Revised contraindications for the use of non-medical WB-electromyostimulation. Evidence-based German consensus recommendations.

Whole-body electromyostimulation has proven to be a highly effective alternative to conventional resistance-type exercise training. However, due to adverse effects in the past, very extensive contraindications have been put in place for the commercial, non-medical WB-EMS market. Considering recent positive innovations e.g., federal regulation, mandatory trainer education, revised guidelines, and new scientific studies on WB-EMS application, we believe that a careful revision of the very restrictive contraindications on WB-EMS is needed. This applies all the more because many cohorts with limited options for conventional exercise have so far been excluded. During a first meeting of an evidence-based consensus process, stakeholders from various backgrounds (e.g., research, education, application) set the priorities for revising the contraindications. We decided to focus on four categories of absolute contraindications: "Arteriosclerosis, arterial circulation disorders", "Diabetes mellitus" (DM), "Tumor and cancer" (TC), "Neurologic diseases, neuronal disorders, epilepsy". Based on scientific studies, quality criteria, safety aspects and benefit/risk assessment of the category, DM and TC were moved to the relative contraindication catalogue, while arteriosclerosis/arterial circulation disorders and neurologic diseases/neuronal disorders/epilepsy were still considered as absolute contraindications. While missing evidence suggests maintaining the status of neurologic diseases/neuronal disorders as an absolute contraindication, the risk/benefit-ratio does not support the application of WB-EMS in people with arteriosclerosis/arterial circulation diseases. Despite these very cautious modifications, countries with less restrictive structures for non-medical WB-EMS should consider our approach critically before implementing the present revisions. Considering further the largely increased amount of WB-EMS trials we advice regular updates of the present contraindication list.

Dual inhibition of EZH2 and G9A/GLP histone methyltransferases by HKMTI-1-005 promotes differentiation of acute myeloid leukemia cells.

All-trans-retinoic acid (ATRA)-based differentiation therapy of acute promyelocytic leukemia (APL) represents one of the most clinically effective examples of precision medicine and the first example of targeted oncoprotein degradation. The success of ATRA in APL, however, remains to be translated to non-APL acute myeloid leukemia (AML). We previously showed that aberrant histone modifications, including histone H3 lysine 4 (H3K4) and lysine 27 (H3K27) methylation, were associated with this lack of response and that epigenetic therapy with small molecule inhibitors of the H3K4 demethylase LSD1/KDM1A could reprogram AML cells to respond to ATRA. Serving as the enzymatic component of Polycomb Repressive Complex 2, EZH2/KMT6A methyltransferase plays a critical role in normal hematopoiesis by affecting the balance between self-renewal and differentiation. The canonical function of EZH2 is methylation of H3K27, although important non-canonical roles have recently been described. EZH2 mutation or deregulated expression has been conclusively demonstrated in the pathogenesis of AML and response to treatment, thus making it an attractive therapeutic target. In this study, we therefore investigated whether inhibition of EZH2 might also improve the response of non-APL AML cells to ATRA-based therapy. We focused on GSK-343, a pyridone-containing S-adenosyl-L-methionine cofactor-competitive EZH2 inhibitor that is representative of its class, and HKMTI-1-005, a substrate-competitive dual inhibitor targeting EZH2 and the closely related G9A/GLP H3K9 methyltransferases. We found that treatment with HKMTI-1-005 phenocopied EZH2 knockdown and was more effective in inducing differentiation than GSK-343, despite the efficacy of GSK-343 in terms of abolishing H3K27 trimethylation. Furthermore, transcriptomic analysis revealed that in contrast to treatment with GSK-343, HKMTI-1-005 upregulated the expression of differentiation pathway genes with and without ATRA, while downregulating genes associated with a hematopoietic stem cell phenotype. These results pointed to a non-canonical role for EZH2, which was supported by the finding that EZH2 associates with the master regulator of myeloid differentiation, RARα, in an ATRA-dependent manner that was enhanced by HKMTI-1-005, possibly playing a role in co-regulator complex exchange during transcriptional activation. In summary, our results strongly suggest that addition of HKMTI-1-005 to ATRA is a new therapeutic approach against AML that warrants further investigation.

Effects of different exercise intensity on bone mineral density in adults: a comparative systematic review and meta-analysis.

