The level of minimal residual disease in the bone marrow of patients with multiple myeloma before high-dose therapy and autologous blood stem cell transplantation is an independent predictive parameter.

The prognostic relevance of minimal residual disease (MRD) in patients with multiple myeloma is still an open question. We measured MRD levels in bone marrow (BM) samples of 53 patients treated with high-dose therapy (HDT) and autologous peripheral blood stem cell transplantation using real-time quantitative (RQ)-IgH-PCR with allel-specific oligonucleotide probes. We identified a prognostically relevant threshold level of 0.2% 2IgH/ß-actin ratio in the BM before HDT. Twenty-six patients with MRD levels below this value were termed as the "low-MRD group," whereas 27 patients with levels above this threshold were allocated to the "high-MRD group." Median event-free-survival (EFS) in the low-MRD group was significantly (P = .001) longer than in the high-MRD group with 35 versus 20 months, respectively. Overall survival (OS) within the low-MRD group was also significantly longer with 70 versus 45 months (P = .04). Using multivariate analysis, we found that the pretransplantation MRD level was an independent prognostic factor for EFS (P = .003) and OS (P = .05). Further, EFS of patients in the high-MRD could be improved (P = .005) when they achieved a low MRD level after HDT. In conclusion, measuring MRD is of prognostic relevance in patients with MM, and low MRD levels should be a goal of treatment.

Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.

BACKGROUND: Early administration of intravenous recombinant tissue plasminogen activator (rt-PA) after ischaemic stroke improves outcome. Previous analysis of combined data from individual patients suggested potential benefit beyond 3 h from stroke onset. We re-examined the effect of time to treatment with intravenous rt-PA (alteplase) on therapeutic benefit and clinical risk by adding recent trial data to the analysis. METHODS: We added data from ECASS III (821 patients) and EPITHET (100 patients) to a pool of common data elements from six other trials of alteplase for acute stroke (2775 patients). We used multivariate logistic regression to assess the relation of stroke onset to start of treatment (OTT) with treatment on favourable 3-month outcome (defined as modified Rankin score 0-1), mortality, and occurrence and outcome of clinically relevant parenchymal haemorrhage. The presence of an arterial occlusion was inferred from the patient's symptoms and absence of haemorrhage or other causes of ischaemic stroke. Vascular imaging was not a requirement in the trials. All patients with confirmed OTT within 360 min were included in the analysis. FINDINGS: Treatment was started within 360 min of stroke onset in 3670 patients randomly allocated to alteplase (n=1850) or to placebo (n=1820). Odds of a favourable 3-month outcome increased as OTT decreased (p=0.0269) and no benefit of alteplase treatment was seen after around 270 min. Adjusted odds of a favourable 3-month outcome were 2.55 (95% CI 1.44-4.52) for 0-90 min, 1.64 (1.12-2.40) for 91-180 min, 1.34 (1.06-1.68) for 181-270 min, and 1.22 (0.92-1.61) for 271-360 min in favour of the alteplase group. Large parenchymal haemorrhage was seen in 96 (5.2%) of 1850 patients assigned to alteplase and 18 (1.0%) of 1820 controls, with no clear relation to OTT (p=0.4140). Adjusted odds of mortality increased with OTT (p=0.0444) and were 0.78 (0.41-1.48) for 0-90 min, 1.13 (0.70-1.82) for 91-180 min, 1.22 (0.87-1.71) for 181-270 min, and 1.49 (1.00-2.21) for 271-360 min. INTERPRETATION: Patients with ischaemic stroke selected by clinical symptoms and CT benefit from intravenous alteplase when treated up to 4.5 h. To increase benefit to a maximum, every effort should be taken to shorten delay in initiation of treatment. Beyond 4.5 h, risk might outweigh benefit. FUNDING: None.

Functional biodynamics of human-body system: A mathematical axiomatics with functional learning and aging in life cycle.

"Systems neuroergonomics" (Mau, J. In: R. Wang and X. Pan, editors, Advances in Cognitive Neurodynamics (V), chapter 59, pages 431-437, Springer Science+Business Media, Singapore, 2016) showed a separation of human-body system's functional organization from its cellular material in order to open a holistic perspective that can comprise all body functions. This was achieved with a strictly hierarchical structure in drill-down from system's functional whole to base functional elements. Implied multi-scale functional dynamics with coherent up-scaling were mathematically described in an axiomatic way, but the daily wake/sleep dynamics cover mainly anticipated functional challenges. Here, the theory is expanded to permit "functional learning" in the sense of adjustment of functional capacities to meet higher demand. "Functional aging" as a whole-body frailty is derived from biodynamic entropy that eventually drives the living to meet its inevitable destiny, death. The ages at which frailty begins to dominate can currently be obtained only from official life tables as population averages and are different for men and women, accordingly. The objective is to develop a mathematical theory in medicine from an axiomatic approach to phenomenological biodynamics, in which cognition is viewed as an embodied activity.

