in monologue, vocalization, and sentences while voice handicap index (VHI) measured voice self-perception. Outcomes were assessed by a blinded observer at baseline, post-treatment, and 15-month follow-up (FU)., Results: Linear models revealed a significant post-intervention between-group mean difference in favor of LSVT-LOUD for monologue: +6.3 dB (95% CI: 2.5 to 10.1); vocalization: +7.4 dB (95% CI: 2.3 to 12.5); and sentences: +9.5 dB (95% CI: 4.7 to 14.3). However, 43.7% PwMS in the LSVT-LOUD and 10% in the conventional treatment group obtained a full recovery of voice intensity (>60 dB) post-treatment, Fisher's test = 13.3, p  < 0.01. However, these improvements were not maintained at FU. Between-group differences at VHI were -10.8 (95% CI: -21.2 to -0.4) and -11.3 (95% CI: -24.3 to -1.7) in favor of LSVT-LOUD at post and FU., Conclusion: LSVT-LOUD can be a valid treatment to increase voice intensity in PwMS. However, results suggest the need for FU interventions targeting maintenance.

Background: Despite a shared purpose of improving functional capacity, the principles of progressive resistance training (PRT) and balance and motor control training (BMCT) are fundamentally different., Objectives: To investigate the effects of PRT and BMCT on gait performance and fatigue impact in people with multiple sclerosis (PwMS)., Methods: A multi-center, single-blinded, cluster-randomized controlled trial with two intervention groups (PRT and BMCT) and a control group (CON). The interventions lasted 10 weeks. A total of 71 participants with impaired mobility (Timed 25-Foot Walk (T25FW) > 5 seconds or Six Spot Step Test (SSST) > 8 seconds) were enrolled. Primary outcomes were the T25FW and the SSST. Fatigue impact, self-perceived gait function, 6-minute walk, balance, and muscle strength were secondary outcomes., Results: In total, 83% completed the study. The primary comparisons showed that BMCT, but not PRT, improved T25FW, SSST, and self-perceived gait function when compared to CON. Secondary comparisons showed that BMCT improved SSST more than PRT, while T25FW did not differ. Both BMCT and PRT reduced the fatigue impact. Finally, the effect of BMCT was superior to PRT on dynamic balance, while PRT was superior to BMCT on knee extensor muscle strength., Conclusion: BMCT, but not PRT, was superior to CON in improving gait performance, while both BMCT and PRT reduced fatigue.

Background: Only few data are available on the influence of CYP2B6 and CYP3A4/A5 polymorphisms on nevirapine plasma concentrations in the Caucasian population. Our aim was to assess the impact of CYP2B6 and CYP3A4/A5 polymorphisms on nevirapine plasma concentrations consecutively collected., Methods: We retrospectively analyzed clinical data of all HIV-positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan between January 2000 and December 2015. All patients with at least one nevirapine plasma trough concentration (NVP C min ) determination were tested for CYP2B6 c.516 G>T, CYP3A4*22C>T and CYP3A5*3 A>G polymorphisms. Univariate and multivariate regression analyses were carried out considering NVP C min as the dependent variable and genetic polymorphisms and clinical characteristics as independent variables., Results: A total of 143 patients were evaluated. Most of them were males (61.5%) and Caucasian (92.3%). Overall, NVP C min varied from 1571 to 14,189  ng/mL (median  =  5063  ng/mL, interquartile range  =  3915-6854). The median NVP C min significantly differed in patients with different CYP2B6 genotypes, but did not vary in those with different CYP3A phenotypes. In the final general linear model, factors significantly associated with a higher NVP C min were each extra unit of T alleles of CYP2B6 rs3745274 (β  =  0.328, 95% confidence interval  =  0.172-0.484; p   <  0.0001), older age (β  =  0.362, 95% confidence interval  =  0.193-0.532; p   <  0.0001) and hepatitis C virus coinfection (β  =  0.161, 95% confidence interval  =  0.006-0.315; p   <  0.041)., Conclusion: Our study, conducted in a prevalent Caucasian population, highlighted the importance of CYP2B6 genetic variants in influencing nevirapine plasma trough concentration. Furthermore, older age and hepatitis C virus coinfection significantly increase exposure to nevirapine., Competing Interests: Declaration of Conflicting Interest: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.R. has received research grants, consultancy payments and speaker’s fees from Bristol-Myers Squibb, Gilead, ViiV Healthcare, Merck Sharp & Dohme, ABBvie and Janssen. M.G. has received research grants, consultancy payments and speaker’s fees from Bristol-Myers Squibb, Gilead, ViiV Healthcare, Merck Sharp & Dohme, ABBvie, Janssen and Roche.

