Ruxolitinib Adherence in Myelofibrosis and Polycythemia Vera: the "RAMP" Italian multicenter prospective study.

Ruxolitinib is beneficial in patients with myelofibrosis (MF) and polycythemia vera (PV). Information on ruxolitinib adherence is scant. The Ruxolitinib Adherence in Myelofibrosis and Polycythemia Vera (RAMP) prospective multicenter study (NCT06078319) included 189 ruxolitinib-treated patients. Patients completed the Adherence to Refills and Medications Scale (ARMS) and Distress Thermometer and Problem List (DTPL) at the earliest convenience, after registration in the study, and at later timepoints. At week-0, low adherence (ARMS > 14) and high distress (DT ≥ 4) were declared by 49.7% and 40.2% of patients, respectively. The main reason for low adherence was difficult ruxolitinib supply (49%), intentional (4.3%) and unintentional (46.7%) non-take. In multivariable regression analysis, low adherence was associated to male sex (p = 0.001), high distress (p < 0.001), and treatment duration ≥ 1 year (p = 0.03). Over time, rates of low adherence and high distress remained stable, but unintentional non-take decreased from 47.9% to 26.0% at week-48. MF patients with stable high adherence/low distress were more likely to obtain/maintain the spleen response at week-24. Low adherence to ruxolitinib represents an unmet clinical need that require a multifaceted approach, based on reason behind it (patients characteristics and treatment duration). Its recognition may help distinguishing patients who are truly refractory and those in need of therapy optimization.

Treatment discontinuation following low-dose TKIs in 248 chronic myeloid leukemia patients: Updated results from a campus CML real-life study.

TKIs long-term treatment in CML may lead to persistent adverse events (AEs) that can promote relevant morbidity and mortality. Consequently, TKIs dose reduction is often used to prevent AEs. However, data on its impact on successful treatment-free remission (TFR) are quite scarce. We conducted a retrospective study on the outcome of CML subjects who discontinued low-dose TKIs from 54 Italian hematology centers participating in the Campus CML network. Overall, 1.785 of 5.108 (35.0%) regularly followed CML patients were treated with low-dose TKIs, more frequently due to relevant comorbidities or AEs (1.288, 72.2%). TFR was attempted in 248 (13.9%) subjects, all but three while in deep molecular response (DMR). After a median follow-up of 24.9 months, 172 (69.4%) patients were still in TFR. TFR outcome was not influenced by gender, Sokal/ELTS risk scores, prior interferon, number and last type of TKI used prior to treatment cessation, DMR degree, reason for dose reduction or median TKIs duration. Conversely, TFR probability was significantly better in the absence of resistance to any prior TKI. In addition, patients with a longer DMR duration before TKI discontinuation (i.e., >6.8 years) and those with an e14a2 BCR::ABL1 transcript type showed a trend towards prolonged TFR. It should also be emphasized that only 30.6% of our cases suffered from molecular relapse, less than reported during full-dose TKI treatment. The use of low-dose TKIs does not appear to affect the likelihood of achieving a DMR and thus trying a treatment withdrawal, but might even promote the TFR rate.

Nine Hole Peg Test asymmetry in refining upper limb assessment in multiple sclerosis.

BACKGROUND: The Expanded Disability Status Scale (EDSS) is the most frequently used scale to measure neurologic impairment and quantify the level of disability in Multiple Sclerosis (MS) even though the scale focuses on ambulation and undervalues upper limb (UL) impairment. The 9-Hole Peg Test (9-HPT) is the gold standard for UL assessment in MS, calculating a mean score from right and left arms, even though subjects with MS often show a lateralization of neurological deficit. OBJECTIVE: The study aimed to determine whether an interaction exists between mean right-left 9-HPT scores or 9HPT score asymmetry (difference between right and left side) in predicting EDSS in MS subjects. METHODS: Demographic and disease variables and 9-HPT scores were obtained from medical records of individuals with MS collected in an ad-hoc database. Subjects with 9-HPT score ≤180 s for each arm were included. An asymmetry score was represented as the absolute value of the difference between 9-HPT scores for both arms. RESULTS: 549 subjects were included: 67.8% female, mean age 45±13.14 years, mean EDSS 3.98±2.12, 356 relapsing-remitting, 68 primary and 125 secondary progressive, mean 9-HPT scores: right arm 30.20 ± 19.99 s, left arm 31.80 ± 20.35 s. Mean asymmetry was 9.35±18.20 s. Correlation between mean right-left 9-HPT scores and EDSS was 0.58 (p<.001). Significant interaction between mean right-left 9-HPT scores and 9-HPT asymmetry in predicting EDSS scores was found. Regression slope of EDSS on mean right-left 9-HPT score decreases as asymmetry value increases (non-significance area values ≥ 40.93 s). CONCLUSIONS: Findings suggest interaction exists between mean right-left 9-HPT scores and asymmetry in predicting EDSS. A consequence of this is that, by disregarding information about asymmetry, studies exploring the association between mean right-left 9-HPT scores and global measures of disability may provide biased results. The bias tends to increase as asymmetry increases, and to be most prevalent among patients with EDSS scores > 6.

