Executive dysfunction and effectiveness of physical program in older adults: which association?

BACKGROUND: Little is known about the association between executive function and the magnitude of improvement from personalised exercise interventions on gait performance among older-old adults. AIM: We examined whether the effectiveness of personalised intervention on gait performance is dependent on the patient's baseline dysexecutive syndrome, as assessed by the Frontal Assessment Battery. METHODS: A total of 175 older community-dwellers (83.57 ± 5.2 years; 70.2% female) were recruited from the day centre for after-care and rehabilitation in the Nantes Ambulatory Centre of the Clinical Gerontology (France), and were followed during a pre-post-intervention, single-arm retrospective design. The intervention consisted of an individual personalised rehabilitation program over a period of 7 weeks, with twice-weekly sessions (45 min each). Gait speed in four conditions (preferred, fast, and under two dual-task conditions), Timed Up and Go test, and handgrip strength test were assessed. RESULTS: Using a pre-post analysis of covariance, a significant increase in dual-task gait speed while counting (+ 0.10 m/s; + 15%) and in dual-fluency gait speed (+ 0.06 m/s; + 10%), and in Timed Up and Go performance (- 2.9 s; + 17.8%) was observed after the rehabilitation program, regardless the baseline executive status. DISCUSSION: An individual personalized intervention is effective to improve mobility performance and the dual-task gait speed in older-old adults. The magnitude of those effects is independent of the patient's baseline characteristics including the executive function status. CONCLUSIONS: Even the most deficient baseline characteristics of patients should not be viewed as clinical barrier for implementing a beneficial individual intervention in high-risk older adults.

Impact of an individual personalised rehabilitation program on mobility performance in older-old people.

BACKGROUND: Studies have shown benefits of exercise interventions on preferred and fast gait speed in healthy older adults, but the impact of a personalised rehabilitation program targeting a large cohort of non-disabled older-old adults has rarely been examined. AIMS: The purpose was to determine whether personalised intervention-related improvements in gait and mobility performance in older-old adults were dependent on cognitive status and/or history of falls. METHODS: Based on a pre-post design, 483 older-old persons (mean age: 83.3 ± 5.1 years) were followed during a personalised rehabilitation program over a period of 7 weeks, with twice-weekly sessions (45 min each). Gait speed in four conditions (preferred, fast, and under two dual-task conditions), static postural sway, Timed Up and Go test, Five Times Sit to Stand test, the ability to rise from the floor, and handgrip strength test were assessed. RESULTS: Using a pre-post analysis of covariance, a significant increase in preferred gait speed (+ 20.1%), fast gait speed (+ 15.8%), and dual-task speed while counting (+ 13.4%) was observed after the rehabilitation, regardless of the baseline cognitive status and fall history. Similar improvements in TUG and maximal handgrip force were observed, with a significant reduction of performance time (-19.5%) or an increase of handgrip strength (+ 6.2%). DISCUSSION: Results suggest the effectiveness of personalised intervention to improve a battery of physical performance measures in older-old adults, even for the frailest participants. CONCLUSION: Implementing a personalised intervention for targeting the high-risk older-old adults in priority is critical regarding the clinically meaningful change in gait speed.

Retreatment and prolonged therapy with subcutaneous bortezomib in patients with relapsed multiple myeloma: A randomized, controlled, phase III study.

OBJECTIVES: This randomized, international, multicenter, open-label phase III study investigated the effects of experimental retreatment with subcutaneous bortezomib plus dexamethasone (VD) followed by prolonged bortezomib therapy vs standard VD retreatment in patients with relapsed/refractory multiple myeloma. METHODS: Patients were randomized (2:1) to receive either experimental (n = 53) or standard (n = 27) retreatment, stratified by the number of prior therapy lines. RESULTS: The study was terminated prematurely with insufficient enrollment to adequately compare the retreatment therapies; results should be considered descriptive. After a median follow-up of 21.2 and 20.0 months in the experimental and standard arms, respectively, the median progression-free survival (primary endpoint) was 7.2 months (95% confidence interval 5.7-9.0) vs 7.8 months (4.9-11.7). The overall response rate was 66% and 52% for experimental and standard retreatment regimens, respectively. Thrombocytopenia was the most common and most differentially observed grade ≥3 adverse event (experimental: 9% vs standard: 22%). Any-grade peripheral neuropathies (including peripheral sensory neuropathies) were reported in 23% vs 37% of patients. CONCLUSIONS: This study showed no significant benefit with experimental vs standard VD retreatment therapy. Further investigations are required to determine whether the experimental retreatment regimen is a suitable alternative to the current standard retreatment regimen.