Myelofibrosis (MF) is a BCR-ABL1 -negative myeloproliferative neoplasm that is mainly characterised by reactive bone marrow fibrosis, extramedullary haematopoiesis, anaemia, hepatosplenomegaly, constitutional symptoms, leukaemic progression, and shortened survival. As such, this malignancy is still orphan of curative treatments; indeed, the only treatment that has a clearly demonstrated impact on disease progression is allogeneic haematopoietic stem cell transplantation, but only a minority of patients are eligible for such intensive therapy. However, more recently, the discovery of JAK2 mutations has also led to the development of small-molecule JAK1 / 2 inhibitors, the first of which, ruxolitinib, has been approved for the treatment of MF in the United States and Europe. In this article, we report on old and new therapeutic strategies that proved effective in early preclinical and clinical trials, and subsequently in the daily clinical practice, for patients with MF, particularly concerning the topics of anaemia, splenomegaly, iron overload, and allogeneic stem cell transplantation., Competing Interests: DECLARATION OF CONFLICTING INTERESTS: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

One of the priorities of personalized medicine regards the role of early integration of palliative care with cancer-directed treatments, called simultaneous care. This article, written by the Italian Association of Medical Oncology (AIOM) Simultaneous and Continuous Care Task Force, represents the position of Italian medical oncologists about simultaneous care, and is the result of a 2-step project: a Web-based survey among medical oncologists and a consensus conference. We present the opinion of more than 600 oncologists who helped formulate these recommendations. This document covers 4 main aspects of simultaneous care: 1) ethical, cultural, and relational aspects of cancer and implications for patient communication; 2) training of medical oncologists in palliative medicine; 3) research on the integration between cancer treatments and palliative care; and 4) organizational and management models for the realization of simultaneous care. The resulting recommendations highlight the role of skills and competence in palliative care along with implementation of adequate organizational models to accomplish simultaneous care, which is considered a high priority of AIOM in order to grant the best quality of life for cancer patients and their families.

Here we describe a case of an HIV-infected young woman with extensive drug-resistant virus, who was successfully switched from a raltegravir-based regimen to a dolutegravir-based intensified antiretroviral regimen a few days before scheduled caesarean section because of the still detectable viral load. The trough concentrations of all antiretroviral drugs before and after delivery are also described. Our case underlines both the difficult management of young women, HIV-infected at young age with very limited treatment options and the great variability in the pregnancy-related physiological changes affecting the pharmacokinetics of antiretrovirals.

Ocular toxicity may not only be caused by medication overdoses and drug-drug interactions, but also by chronic administration of medications at recommended doses. We describe a case of an HIV-infected patient who experienced significant and sustained bilateral visual loss 2 months after starting treatment with elvitegravir/cobicistat/tenofovir/emtricitabine. Given the absence of any evidence of tenofovir- or emtricitabine-induced optical neuropathy after several years of clinical use, the antiretroviral therapy was promptly changed to tenofovir/emtricitabine plus atazanavir/ritonavir, which led to a progressive improvement in visual acuity. However, visual evoked potentials never returned to normal amplitudes. This is the first report of toxic optical neuropathy associated with the use of elvitegravir/cobicistat. It is imperative to recognize any signs of possible eye toxicity as rapidly as possible, and refer affected patients to an ophthalmologist promptly because early detection and the withdrawal of the offending agent are crucial in reversing this adverse ocular event.

Background: Studies in healthy volunteers have shown that the recently approved HIV integrase inhibitor dolutegravir has limited drug-to-drug interaction profile. Here we carried out a pharmacokinetic survey in HIV-infected patients given dolutegravir as part of their antiretroviral therapy., Methods: Dolutegravir plasma trough concentrations were measured in 78 HIV-infected patients given the drug in combination with a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor or abacavir/lamivudine. Drug concentrations were assessed by high performance liquid chromatography method with UV-detection., Results: All patients were given dolutegravir at 50 mg once daily, with median trough drug concentrations of 1,096 (664-2,356) ng/ml (interindividual coefficient of variation: 85.3%). Patients given dolutegravir with atazanavir had significantly higher drug concentrations compared with those given darunavir, rilpivirine or abacavir/lamivudine (2,399 [1,929-4,070] versus 738 [552-1,048], 603 [432-1,373] or 1,045 [856-1,115] ng/ml; P<0.001 for all comparisons). By multivariate analyses, only companion antiretroviral drug resulted in significant association with dolutegravir plasma trough concentrations (P=0.012)., Conclusions: Atazanavir coadministration significantly inhibited dolutegravir metabolism, ultimately resulting in a two- to fourfold increase in drug disposition compared with other antiretroviral drugs. This boosting effect of atazanavir could be used to optimize dolutegravir dosing in particular clinical settings.