Box and block test, hand grip strength and nine-hole peg test: correlations between three upper limb objective measures in multiple sclerosis.

BACKGROUND AND PURPOSE: Limited data are available in the literature for upper limb impairment in multiple sclerosis (MS). This study aimed to report the distribution of values of hand grip strength (HGS), of the box and block test (BBT) and of the nine-hole peg test (9HPT) correlated with demographic and clinical data in subjects with MS. METHODS: This study involved five Italian neurological centres. The inclusion criteria were age ≥ 18, MS diagnosis, stable disease phase, right-hand dominance. All subjects underwent HGS, BBT and 9-HPT evaluation. RESULTS: In all, 202 subjects with MS were enrolled: 137 females; mean age 48.4 years; mean Expanded Disability Status Scale (EDSS) 4.17; mean disease duration 14.12 years; disease course 129 relapsing-remitting, 21 primary progressive and 52 secondary progressive MS subjects; mean right HGS 25.3 kg, left 23.2 kg; mean right BBT 45.7 blocks, left 44.9 blocks; mean right 9-HPT 30.7 s, left 33.4 s. All results were statistically significantly different compared to healthy controls. HGS, BBT and 9-HPT were associated with age, EDSS and disease duration, whilst disease course correlated with BBT and 9-HPT. The BBT and 9-HPT scores significantly differed according to level of disability (EDSS ≤3.0, 3.5-5.5, ≥6.0). CONCLUSION: Hand grip strength and BBT value distribution in a large MS population is reported. Correlations between HGS, BBT and 9-HPT were generally low.

How to design a study to evaluate therapeutic drug monitoring in infectious diseases?

BACKGROUND: Therapeutic drug monitoring (TDM) is a tool to personalize and optimize dosing by measuring the drug concentration and subsequently adjusting the dose to reach a target concentration or exposure. The evidence to support TDM is however often ranked as expert opinion. Limitations in study design and sample size have hampered definitive conclusions of the potential added value of TDM. OBJECTIVES: We aim to give expert opinion and discuss the main points and limitations of available data from antibiotic TDM trials and emphasize key elements for consideration in design of future clinical studies to quantify the benefits of TDM. SOURCES: The sources were peer-reviewed publications, guidelines and expert opinions from the field of TDM. CONTENT: This review focuses on key aspects of antimicrobial TDM study design: describing the rationale for a TDM study, assessing the exposure of a drug, assessing susceptibility of pathogens and selecting appropriate clinical endpoints. Moreover we provide guidance on appropriate study design. IMPLICATIONS: This is an overview of different aspects relevant for the conduct of a TDM study. We believe that this paper will help researchers and clinicians to design and conduct high-quality TDM studies.

The impact of balance specific physiotherapy, intensity of therapy and disability on static and dynamic balance in people with multiple sclerosis: A multi-center prospective study.