Effects of single-agent bortezomib as post-transplant consolidation therapy on multiple myeloma-related bone disease: a randomized phase II study.

This phase II study explored the effects of bortezomib consolidation versus observation on myeloma-related bone disease in patients who had a partial response or better after frontline high-dose therapy and autologous stem cell transplantation. Patients were randomized to receive four 35-day cycles of bortezomib 1·6 mg/m2 intravenously on days 1, 8, 15 and 22, or an equivalent observation period, and followed up for disease status/survival. The modified intent-to-treat population included 104 patients (51 bortezomib, 53 observation). There were no meaningful differences in the primary endpoint of change from baseline to end of treatment in bone mineral density (BMD). End-of-treatment rates (bortezomib versus observation) of complete response/stringent complete response were 22% vs. 11% (P = 0·19), very good partial response or better of 80% vs. 68% (P = 0·17), and progressive disease of 8% vs. 23% (P = 0·06); median progression-free survival was 44·9 months vs. 21·8 months (P = 0·22). Adverse events observed ≥15% more frequently with bortezomib versus observation were diarrhoea (37% vs. 0), peripheral sensory neuropathy (20% vs. 4%), nausea (18% vs. 0) and vomiting (16% vs. 0). Compared with observation, bortezomib appeared to have little impact on bone metabolism/health, but was associated with trends for improved myeloma response and survival.

Retrospective matched-pairs analysis of bortezomib plus dexamethasone versus bortezomib monotherapy in relapsed multiple myeloma.

Bortezomib-dexamethasone is widely used for relapsed myeloma in routine clinical practice, but comparative data versus single-agent bortezomib are lacking. This retrospective analysis compared second-line treatment with bortezomib-dexamethasone and bortezomib using 109 propensity score-matched pairs of patients treated in three clinical trials: MMY-2045, APEX, and DOXIL-MMY-3001. Propensity scores were estimated using logistic regression analyses incorporating 13 clinical variables related to drug exposure or clinical outcome. Patients received intravenous bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, in 21-day cycles, alone or with oral dexamethasone 20 mg on the days of/after bortezomib dosing. Median bortezomib cumulative dose (27.02 and 28.60 mg/m(2)) and treatment duration (19.6 and 17.6 weeks) were similar with bortezomib-dexamethasone and bortezomib, respectively. The overall response rate was higher (75% vs. 41%; odds ratio=3.467; P<0.001), and median time-to-progression (13.6 vs. 7.0 months; hazard ratio [HR]=0.394; P=0.003) and progression-free survival (11.9 vs. 6.4 months; HR=0.595; P=0.051) were longer with bortezomib-dexamethasone versus bortezomib, respectively. Rates of any-grade adverse events, most common grade 3 or higher adverse events, and discontinuations due to adverse events appeared similar between the groups. Two patients per group died of treatment-related adverse events. These data indicate the potential benefit of bortezomib-dexamethasone compared with single-agent bortezomib at first relapse in myeloma. The MMY-2045, APEX, and DOXIL-MMY-3001 clinical trials were registered at, respectively, clinicaltrials.gov identifier: 00908232, 00048230, and 00103506.

Phase II study of bortezomib-dexamethasone alone or with added cyclophosphamide or lenalidomide for sub-optimal response as second-line treatment for patients with multiple myeloma.