Characteristics of blood pressure profiles as predictors of long-term outcome after acute ischemic stroke.

BACKGROUND AND PURPOSE: Most patients have elevated blood pressure (BP) in the early phase after an acute ischemic stroke. Mechanism and effects of this BP elevation are not well understood. The benefits of intervention by lowering the initial BP or waiting for spontaneous return to normal values remain debated. We studied the hypothesis that increased BP level and profile variability will adversely affect long-term outcome after stroke with and without thrombolytic treatment. METHODS: We studied the 615 patients with acute ischemic hemispheric stroke in the first European Cooperative Acute Stroke Study (ECASS). BP was measured at 2-hour intervals during the first 20 hours after randomization, and then every 4 hours, up to 72 hours after admission. Studied features of individual 0- to 72-hour BP profiles were: baseline BP, maximum and minimum BP, mean level, and successive variation in the BP profile. The end point was good functional recovery (modified Rankin Scale [mRS] score of 0 to 1) at 90 days. Logistic regression was used to adjust for known prognostic factors, demographic, initial stroke severity, disease and medication histories, and computed tomography signs. RESULTS: Higher systolic BP or diastolic BP at baseline were associated with favorable outcome assessed on modified mRS at 90 days (adjusted odds ratio [OR], 1.22; 95% CI, 1.01 to 1.49; and OR, 1.22; 95% CI, 1.01 to 1.49 per 10 mm Hg), lower within-patient 0- to 72-hour average systolic BP (SBP), or DBP implied favorable outcome (OR, 0.74; 95% CI, 0.61 to 0.90; and OR, 0.61; 95% CI, 0.41 to 0.90 per 10 mm Hg). Reduced variability of 0- to 72-hour DBP profile was an independent predictor of favorable outcome (OR, 0.58; 95% CI, 0.39 to 0.85 per 5 mm Hg). CONCLUSIONS: Higher baseline SBP or DBP was associated with favorable outcome after stroke. Other characteristics of first 72-hour BP profiles: lower mean level of SBP or DBP and reduced successive variability of DBP profile were independent predictors of favorable outcome at 90 days.

Does acupuncture improve the orthopedic management of chronic low back pain--a randomized, blinded, controlled trial with 3 months follow up.

This prospective, randomised controlled trial, with three parallel groups, patient and observer blinded for verum and sham acupuncture and a follow up of 3 months raises the question: "Does a combination of acupuncture and conservative orthopedic treatment improve conservative orthopedic treatment in chronic low back pain (LBP). 186 in-patients of a LBP rehabilitation center with a history of LBP >or=6 weeks, VAS >or=50mm, and no pending compensation claims, were selected; for the three random group 4 weeks of treatment was applied. 174 patients met the protocol criteria and reported after treatment, 124 reported after 3 months follow up. Patients were assorted 4 strata: chronic LBP, or=5 years. Analysis was by intention to treat. Group 1 (Verum+COT) received 12 treatments of verum acupuncture and conservative orthopedic treatment (COT). Group 2 (Sham+COT) received 12 treatments of non-specific needling and COT. Group 3 (nil+COT) received COT alone. Verum- and Sham acupuncture were blinded against patient and examiner. The primary endpoints were pain reduction >or=50% on VAS 3 months after the end of the treatment protocol. Secondary endpoints were pain reduction >or=50% on VAS and treatment efficacy on a four-point box scale directly after the end of the treatment protocol and treatment efficacy after 3 months. In the whole sample a pain relief of >or=50% on VAS was reported directly after the end of treatment protocol: Verum+COT 65% (95%CI 51-77%), Sham+COT 34% (95%ci 22-49%), nil+COT 43% (95%ci 29-58%) - results are significant for Verum+COT over Sham+COT (P

Randomized multicenter comparison of 2 IMZ and 4 TPS screw implants supporting bar-retained overdentures in 425 edentulous mandibles.