BACKGROUND: A high-quality research identifying the best physiotherapeutic approach for the improvement of balance in people with multiple sclerosis is missing. This study compared aspects of balance improvement such as therapy specificity to balance, therapy method and category, country, intensity and medical conditions. METHODS: A multicentric randomised rater-blinded controlled trial comprised three different physiotherapy programs (Czech and Italian outpatient or inpatient programs). All patients received 20 therapy sessions. Experimental group underwent balance specific physiotherapy (it was Motor Program Activating Therapy in the Czech cohort and Sensory-motor Integration Training in the Italian cohort), control group underwent non-balance specific physiotherapy (it was Vojta reflex locomotion in the Czech cohort and conventional dynamic strengthening exercises in the Italian cohort, respectively). Static balance was evaluated by Berg Balance Scale and dynamic balance was assessed by Timed Up-and-Go Test. RESULTS: A total of 149 patients entered the study. Physiotherapy significantly improved static balance (p < 0.0001, increase by mean 2.6 points (95% confidence interval 2.0-3.5) in BBS score). Balance specific approach had a higher effect than non-specific balance approach (increase in BBS by 1.9 points, 95% confidence interval 0.9-3.7 points). The intensity of the physiotherapy significantly influenced static balance (BBS by 2.7 points higher in the inpatient setting, p= 0.007). Dynamic balance was also improved (TUG decrease by -0.8 s (95% CI -1.4 - -0.1s, p = 0.011)); the balance specificity had no impact. The level of disability played the most important role (p= 0.022). CONCLUSION: Although the overall changes in static and dynamic balance were statistically significant, they were quite small in a clinical sense. A small statistically significant difference between balance specific and non-specific treatment was found. It seems that a high intensity of the therapy is critical to maximize the effectiveness.

Time course of the upper limb motor recovery in subacute stroke patients undergoing conventional or robotic rehabilitation. A preliminary report.

Upper limb recovery is a complex process and a strong challenge in the rehabilitation of patients after stroke. Several studies have been conducted to compare the efficacy of conventional and robotic rehabilitation to restore the upper limb motor impairment following a stroke. However, the evolution of the upper limb motor ability during an intervention, as well as the time point when the patient stops improving (the so call plateau), are rarely measured, and never compared between the two approaches. These latter aspects are very important considering the need for an optimization of the economic resources. In this study, the time course of the upper limb motor recovery of 24 subacute stroke patients undergoing a 30-session robotic or conventional treatment was analyzed through the upper extremity portion of the Fugl-Meyer Assessment scale (FMA-UE). The FMA-UE was administered before the treatment, and after 10, 20, and 30 rehabilitation sessions. Statistical analysis showed that, according to the FMA-UE, the time course in the two groups was similar: patients did not change between the baseline and the 10-session assessment, while they improved between 10 and 20 sessions, and between 20 and 30 sessions, with most of the gain observed between 10 and 20 sessions. This result suggests that 30-session robotic or conventional rehabilitation programs induce a similar curve trend in the upper limb motor recovery of patients with subacute stroke, with an important increase in the middle of the program and without reaching a clear plateau in the analyzed time interval.

WITHDRAWN: Assessment of the inter-laboratory repeatability of gait analysis measurements in patients with multiple sclerosis.

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The predictive value of ABCB1, ABCG2, CYP3A4/5 and CYP2D6 polymorphisms for risperidone and aripiprazole plasma concentrations and the occurrence of adverse drug reactions.

We investigated in ninety Caucasian pediatric patients the impact of the main polymorphisms occurring in CYP3A, CYP2D6, ABCB1 and ABCG2 genes on second-generation antipsychotics plasma concentrations, and their association with the occurrence of adverse drug reactions. Patients with the CA/AA ABCG2 genotype had a statistically significant lower risperidone plasma concentration/dose ratio (Ct/ds) (P-value: 0.007) and an higher estimated marginal probability of developing metabolism and nutrition disorders as compared to the ABCG2 c.421 non-CA/AA genotypes (P-value: 0.008). Multivariate analysis revealed that the ABCG2 c.421 CA/AA genotype was found associated to a higher hazard (P-value: 0.004) of developing adverse drug reactions classified as metabolism and nutrition disorders. The ABCB1 2677TT/3435TT genotype had a statistically significant lower aripiprazole Ct/ds if compared with patients with others ABCB1 genotypes (P-value: 0.026). Information obtained on ABCB1 and ABCG2 gene variants may result useful to tailor treatments with these drugs in Caucasian pediatric patients.

Quetiapine-Induced Hypomania and its Association with Quetiapine/Norquetiapine Plasma Concentrations: A Case Series of Bipolar Type 2 Patients.