Background: There has been limited research on upper limb dysfunction in people with multiple sclerosis (PwMS)., Objective: The objective of this paper is to study unilateral and bilateral upper limb dysfunction at different International Classification of Functioning (ICF) levels according to overall disability in PwMS., Methods: A total of 105 PwMS (16 with EDSS<4 (mild); 17 with EDSS 4-5.5 (moderate); 37 with EDSS 6-6.5 (severe); 35 with EDSS>6.5 (severe non-ambulant)) were recruited from two rehabilitation centers and assessed in a cross-sectional study., Results: The whole sample showed a diminished sensory function (median (first/third interquartile)) score of 3 (2/3) on the Monofilament Test and a reduced strength 91 (76/100) points on the Motricity Index (Body-Function level). Sensory dysfunction did not increase with higher EDSS while strength decreased from 100 (86/100) in the mild subgroups to 91 (80/100) points in the severe subgroup. All showed diminished dexterity, scoring 0.28 peg/s (0.17/0.35) on the Nine-Hole Peg Test (NHPT) (activity level). Score was better for the mild (0.38 (0.35/0.46)) peg/s compared to the severe subgroup (0.28 (0.17/0.35)). Sixty-eight percent, 44% and 75% of PwMS showed bilateral disorders in sensation, strength and dexterity, respectively. The Community Integration Questionnaire (participation level) showed a 35% reduction in home activities, even among PwMS with EDSS<4., Conclusion: This study showed uni-/bilateral upper limb abnormalities at all ICF levels increasing with the overall disability., (© The Author(s), 2015.)

Background: Emerging evidence shows that standard atazanavir (ATV) dosages are associated with considerable interindividual variability in plasma drug concentrations. Given the potential impact of ATV exposure on clinical outcome, in this retrospective study we sought to assess demographic and clinical factors influencing ATV plasma concentrations in a large cohort of HIV-infected patients., Methods: HIV-infected patients treated with ATV for at least 3 months and with at least one assessment of ATV trough concentrations were enrolled. Blood trough samples were collected from all patients immediately before the next drug intake. Plasma ATV and ritonavir concentrations were quantified by a validated chromatographic method coupled with tandem mass spectrometric detection. Univariate and multivariate regression analyses were performed using ATV plasma concentrations as the dependent variable, with demographic and clinical characteristics as the independent ones., Results: A total of 273 HIV-infected adult patients were included in the present study. Factors significantly associated with increased ATV concentrations by univariate analysis were ATV dosage, number of concomitant drugs, ritonavir or statin use. However, with multivariate regression analysis, the only factors independently and significantly associated with ATV concentrations were ritonavir use (r=0.291, P<0.0001) and concomitant rosuvastatin therapy (r=0.315, P<0.0001)., Conclusions: We found that patients on ATV/ritonavir given rosuvastatin concomitantly have ATV concentrations that exceed the upper therapeutic threshold of 800 ng/ml known to be associated with a high risk of experiencing ATV-related side effects. In agreement with previous findings we confirmed the lack of association between other demographic and clinical characteristics such as age, gender, body weight and ATV exposure.