This phase II study is the first prospective evaluation of bortezomib-dexamethasone as second-line therapy for relapsed/refractory multiple myeloma. A total of 163 patients were enrolled to receive four cycles of bortezomib-dexamethasone. Patients were investigator-assessed for response at cycle 5 Day 1, then treated as follows: responding patients received another four cycles of bortezomib-dexamethasone, while patients with stable disease were subsequently randomized to sequential treatment with a further four cycles of bortezomib-dexamethasone alone or with added cyclophosphamide or lenalidomide. The primary end point was response to sequential therapy; however, this could not be evaluated because investigator-assessed response rates to bortezomib-dexamethasone after four cycles were high, and an insufficient number of patients were randomized to sequential treatment per protocol. Among all 163 patients, validated best confirmed response rate was 66%, including 37% complete/very good partial responses; median response duration was 9.7 months. After a median follow up of 16.9 months, median time to progression and progression-free survival were 9.5 and 8.6 months, respectively; estimated 1-year overall survival was 81%. Median glomerular filtration rate improved from baseline during treatment. Among 58 patients with baseline glomerular filtration rate below 50 mL/min, 24 had renal responses. Grade 3/4 adverse events included: thrombocytopenia (17%), anemia (10%), constipation (6%), peripheral sensory neuropathy (5%), and polyneuropathy (5%). Overall, 57% of neuropathy events improved/resolved; median time to improvement was 2.1 months. These findings suggest bortezomib-dexamethasone represents an active, feasible second-line treatment option for patients with relapsed/refractory myeloma.

Factors Associated with Dual-Fluency Walk Speed Improvement after Rehabilitation in Older Patients.

Walk speed measured under dual-task conditions (neurocognitive tasks) could reflect patient performance in real-life. Rehabilitation programs are effective in increasing walk speed, but few studies have evaluated the associations between geriatric factors and rehabilitation efficacy under dual-task conditions. Our objective was to investigate the association between geriatric factors and an increase in dual-task walk speed (threshold of 0.1 m/s), after a multidisciplinary rehabilitation program. We performed a retrospective cohort study that included patients aged 75 years and over, who underwent a complete rehabilitation program and who had a neurocognitive assessment at baseline. The primary outcome was the increase in the dual-task (fluency verbal task) walking speed between pre- and post-rehabilitation assessments. In this study, 145 patients were included, with a mean age of 83.6 years old. After rehabilitation, dual-task walk speed increase in 62 (43%) patients. In multivariate analysis, the following factors were associated with an increase in dual-task walk speed: IADL (OR 2.50, 95% CI [1.26; 4.94], p = 0.009), vitamin D level (OR 0.83, 95% CI [0.72; 0.95], p = 0.008), severe sarcopenia (OR 0.00, 95% CI [0.00; 0.32], p = 0.016), depression (OR 15.85, 95% CI [1.32; 190.40], p = 0.029), number of drugs (OR 1.41, 95% CI [1.04; 1.92], p = 0.027), initial dual-fluency walk speed (OR 0.92, 95% CI [0.86; 0.98], p = 0.014) and time interval between initial and final assessments (OR 0.98, 95% CI [0.96; 1.00], p = 0.06). Identifying patients that are less resilient to rehabilitation may promote a centered-patient approach for an individualized and optimized rehabilitation care.

Perceptual Inhibition Is Not a Specific Component of the Sensory Integration Process Necessary for a Rapid Voluntary Step Initiation in Healthy Older Adults.

OBJECTIVES: We investigated whether performing step initiation during a proprioceptive perturbation would require greater perceptual or motor inhibitory control in older adults. METHOD: Fifty-two healthy adults (young: n = 26, mean age 22.5 years vs. older: n = 26, mean age 70.1 years) performed a stepping reaction time task, with different inhibition requirements (i.e., perceptual vs. motor inhibitory conflict), with two proprioceptive configurations: with and without application of Achilles tendon vibrations. RESULTS: Beyond a systematically greater stepping reaction time in older adults (p < .01), no difference was found between the perceptual versus motor inhibitory conflict resolution, regardless of age and proprioceptive configuration. Furthermore, slower reaction time was observed for young participants in the presence of Achilles tendon vibrations unlike older adults, who showed the same reactive stepping performance with or without vibrations (p < .05). DISCUSSION: These findings show that perceptual inhibition cannot be considered as specifically involved in the central processing of proprioceptive signals, at least not in active older adults. Rather than motor system malfunctioning or a reduced amount of proprioceptive afference, we propose that cortical-proprioceptive processing in older adults remains as effective as in young adults, regardless of the high attentional requirements for step responses.

Results of an Early Access Treatment Protocol of Daratumumab Monotherapy in Spanish Patients With Relapsed or Refractory Multiple Myeloma.