International guidelines consider quetiapine at medium doses (300-400 mg/day) as valid options for the treatment of bipolar depression for the supposed lower risk of a switch to hypomania/mania than antidepressants. Norquetiapine is an active metabolite with antidepressant action. We describe three cases of induced hypomania in bipolar type 2 subjects who received quetiapine extended-release monotherapy (300 mg/day) for a mild/moderate major depressive episode. Quetiapine and norquetiapine plasma concentrations were measured after 1 week of treatment. Hypomania appeared after 7-10 days of quetiapine extended-release monotherapy and all subjects had a quetiapine/norquetiapine plasma concentration ratio <1. We propose a ratio value <1 as a predictor of risk for a switch to hypomania in bipolar depressed subjects receiving quetiapine extended-release monotherapy. Future research should ascertain the validity of this laboratory parameter to assess the risk of quetiapine-induced hypomania in large samples of bipolar patients.

Splanchnic vein thrombosis in myeloproliferative neoplasms: risk factors for recurrences in a cohort of 181 patients.

We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis (SVT). Budd-Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors.

High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists.

The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9-8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8-7.3) on VKA and 8.9 (95% CI: 5.7-13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2-8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3-20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19-5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1-4.5) on VKA and 0.7 (95% CI: 0.08-2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.

Comparison of upright balance in stroke, Parkinson and multiple sclerosis.

OBJECTIVE: Multiple sclerosis (MS), Parkinson's disease (PD) and stroke (ST) subjects show balance impairments due to damage of the balance control system. The objective of the study was to assess the impact of MS, PD and ST on upright posture in eyes open condition and when visual and/or proprioceptive inputs are altered. MATERIALS AND METHODS: A total of 188 subjects with MS (n = 80), PD (n = 58) and ST (n = 50), mean age (SD), 57.9 (14.6) years, and 32 healthy subjects (HS) aged 53.7 (15.7) years were assessed by a stabilometric platform in a cross-sectional study. RESULTS: Compared to HS, MS showed large deviations from normal performances with respect to magnitude (P < 0.001) and regularity (P < 0.05) of body sway irrespective of the altered sensory information. Similarly to MS, PD showed large and abnormal levels of body sway (P < 0.001) and postural tremor (P < 0.05), while ST was the least impaired except for an asymmetrical distribution of body weight between legs (P < 0.001). Finally, the MS group compared to PD and ST showed the largest body instability after eye closure (P < 0.05) and when visual and proprioceptive inputs were removed (P < 0.05). PD showed instability mainly after the alteration of proprioceptive inputs (P < 0.05), while ST showed the smallest increase of body instability when sensory inputs were reduced. DISCUSSION: Objective assessment revealed pathology-specific balance disorders and showed the differential impact of MS, PD and ST on the ability to use sensory information for balance control.

Clinical and stabilometric measures predicting falls in Parkinson disease/parkinsonisms.

OBJECTIVES: Clinical predictors of falls in patients with Parkinson disease (PD) are fairly inaccurate. Stabilometric measures appear useful in investigating the relationship between balance, sensory disturbance, and falls. The aim of the study was to identify the best combination of clinical and stabilometric tests to predict falls prospectively. MATERIALS & METHODS: Fifty-three consecutive subjects with PD or parkinsonisms at risk of falls were included and followed for 6 months. Clinical variables were used as fall predictors: the Unified Parkinson Disease's Rating Scale (motor section) and the Longitudinal Aging study Amsterdam Physical Activity Questionnaire (LAPAQ). Variables from stabilometric platform underwent a principal component analysis. Multivariate logistic models were used to predict fallers using fall status (fallers: 1 + falls; recurrent fallers: 2 + falls) as dependent variable. RESULTS: Seven patients were lost to follow up, leaving 46 evaluable subjects. Of these, 32 (70%) were fallers and 22 (48%) were recurrent fallers. The only variable predicting fallers was the LAPAQ (odd ratio [OR] 0.99 (95% confidence interval [CI] 0.98-1.00); accuracy 71.7%; sensitivity 87.5%; specificity 35.7%). For recurrent fallers, Factor 2 (body sway velocity) (OR 2.37; 95% CI 1.01-5.58) and, in part, LAPAQ (OR 0.99; 95% CI 0.98-1.00) retained significance in the multivariate model, showing an accuracy of 76.9%, a sensitivity of 77.8%, and a specificity of 76.2%. CONCLUSIONS: A combination of clinical and instrumental tools is useful to identify fallers in PD or parkinsonisms. Body sway velocity and ability to perform the activities of daily living are the best predictors of recurrent falls.

Automatic knowledge extraction from chemical structures: the case of mutagenicity prediction.