PURPOSE: Two treatment concepts for implant-supported bar retention of mandibular overdentures-2 intramobile cylinder (IMZ) implants and a Dolder bar and 4 titanium plasma-sprayed (TPS) screw implants and an angulated bar-were compared in a randomized controlled clinical trial with respect to postprosthetic efficacy and safety. MATERIALS AND METHODS: Four hundred twenty-five patients with edentulous mandibles were enrolled; 212 were randomized to TPS implants (control group) and 213 to IMZ implants (test group). Endpoints were occurrences of postprosthetic integration deficiency (ID), functional deficiency (FD), and complications. The trial was sized to detect a 10% difference in 5-year ID-free postprosthetic system lifetime with a power of 80%. RESULTS: With 340 protocol-completed cases, the trial achieved its predetermined power. The 2 systems did not show statistically significant differences in occurrences of postprosthetic ID and FD; 5-year occurrence-free postprosthetic system lifetime probabilities were estimated as 42.5% with IMZ and 42.8% with TPS, for ID; and as 82.6% with IMZ and 87.2% with TPS, for FD. However, at 3 to 6 months after surgery, mean Periotest values were significantly higher (P = .0001 without adjustment) with IMZ implants (5.6, SD 4.2) than with TPS implants (0.8, SD 4.3). TPS implants showed a higher incidence of inflammation and recession, while IMZ implants had a higher incidence of implant fracture after functional loading. DISCUSSION: The system-wise approach overcomes potential bias with implant-wise analyses. A combination of radiographic and clinical criteria distinguishes between desirable integration and functional anchorage. The in situ survival rates at 5 years in this study (95% for IMZ, 92% for TPS) match rates reported in the literature. CONCLUSION: This study demonstrated equivalent efficacy of 2 IMZ cylinders and 4 TPS screws in implant-supported, bar-retained mandibular overdentures and indicated a higher rate of complications with the TPS screw implants.

Long-term outcome as function of blood pressure in acute ischemic stroke and effects of thrombolysis.

BACKGROUND: While baseline blood pressure (BP) is a known predictor of 90-day residual deficit after acute ischemic stroke, the effect of thrombolysis on this relationship has not been described. To study the interaction and to find intervals of prognostic significance, the functional forms of this predictive relationship should be found and compared for recombinant tissue plasminogen activator (rt-PA)- and placebo-treated patients of the first European Cooperative Acute Stroke Study. METHODS: We studied the 615 patients with acute ischemic hemispheric stroke randomized and treated in the first European Cooperative Acute Stroke Study. Endpoints were fatal outcome within and favorable outcome (no or negligible long-term handicap on the modified Rankin Scale scores 0 or 1) after 90 +/- 14 days. Functional relationships with baseline BP were estimated fully nonparametrically as moving averages of occurrences of either outcome among placebo- and rt-PA-treated patients, separately. Visual findings were corroborated by conventionally stratified logistic regression. RESULTS: For favorable outcome, an S-shaped functional relationship with baseline systolic BP (SBP) was found with an averaged incremental rate around 10% per 1 mm Hg increase in baseline SBP between 140 and 160 mm Hg, among rt-PA and placebo patients. Similar results were obtained for diastolic BP (DBP) between 80 and 90 mm Hg. Odds ratios in favor of rt-PA were 1.96 (95% CI: 1.02-3.78) and 2.87 (95% CI: 1.36-6.04) for SBP and DBP in these intervals, respectively. For mortality, visible markedly lower risks in the placebo group between 120 and 140 and between 160 and 180 mm Hg SBP were confirmed with adjusted OR of 2.47 (95% CI: 1.09-5.64) and 9.73 (95% CI: 2.02-46.82), respectively. CONCLUSIONS: Patients benefited from rt-PA in terms of no or negligible handicap after 90 days, without excess risk of death, with baseline SBP between 140 and 160 mm Hg or baseline DBP between 80 and 90 mm Hg.

Randomized multicenter comparison of two coatings of intramobile cylinder implants in 313 partially edentulous mandibles followed up for 5 years.

Intramobile cylinder (IMZ) implants with either of two coatings, hydroxyapatite (HA) or titanium plasma-flame (TPF), as distal abutments for combined tooth implant-supported restorations, were compared in 313 partially edentulous mandibles with respect to postprosthetical failure patterns and complication frequencies in a randomized multicenter clinical trial. Within the treatment protocols, the two coatings do not show evidence of different efficacy with respect to occurrence of postprosthetical integration deficiency (ID) or functional deficiency (FD). Statistical equivalence for an absolute effect of +/-15% in event-free survival could only be demonstrated for FD, not for ID, however. Intent-to-treat and per-protocol population analyses gave consistent results. Hazards of occurrence of ID and FD, adjusted for years of follow-up, were estimated for ID as 7% per year (95%CI 4-10% per year) with HA and 5% per year (95%CI 3-7% per year) with TPF, and for FD as 5% per year (95%CI 3-7% per year) with HA and 4% per year (95%CI 2-6% per year) with TPF. The 5-year cumulative success rates for no ID were 69.5% (95%CI 58-81%) with HA and 82.2% (95%CI 74-91%) with TPF. With respect to frequencies of complications, there was no relevant statistically significant difference between the two coatings.