PURPOSE: The primary objective of the present systematic review and meta-analysis was to determine the effect of differing exercise intensity on (areal) bone mineral density (BMD) at lumbar spine and hip in adults by a comparative meta-analysis. METHODS: A systematic review of the literature according to the PRISMA statement included: (a) exercise trials, (b) with ≥two study arms that compared different exercise intensities, (c) intervention ≥6 months, (d) BMD assessments at lumbar spine (LS) or hip. Five electronic databases were scanned without language restrictions up to July 2021. The present analysis of exercise intensity was conducted as a mixed-effect meta-analysis and applied "type of exercise" and "study duration" as moderator in subgroup analyses. Outcome measures were standardized mean differences (SMD) for BMD changes at the LS, and hip. RESULTS: Eleven exercise studies with 26 study arms were included. Although the effect of high-intensity exercise was more pronounced on LS-BMD (SMD: 0.19, 95%-CI: 0.61 to -0.23) and hip-ROI (0.17, 0.38 to -0.04), we did not observe significant differences between the groups (LS-BMD: p=0.373 and hip-BMD: p=0.109). We observed a substantial level of heterogeneity between the trials for LS- but not for hip-BMD. Applying "type of exercise" and "study duration" as moderators did not significantly modify the differences between low and high exercise intensity on BMD at LS or hip. CONCLUSION: There is insufficient evidence for a superior effect of high-intensity exercise on areal BMD at lumbar spine and hip in people aged 50 years and older. Varying exercise intensity with periods of lower exercise intensity intermitted by higher intensity might be a promising option to address the issue of exercise intensities in intervention studies.

Effects of dynamic resistance exercise on bone mineral density in postmenopausal women: a systematic review and meta-analysis with special emphasis on exercise parameters.

This systematic review and meta-analysis set out to determine the effect of dynamic resistance exercise (DRT) on areal bone mineral density (aBMD) in postmenopausal women and derive evidence-based recommendations for optimized training protocols. A systematic review of the literature according to the PRISMA statement included (a) controlled trials, (b) of isolated DRT with at least one exercise and one control group, (c) with intervention durations ≥ 6 months, (d) aBMD assessments at lumbar spine or proximal femur, (e) in cohorts of postmenopausal women. We searched eight electronic databases up to March 2019 without language restrictions. The meta-analysis was performed using a random-effects model. Standardized mean differences (SMD) for BMD changes at lumbar spine (LS), femoral neck (FN), and total hip (TH) were defined as outcome measures. Moderators of the exercise effects, i.e., "intervention length," "type of DRT," "training frequency," "exercise intensity," and "exercise volume," were addressed by sub-group analyses. The study was registered in the international prospective register of systematic reviews (PROSPERO) under ID: CRD42018095097. Seventeen articles with 20 exercise and 18 control groups were eligible. SMD average is 0.54 (95% CI 0.22-0.87) for LS-BMD, 0.22 (0.07-0.38) for FN-BMD, and 0.48 (0.22-0.75) for TH-BMD changes (all p ≤ 0.015). While sub-group analysis for FN-BMD revealed no differences within categories of moderators, lower training frequency (< 2 sessions/week) resulted in significantly higher BMD changes at LS and TH compared to higher training frequency (≥ 2 sessions/week). Additionally, free weight training was significantly superior to DRT devices for improving TH-BMD. This work provided further evidence for significant, albeit only low-moderate, effects of DRT on LS-, FN-, and TH-BMD. Unfortunately, sub-analysis results did not allow meaningful exercise recommendations to be derived. This systematic review and meta-analysis observed a significant low-moderate effect of dynamic resistance exercise on bone mineral density changes in postmenopausal women. However, sub-group analyses focusing on exercise characteristics found no results that enable the derivation of meaningful exercise recommendations in the area of exercise and osteoporosis prevention or therapy.

Longitudinal Changes in Muscle Mass and Function in Older Men at Increased Risk for Sarcopenia - The FrOST-Study.