Objective: To determine whether there are demographic, clinical, and instrumental variables useful to detect fall status of patients with multiple sclerosis., Data Sources: PubMed and the Cochrane Library., Review Methods: Eligible studies were identified by two independent investigators. Only studies having a clear distinction between fallers and non-fallers were included and meta-analysed. Odds ratios (ORs) and standard mean differences (SMDs) were calculated and pooled using fixed effect models., Results: Among 115 screened articles, 15 fulfilled criteria for meta-analyses, with a total of 2425 patients included. Proportion of fallers may vary from 30% to 63% in a time frame from 1 to 12 months. No significant publication bias was found, even though 12/15 studies relied on retrospective reports of falls, thus introducing recall biases. Risk factors for falls varied across studies, owing to heterogeneity of populations included and clinical instruments used. The meta-analytic approach found that, compared with non-fallers, fallers had longer disease duration (SMD = 0.14, p = 0.02), progressive course of disease (OR = 2.02, p < 0.0001), assistive device for walking (OR = 3.16, p < 0.0001), greater overall disability level (SMD = 0.74, p < 0.0001), slower walking speed (SMD = 0.45, p = 0.0005), and worse performances in balance tests (Berg Balance Scale: SMD = -0.48, p = 0.002; Timed up-and-go test, SMD = 0.31, p = 0.04), and force-platform measures (postural sway) with eyes opened (SMD = 0.71, p = 0.006) and closed (SMD = 0.83, p = 0.01), respectively., Conclusion: Elucidations regarding risk factors for accidental falls in patients with multiple sclerosis (PwMs) are provided here, with worse disability score, progressive course, use of walking aid, and poorer performances in static and dynamic balance tests strongly associated with fall status., (© The Author(s) 2014.)

Background: Electromyographic biofeedback (EMG-BFB) has shown equivocal benefits on gait retraining after stroke., Objective: The authors evaluated the efficacy of EMG-BFB applied in a task-oriented approach based on principles of motor learning to increase peak ankle power of the affected leg and gait velocity in patients with chronic mild to moderate hemiparesis., Methods: They assigned 20 participants randomly to the EMG-BFB group or a control group that received conventional therapy for the same duration. Quantitative gait analysis was performed before and after treatment. The EMG-BFB involved the triceps surae during functional gait activities. Treatment was administered with a fading frequency of BFB application and an increasing variability in gait activities. Both groups had 20 treatment sessions of 45 minutes each, including at least 15 minutes of walking-related therapy for the control group. Follow-up (FU) gait analysis was obtained 6 weeks after training., Results: BFB treatment led to significant increases (P < .01) in peak ankle power at push-off (from 0.63 W/kg to 1.04 W/kg) in conjunction with significant increases in velocity (from 28.3 %h/s--normalized to percentage height per second--to 39.6 %h/s) and stride length (from 44.5 %h--normalized to percentage height--to 57.6 %h). Increases remained significant at FU. There were no changes in any gait variable in the control group., Conclusion: A task-oriented BFB treatment was effective in increasing peak ankle power, gait velocity, and stride length in a population with hemiparesis. Further studies should compare the combination intervention with either of its components in more impaired patients.

Experimental evidence indicates that aldosterone, besides its mineralcorticoid properties, directly contributes to accelerate renal damage through promotion of cell growth, fibrosis and inflammation. As a consequence, attenuation of growth-promoting and fibroproliferative effects of aldosterone might contribute to slow progression of chronic renal injury. Preliminary clinical observations have documented that aldosterone blockers added to angiotensin-converting enzyme inhibitor- and/or angiotensin receptor blocker-based regimens exerted significant antiproteinuric effects in patients with diabetic and nondiabetic nephropathies. Further studies in larger cohorts are now required to definitively address the safety and efficacy of aldosterone antagonism in patients with chronic kidney diseases.

Balance disorders and falls are frequently observed in subjects with multiple sclerosis (MS). Along with motor impairment, sensory disorders and integration deficits of sensory inputs lead to inadequate motor responses. The assessment of these sensory disorders in an every day tasks, such as upright stance, increases our knowledge of postural control in this pathology, thus promoting more effective treatments. The aim of the study was to describe sensory impairments and sensory strategies in different sensory conditions. A stabilometric assessment was carried out in a consecutive convenience sample of 53 subjects. The age of the sample was 52.7 (21.1) years; the onset of pathology was 27.20 (14.5) years before the assessment. Balance was assessed in six sensory conditions. The impact of pathology on balance control was shown by the high percentage of abnormal scores: 75% of subjects with MS showed abnormal scores even in the eyes open condition. The alteration of a single sensory input led to an increase of abnormal scores in up to 82% of subjects. Almost all subjects showed abnormal scores in the vestibular conditions where 22% of them fell. The pattern of the subjects' performance in the six sensory conditions suggests that balance control may be more correlated to the number of reliable sensory inputs than the nature of the sensory input itself.