This work proposes a new structure-activity relationship (SAR) approach to mine molecular fragments that act as structural alerts for biological activity. The entire process is designed to fit with human reasoning, not only to make the predictions more reliable but also to permit clear control by the user in order to meet customized requirements. This approach has been tested on the mutagenicity endpoint, showing marked prediction skills and, more interestingly, bringing to the surface much of the knowledge already collected in the literature as well as new evidence.

Hidrosadenitis supurativa glútea y perianal: tratamiento quirúrgico / Perianal and gluteal suppurativa hidradenitis: surgical treatment

Introducción: La hidrosadenitis supurada (HS) es una enfermedad inflamatoria crónica que compromete las glándulas sudoríparas apócrinas, comenzando por la oclusión de los folículos pilosos. Puede localizarse en axilas, ingle, periné, periano y glúteos. Fue descripta en 1.839, es infrecuente y afecta a1 c/300-600 adultos. De acuerdo a sus características y estadio puede ser tratada médicamente o en forma quirúrgica. Objetivo: Comunicación del tratamiento quirúrgico realizado a pacientes portadores de HS localizada en la región glútea y perianal. Diseño: Trabajo descriptivo, retrospectivo y multicéntrico. Lugar de aplicación: Hosp. Santa María Magdalena de Magdalena, Hosp. HIGA San Martin de La Plata y práctica privada. Pacientes y métodos: Se analizan los resultados del tratamiento quirúrgico realizado a 7 pacientes que fueron tratados entre los años 2001 y 2011, que presentaban HS supurada glútea y perianal, con una edad promedio de 35,4 y un rango de 23 a 56. Cuatro de ellos con estadio II de Hurley a los cuales se les realizó marsupialización y drenaje y 3 con estadio III extirpación e injertos diferidos con piel del mismo paciente y una variante de injerto de piel porcina liofilizada que aceleró el tiempo de regeneración. Resultados: No se observó enfermedad de Crohn o carcinoma de células escamosas. De los 4 que fueron tratados con marsupialización, 2 evolucionaron favorablemente y fueron controlados durante 3 y 6 años respectivamente. El resto de ellos tuvieron recidivas a los 4 y 8 meses respectivamente, siendo tratados de la misma forma. Solamente 1 permanece en control desde hace tres años. Los 3 con extirpaciones e injertos diferidos son controlados en la actualidad sin presentar nuevas alteraciones, con un periodo de evolución de 5, 3 y 2 años respectivamente. No se realizaron colostomías de derivación. Conclusiones: Los métodos conservadores de tratamiento tienen poco efecto cuando la HS glútea y perianal es extensa...

Introduction: The hidrosadenitis suppurativa (HS) is a chronic inflammatory disease that affects the apocrine sweat glands. This condition occludes the hair follicles and it can be found in the armpits, the groin, the perineum, the perianal area and the gluteus. It was first described in 1839 and it is a rare disease that affects 1 among 300-600 adults. Due to the stage and the features of the disease, it can be treated either with medication or with surgery. Purpose: The aim of this study is to report the surgical treatment carried out on patients suffering from HS in the perianal area and the gluteus. Layout: This is a descriptive, retrospective and multicentre study. Place: This study was carried out in the 'Hospital Santa María Magdalena', Magdalena, in the 1 Hospital HIGA San Martín, La Plata and in private practice. Patients and Methods: The results of the surgical treatment carried out on 7 patients who suffered from HS in the perianal area and the gluteus during the years 2001 and 2011 are analyzed. Those patients were 23-56 years old on average 35.4. Marsupialization and drainage was carried out on 4 patients who were in Hurley stage II. Surgical excisions and skin grafts stage III with the patient's own skin and lyophilized pigskin that speeded the time of regeneration were done to 3 patients. Results: Crohn's Disease or squamous cell carcinoma was not observed. 2 of the 4 patients who were treated with marsupialization recovered favorably and they were monitored during 3 and 6 years. The rest of the patients had recurrences within a period of 4 and 8 months. Only 1 patient has still been monitored for the last three years. The 3 patients who had excisions and skin grafts are monitored at present and they do not show alterations within a period of evolution of 5,3 and 2 years. No colostomy was perfonned. Conclusion: The traditional methods do not show useful results when the HS in the perianal area and the gluteus is extensive...