BACKGROUND: Declines in muscle mass and function are inevitable developments of the advanced aging process. Corresponding dimensions of longitudinal changes in at-risk populations are still scarce although clinically relevant. The present study monitored changes in morphologic and functional sarcopenia criteria related to sarcopenia in older men with low muscle mass over a period of 24 months. OBJECTIVES: The main objective of the present study was to determine whether changes in muscle mass and function were comparable across the body. Our hypothesis was that both (1) fat free mass (FFM) and (2) function decline at a significantly higher rate in the lower versus the upper extremities. DESIGN: We conducted an observational study of 24 months. SETTING: Community dwelling men living in the area of Northern Bavaria were initially included in the Franconian Sarcopenic Obesity (FranSO) study by the Institute of Medical Physics University of Erlangen-Nürnberg, Germany. PARTICIPANTS: One hundred and seventy-seven (177) men (77.5±4.5 years) within the lowest skeletal muscle mass index (SMI) quartile of the FranSO study were included in the present 24 month analysis. MEASUREMENTS: Fat free mass (direct-segmental, multi-frequency Bio-Impedance-Analysis (DSM-BIA)), handgrip strength (hand-dynamometer) and 10-m habitual gait velocity (photo sensors) were assessed at baseline and 24-month follow-up. RESULTS: Lower extremity fat free mass (LEFFM: -2.0±2.4%), handgrip strength (-12.8±11.0%) and gait velocity (-3.5±9.0%) declined significantly (p<.001) during the follow-up period, while upper extremity FFM was maintained unchanged (UEFFM: 0.1±3.1%). Changes in LEFFM were significantly higher (p<.001) compared with UEFFM, however contrary to our expectation the decline in handgrip strength representing upper extremity muscle function was 3.7-fold higher (p<.001) than the decline in gait velocity. CONCLUSION: Medical experts involved in diagnosis, monitoring and management of sarcopenia should consider that parameters constituting morphologic and functional sarcopenia criteria feature different rates of decline during the aging process.

Exercise effects on bone mineral density in older men: a systematic review with special emphasis on study interventions.

This systematic review detected only limited positive effects of exercise on bone mineral density in older men. Further, based on the present literature, we were unable to suggest dedicated exercise prescriptions for this male cohort that might differ from recommendations based on studies with postmenopausal women. The primary aim of this systematic review was to determine the effect of exercise on bone mineral density (BMD) in healthy older men. A systematic review of the literature according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement included only randomized or non-randomized controlled trials of exercise training ≥ 6 months with study groups of ≥ eight healthy men aged 50 years or older, not using bone-relevant pharmacological therapy, that determined BMD by dual-energy X-ray absorptiometry. We searched PubMed, Scopus, Web of Science, Cochrane, Science Direct, and Eric up to November 2016. Risk of bias was assessed using the PEDro scale. We identified eight trials with 789 participants (PEDro-score, mean value 6 of 10) which satisfied our eligibility criteria. Studies vary considerably with respect to type and composition of exercise. Study interventions of six trials were considered to be appropriate for successfully addressing BMD in this cohort. Between-group differences were not or not consistently reported by three studies. Three studies reported significant exercise effects on BMD for proximal femur; one of them determined significant differences between the exercise groups. None of the exercise trials determined significant BMD effects at the lumbar spine. Based on the present studies, there is only limited evidence for a favorable effect of exercise on BMD in men. More well-designed and sophisticated studies on BMD in healthy older men have to address this topic. Further, there is a need to define intervention quality standards and implement a universal scoring system that allows this pivotal determinant to be addressed much more intensively.

Prevalence of sarcopenia and sarcopenic obesity in older German men using recognized definitions: high accordance but low overlap!