Daratumumab is a human CD38-targeted monoclonal antibody approved as monotherapy for heavily pretreated relapsed and refractory multiple myeloma. We report findings for the Spanish cohort of an open-label treatment protocol that provided early access to daratumumab monotherapy and collected safety and patient-reported outcomes data for patients with relapsed or refractory multiple myeloma. At 15 centers across Spain, intravenous daratumumab (16 mg/kg) was administered to 73 patients who had ≥3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double refractory to both. The median duration of daratumumab treatment was 3.3 (range: 0.03-13.17) months, with a median number of 12 (range: 1-25) infusions. Grade 3/4 treatment-emergent adverse events were reported in 74% of patients and included lymphopenia (28.8%), thrombocytopenia (27.4%), neutropenia (21.9%), leukopenia (19.2%), and anemia (15.1%). Common (>5%) serious treatment-emergent adverse events included respiratory tract infection (9.6%), general physical health deterioration (6.8%), and back pain (5.5%). Infusion-related reactions occurred in 45% of patients. The median change from baseline in all domains of the EQ-5D-5L and EORTC QLQ-C30 was mostly 0. A total of 18 (24.7%) patients achieved a partial response or better, with 10 (13.7%) patients achieving a very good partial response or better. Median progression-free survival was 3.98 months. The results of this early access treatment protocol are consistent with previously reported trials of daratumumab monotherapy and confirm its safety and antitumoral efficacy in Spanish patients with heavily treated relapsed or refractory multiple myeloma. European Clinical Trials Database number: 2015-002993-19.

Distribution and antibacterial susceptibility of macrolide resistance genotypes in Streptococcus pneumoniae: PROTEKT Year 5 (2003-2004).

The distribution and antibacterial susceptibility of macrolide resistance genotypes among 7083 Streptococcus pneumoniae isolates collected worldwide during 2003-2004 from patients with community-acquired respiratory tract infections, including patients within 48h of admission to hospital, were analysed. The overall rate of erythromycin resistance was 37.2% (intercountry range <10% to >50%). The most common resistance mechanism globally was erm(B) (55.0% of erythromycin-resistant S. pneumoniae (ERSP)), followed by mef(A) (30.6%) and erm(B)+mef(A) (12.0%). Genotype distribution varied by age group (P<0.0001); erm(B)+mef(A) was more prevalent (21.8% of isolates) among patients 0-2 years of age than among other age groups (P<0.001). The prevalence of tetracycline resistance among mef(A) isolates varied between different countries. Of the erm(B)+mef(A) strains, 43.5% were resistant to amoxicillin/clavulanic acid. Most ERSP isolates were susceptible to levofloxacin (98.3%) and telithromycin (99.4%).

Monitoring how changes in pedagogical practices have improved student interest and performance for an introductory biochemistry course.

This study describes feedback on the effects of changes introduced in our teaching practices for an introductory biochemistry course in the Life Sciences curriculum. Students on this course have diverse educational qualifications and are taught in large learning groups, creating challenges for the management of individual learning. We used the constructive alignment principle, refining the learning contract and re-drafting the teaching program to introduce active learning and an organization of activities that promotes the participation of all the students and helps their understanding. We also created teaching resources available through the university virtual work environment. Our research aimed to measure the effects of those changes on the students' success. Monitoring of the student performance showed a continuous increase in the percentage of students who passed the course, from 2.13% to 33.5% in 4 years. Analysis of student perceptions highlighted that the teaching methodology was greatly appreciated by the students, whose attendance also improved. The recent introduction of clickers-questions constituted a complementary leverage. The active involvement of the students and better results for summative assessments are altogether a strong motivation for teaching staff to continue to make improvements.

Neural and muscular factors both contribute to plantar-flexor muscle weakness in older fallers.