Objective: The impact of electromyographic biofeedback (EMG BFB) applied during functional gait activities and employed in accord with theories on motor learning was investigated in a chronic hemiplegic patient., Methods: A single-subject A-B design was used. EMG BFB was applied to the triceps surae during gait. A rehabilitation program with a fading frequency of BFB application and an increasing variability in the task training was implemented. Responses to the rehabilitation program were documented via multiple quantitative gait analyses, performed during a baseline, treatment, and at follow-up 6 weeks after the end of treatment., Results: From baseline to end of treatment, there were significant changes in ankle power at push-off, both in amplitude and timing, as well as onset of ankle power at push-off relative to heel strike of the healthy leg. There was a significant increase in gait velocity, step length of the healthy side, stride length, and stride frequency. At follow-up, changes were still significantly different from baseline and the patient had reduced the use of the cane in activities of daily living., Conclusions: BFB appears to have been effective in promoting positive changes in gait in this pilot study. The rehabilitation protocol also appeared to be effective in promoting learning and the incorporation of trained activities into daily activities.

Purpose: The purpose of this study was to investigate the short-term effect of a therapeutical approach called "Grimaldi's method." The authors hypothesized that Grimaldi's method would improve active muscle recruitment. The treatment was focused on hip abductors. The authors collected data of hip's active range of motion against gravity (AROM), maximum isometric endurance (END), and maximum mechanical work (WORK)., Participants and Methods: Forty patients suffering from multiple sclerosis were randomized into 2 groups, 20 were allocated to the Grimaldi's group and 20 to the control group., Results: After 3 sessions of Grimaldi's treatment parameter, AROM increased from 21.4 degrees to 37.2 degrees in the experimental group; the improvement was statistically significant. Parameter END did not show any improvement, whereas mechanical work had a sharp increase: from 103.9 Nm to 149.6 Nm., Conclusion: The findings suggest that Grimaldi's method could be useful in increasing muscular recruitment of hip abductors, improving active range of motion and mechanical work of the hip in patients suffering from multiple sclerosis.

Aims and Background: MRCC responds poorly to usual treatments. Recently floxuridine (FUDR) has been administered by chronomodulated infusion, obtaining interesting results. In order to simplify the infusion, we used continuous non chronomodulated infusion., Methods: We treated 17 patients affected by MRCC with continuous non chronomodulated infusion of FUDR. Toxicity was evaluated according to WHO criteria. Responses were recorded as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD)., Results: Sixty-four courses of therapy were administered; 15/17 patients, treated with a median of 4 cycles, were evaluable for the response. Only 1 patient showed a grade 3 toxicity (mucositis and diarrhoea); 6 patients showed grade 1-2 diarrhoea; 2 grade 1-2 nausea and vomiting; 1 grade 2 anaemia and thrombocytopenia. No patient obtained CR; 2 PR (lasting 7 and 9 months respectively) and 4 SD (lasting 4,5,6 and 9 months) were observed., Conclusions: In our experience continuous non chronomodulated infusion of FUDR did not show important general toxicity. The observed responses were not good enough. We think that a better selection of patients (good performance status) and the use of FUDR in an earlier stage of disease, can obtain better results.

Background: Metastatic renal cell carcinoma is a "capricious" tumor. Many prognostic factors have been evaluated, treatment is still controversial, and results are not coincident., Methods: We reviewed 156 patients with metastatic renal cell carcinoma. Survival from the time of diagnosis was the end point of the study. The influence on survival of age, sex, nephrectomy, disease-free interval, performance status, site and number of metastases was analyzed. Univariate and multivariate analysis were done. Survival according to different therapies was also evaluated., Results: In our study, no nephrectomy, a disease-free interval < 24 months, > 2 metastatic sites and a performance status > 2 proved to be risk factors. According to the number of risk factors, 3 groups of patients were identified (low, intermediate and high risk). We observed 3 kinds of responses to treatments: 1) in untreated patients (n = 48), median overall survival was 6 months, and the 24-month survival rate was 8%; 2) in patients treated with hormone therapy and/or chemotherapy (n = 73), median overall survival was 13 months, and the 24-month survival rate was 24%; 3) in patients treated with interferon and/or interleukin-2 (n = 35), median overall survival was 16 months and the 24-month survival rate was 34%., Conclusions: Our results are only partially in accordance with those observed by other authors. Risk factors and treatment must be determined in more defined and selected studies.

We report nasopharyngeal angiofibroma in a 13 year old boy treated with embolization, surgical excision and radiotherapy, which recurred 13 years later. No features of sarcomatous transformation were found, but the tumor had a locally aggressive course, possibly due to the HIV-positivity of the patient who then died of AIDS. The relations between the clinical course of the tumor and severe immunodeficiency are discussed.