The relevance of sarcopenia and sarcopenic Obesity (SO) is rising in our aging societies. Applying recognized definitions to 965 community-dwelling Bavarian men 70 years+ resulted in a prevalence for sarcopenia between 3.7 and 4.9 and between 2.1 and 4.1% for SO. Despite this high consistency, the overlap between the definitions/approaches was <50%. INTRODUCTION: The relevance of sarcopenia and sarcopenic obesity (SO) is rising steadily in the aging societies of most developed nations. However, different definitions, components, and cutoff points hinder the evaluation of the prevalence of sarcopenia and SO. The purpose of this contribution was to determine the prevalence of sarcopenia and SO in a cohort of community-dwelling German men 70+ applying established sarcopenia (European Working Group on Sarcopenia in Older People, Foundation National Institute of Health, International Working Group on Sarcopenia) and obesity definitions. Further, we addressed the overlap between the definitions. METHODS: Altogether, 965 community-dwelling men 70 years and older living in Northern Bavaria, Germany, were assessed during the screening phase of the Franconian Sarcopenic Obesity project. Segmental multi-frequency bio-impedance analysis (BIA) was applied to determine weight and body composition. RESULTS: Applying the definitions of EWGSOP, IWGS, and FNIH, 4.9, 3.8, and 3.7% of the total cohort were classified as sarcopenic, respectively. When further applying body fat to diagnose obesity, SO prevalence in the total cohort ranged from 4.1% (EWGSOP + body fat >25%) to 2.1% (IWGS + body fat >30%). Despite the apparently high consistency of the approaches with respect to prevalence, the overlap in individual sarcopenia diagnosis between the sarcopenia definitions was rather low (<50%). CONCLUSION: The prevalence of sarcopenia and SO in community-dwelling German men 70 years+ is relatively low (<5%) independently of the definition used. However, consistency of individual sarcopenia diagnosis varies considerably between the three definitions. Since sarcopenia is now recognized as an independent condition by the International Classification of Diseases, a mandatory definition must be stated. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT2857660.

Whole-body electromyostimulation to fight sarcopenic obesity in community-dwelling older women at risk. Resultsof the randomized controlled FORMOsA-sarcopenic obesity study.

The effect of whole body-electromyostimulation in community-dwelling women ≥70 with sarcopenic obesity was heterogeneous, with high effects on muscle mass, moderate effects on functional parameters, and minor effects on fat mass. Further, we failed to determine a supportive effect of additional protein-enriched dietary supplementation in this albeit predominately well-nourished group. INTRODUCTION: The aim of the study was to determine the effect of whole-body electromyostimulation (WB-EMS) on sarcopenic obesity (SO) in community-dwelling women more than 70 years with sarcopenic obesity. METHODS: Seventy-five community-dwelling women ≥70 years with SO were randomly allocated to either a WB-EMS-application with (WB-EMS &P; 24.9 ± 1.9 kg/m2) or without (WB-EMS; 25.2 ± 1.8 kg/m2) dietary supplementation (150 kcal/day, 56 % protein) or a non-training control group (CG; 24.7 ± 1.4 kg/m2). WB-EMS consisted of one weekly session of 20 min (85 Hz, 350 µs, 4 s of strain-4 s of rest) performed with moderate to high intensity. Primary study endpoint was the Sarcopenia Z-Score constituted by skeletal muscle mass index (SMI, as assessed by dual energy X-ray absorptiometry), grip strength, and gait speed, and secondary study endpoint was body fat (%). RESULTS: Sarcopenia Z-score comparably increases in the WB-EMS and the WB-EMS&P-group (p ≤ .046). Both groups differ significantly (p ≤ .001) from the CG which deteriorated significantly (p = .006). Although body fat changes were most pronounced in the WB-EMS (-0.9 ± 2.1; p = .125) and WB-EMS&P (-1.4 ± 2.5; p = .028), reductions did not statistically differ (p = .746) from the CG (-0.8 ± 2.7; p = .179). Looking behind the covariates, the most prominent changes were determined for SMI, with a significant increase in both EMS-groups (2.0-2.5 %; p ≤ .003) and a decrease in the CG (-1.2 ± 3.1 %; p = .050) with significant between-group differences (p = .001). CONCLUSION: WB-EMS is a safe and attractive method for increasing muscle mass and functional capacity in this cohort of women 70+ with SO; however, the effect on body fat is minor. Protein-enriched supplements did not increase effects of WB-EMS alone.

Prevalence of sarcopenic obesity in Germany using established definitions: Baseline data of the FORMOsA study.