Plantar-flexor muscles are key muscles in the control of postural sway. Older fallers present lower maximal plantar-flexor performance than older non-fallers; however, the mechanisms underlying this motor impairment remain to be elucidated. This study aimed to determine whether muscular and neural factors are both involved in the lower maximal plantar-flexor performance of older fallers. The maximal voluntary contraction (MVC) torque, resting twitch torque, voluntary activation level (VAL), and electromyographic (EMG) activities for the soleus, gastrocnemius medialis, gastrocnemius lateralis and tibialis anterior during plantar-flexor MVCs were recorded in 23 older non-fallers (age: 83.3 ±â€¯3.9 years) and 25 older fallers (age: 84.0 ±â€¯4.1 years). The maximal plantar-flexor Hoffmann reflex normalized to the maximal motor potential (Hmax/Mmax) was measured to assess the efficacy of spinal transmission from the Ia-afferent fibers to the α-motoneurons. Older fallers presented lower plantar-flexor MVC torque, resting twitch torque, VAL and EMG activity (P < 0.05). No significant differences between older fallers and non-fallers were found for the Hmax/Mmax ratio and dorsi-flexor coactivation. The current findings showed for the first time that both neural and muscular factors associated with the plantar-flexors contributed to the specific alteration of maximal motor performance in older fallers. The lack of a difference in the Hmax/Mmax ratio indicated that the efficacy of spinal transmission from the Ia-afferent fibers to the α-motoneurons was not involved in the lower voluntary muscle activation of older fallers. This suggests that supraspinal centers are likely to be involved in the lower voluntary muscle activation observed in older fallers.

Multiple Myeloma Treatment in Real-world Clinical Practice: Results of a Prospective, Multinational, Noninterventional Study.

BACKGROUND: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. PATIENTS AND METHODS: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months. RESULTS: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide. CONCLUSION: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits.

Efficacy and safety of bortezomib-based retreatment at the first relapse in multiple myeloma patients: A retrospective study.

OBJECTIVE: Multiple myeloma remains incurable and retreatment with available therapies is of substantial interest. METHODS: This retrospective observational study included data from 35 patients treated initially and at the first relapse with bortezomib-containing regimens. RESULTS: Bortezomib retreatment provided a similar depth and time to response as first-line therapy; however, as could be expected, the duration of response was shorter with retreatment. The tolerability profile was similar with bortezomib as the first- and second-line therapy, with no evidence of cumulative toxicity. CONCLUSION: These findings support bortezomib retreatment after a treatment-free interval of ≥6 months in patients who achieved at least a partial response to the first-line bortezomib-based therapy.

Activities of a new oral streptogramin, XRP 2868, compared to those of other agents against Streptococcus pneumoniae and haemophilus species.

MIC methodology was used to test the antibacterial activity of XRP 2868, a new oral combination of two semisynthetic streptogramins, RPR 132552A and RPR 202868, compared to activities of other antibacterial agents against pneumococci, Haemophilus influenzae, and Haemophilus parainfluenzae. For 261 pneumococci, XRP 2868 and pristinamycin MICs were similar, irrespective of penicillin G and erythromycin A susceptibilities (MIC at which 50% of isolates were inhibited [MIC(50)], 0.25 micro g/ml; MIC(90), 0.5 micro g/ml), while quinupristin/dalfopristin had MICs which were 1 to 2 dilutions higher. Single components of both XRP 2868 and quinupristin/dalfopristin had higher MICs. Erythromycin A, azithromycin, clarithromycin, and clindamycin MICs were higher for penicillin G-intermediate and -resistant than -susceptible pneumococci. Against 150 H. influenzae strains, all compounds tested had unimodal MIC distributions. XRP 2868 had an overall MIC(50) of 0.25 micro g/ml and an MIC(90) of 1.0 micro g/ml, with no differences between beta-lactamase-positive, beta-lactamase-negative, and beta-lactamase-negative ampicillin-resistant strains. Of note was the similarly low activity of one of its components, RPR 132552A. Pristinamycin and quinupristin/dalfopristin had MICs of 0.125 to 8.0 micro g/ml; quinupristin alone had MICs of 8.0 to >64.0 micro g/ml, and dalfopristin had MICs of 1.0 to >64.0 micro g/ml. Erythromycin A, azithromycin, and clarithromycin had modal MICs of 4.0, 1.0, and 8.0 micro g/ml, respectively. MICs of all compounds against H. parainfluenzae were 1 to 2 dilutions higher than against H. influenzae. XRP 2868 showed potent activity against pneumococci and Haemophilus strains irrespective of their susceptibility to other agents.