UNLABELLED: The prevalence of sarcopenic obesity in community-dwelling women 70 years and older according to established sarcopenia and obesity definitions averaged between 0 and 2.3 % and can thus be considered as relatively low. However, the converse argument that sarcopenic obesity was incompatible with an independent life cannot be confirmed. INTRODUCTION: The primary aim of the study was to determine the prevalence of sarcopenic obesity (SO) in community-dwelling (CD) older females in Germany. The secondary aim was to assess whether these females really live independently and autonomously. METHODS: A total of 1325 CD females 70 years and older living in the area of Erlangen-Nürnberg, Germany were assessed. Sarcopenia as defined by (a) the European Working Group on Sarcopenia in older people (EWGSOP) and (b) the International working group on Sarcopenia (IWGS) combined with obesity defined as (a) BMI ≥ 30 kg/m(2) (NIH) or (b) body-fat ≥ 35 % (WHO) was determined. In participants with SO, Barthel Index, care level and social network were retrospectively evaluated via personal interview. RESULTS: Based on anthropometric data, family, education and social status, lifestyle, number and distribution of diseases and medication, the present cohort is representative for the corresponding German population. Sarcopenia prevalence was 4.5 % according to EWGSOP and 3.3 % according to the IWGS criteria. Obesity prevalence in our cohort averaged 19.8 % (BMI, NIH) and 63.8 % (body fat, WHO). The overlap between both factors (i.e. SO) ranged from 0 % (EWGSOP + NIH criteria) to 2.3 % (EWGSOP + WHO criteria). Factors that may represent limited autonomy or independence were very rarely identified in this SO cohort. CONCLUSION: The prevalence of sarcopenic obesity in the CD (female) German population 70 years + is relatively low. With respect to our second research aim, the hypothesis that SO was incompatible with independent life was rejected. However, the latter finding should be addressed with more dedicated study designs.

Exercise and fractures in postmenopausal women. Final results of the controlled Erlangen Fitness and Osteoporosis Prevention Study (EFOPS).

UNLABELLED: The EFOPS trial clearly established the positive effect of long-term exercise on clinical low-trauma fractures in postmenopausal women at risk. Bearing in mind that the complex anti-fracture exercise protocols also affect a large variety of diseases of increased age, we strongly encourage older adults to perform multipurpose exercise programs. INTRODUCTION: Physical exercise may be an efficient option for autonomous fracture prevention during increasing age. The aim of the study was to evaluate the effect of exercise on clinical overall fracture incidence and bone mineral density (BMD) in elderly subjects at risk. METHODS: In 1998 initially, 137 early-postmenopausal, osteopenic women living in Erlangen-Nuremberg, Germany, were included in the EFOPS trial. Subjects of the exercise group (EG; n = 86) conducted two supervised group and two home exercise sessions/week while the control group (CG; n = 51) was requested to maintain their physical activity. Primary study endpoints were clinical overall low-trauma fractures determined by questionnaires, structured interviews, and BMD at the lumbar spine and femoral neck assessed by dual-energy X-ray absorptiometry. RESULTS: In 2014, 105 subjects (EG: n = 59 vs. CG: n = 46) representing 1680 participant-years were included in the 16-year follow-up analysis. Risk ratio in the EG for overall low-trauma fractures was 0.51 (95% confidence interval (95% CI) 0.23 to 0.97, p = .046), rate ratio was 0.42 (95% CI 0.20 to 0.86, p = .018). Based on comparable baseline values, lumbar spine (MV -1.5%, 95% CI -0.1 to -2.8 vs. -5.8%, -3.3 to -7.2%) and femoral neck (-6.5%, -5.2 to -7.7 vs. -9.6%, -8.2 to 11.1%) BMD decreased in both groups; however, the reduction was more pronounced in the CG (p ≤ .001). CONCLUSION: This study clearly evidenced the high anti-fracture efficiency of multipurpose exercise programs. Considering furthermore the favorable effect of exercise on most other risk factors of increasing age, we strongly encourage older adults to perform multipurpose exercise programs.

[High versus moderate intense running exercise - effects on cardiometabolic risk-factors in untrained males]. / Hoch- versus moderat-intensive Laufbelastung - Einfluss auf kardio-metabolische Risikogrößen bei untrainierten Männern.

Introduction | The philosophy on how to improve cardiometabolic risk factors most efficiently by endurance exercise is still controversial. To determine the effect of high-intensity (interval) training (HI[I]T) vs. moderate-intensity continuous exercise (MICE) training on cardiometabolic risk factors we conducted a 16-week crossover randomized controlled trial. Methods | 81 healthy untrained middle aged men were randomly assigned to a HI(I)T-group and a control-group that started the MICE running program after their control status. HI(I)T consisted of running exercise around or above the individual anaerobic threshold (≈ 80- 100 % HRmax); MICE focused on continuous running exercise at ≈ 65-77.5 % HRmax. Both protocols were comparable with respect to energy consumption. Study endpoints were cardiorespiratory fitness (VO2max), left ventricular mass index (LVMI), metabolic syndrome Z-score (MetS-Z-score), intima-media-thickness (IMT) and body composition. Results | VO2max-changes in this overweighed male cohort significantly (p=0.002) differ between HIIT (14.7 ± 9.3 %, p=0.001) and MICE (7.9 ± 7.4 %,p=0.001). LVMI, as determined via magnetic resonance imaging, significantly increased in both exercise groups (HIIT: 8.5 ± 5.4 %, p=0.001 vs. MICE: 5.3 ± 4.0 %, p=0.001), however the change was significantly more pronounced (p=0.005) in the HIIT-group. MetS-Z-score (HIIT: -2.06 ± 1.31, p=0.001 vs. MICE: -1.60 ± 1.77, p=0.001) and IMT (4.6 ± 5.9 % p=0.011 vs. 4.4 ± 8.1 %, p=0.019) did not show significant group-differences. Reductions of fat mass (-4.9 ± 9.0 %, p=0.010 vs. -9.5 ± 9.4, p=0.001) were significantly higher among the MICE-participants (p=0.034), however, the same was true (p=0.008) for lean body mass (0.5 ± 2.3 %, p=0.381 vs. -1.3 ± 2.0 %, p=0.003). Conclusion | In summary high-intensity interval training tends to impact cardiometabolic health more favorable compared with a moderate-intensity continuous endurance exercise protocol.

Peak-bone-mass development in young adults: effects of study program related levels of occupational and leisure time physical activity and exercise. A prospective 5-year study.

SUMMARY: Young adulthood is characterized by profound life-style changes. This study suggests that reduction of sport or exercise, induced by alteration of the occupational situation, negatively impacts generation/maintenance of peak bone mass. In order to compensate occupational-related reductions of physical activity, workplace exercise programs will be helpful. INTRODUCTION: Only few studies have determined the effect of physical activity or physical exercise on bone mineral density (BMD) in the period of late skeletal maturation, i.e. around peak bone mass. The aim of this article was to determine the long-term effect of different levels of physical activity and exercise directly and indirectly derived by occupation during young adulthood. METHODS: Sixty-one male and female dental students (DES) and 53 male and female sport students (SPS) 21±2 years old were accompanied over the course (4.8±0.5 years) of their study program. BMD at the lumbar spine (LS), hip, and whole body (WB) were determined using dual-energy X-ray absorptiometry. RESULTS: Parameters of physical activity increased non-significantly in both groups with no relevant differences between the groups. Indices of exercise, however, increased significantly in the SPS group while a significant decrease was assessed for the DES group. Independent of gender, BMD of the SPS increased significantly (p≤0.007) at all skeletal sites (LS, 2.4±3.9%; hip, 1.6±3.5%; WB, 1.8±2.8%) while BMD of the DES remained unchanged at LS (-0.6±4.4%, p=0.432) and WB (0.5±1.9%, p=0.092) but decreased significantly at the hip (-1.9±4.3%, p=0.010). BMD-changes at LS, hip, and WB differ significantly between SPS and DES (p≤0.017). Results remained unchanged after adjusting for baseline BMD-values that differed (p=0.030 to p=0.082) in favor of the SPS group. CONCLUSION: Changes of exercise levels directly or indirectly caused by occupational factors during young adulthood significantly affected generation and/or maintenance of peak bone mass. Compensatory exercise is thus highly relevant for bone health of young adults.

Comparison of three models for sepsis patient discrimination according to PIRO: predisposition, infection, response and organ dysfunction.

BACKGROUND: Sepsis remains one of the most challenging burdens of critically ill patients. But for interventional studies significant heterogeneity remains in classifying patients. PIRO (Predisposition, Response, Infection and Organ dysfunction) has been introduced as innovative option for improved patient characterization. Aim of this study was to evaluate precision to predict hospital mortality of three different proposed PIRO classification systems. METHODS: Data were prospectively obtained data in five ICUs in a university hospital in Berlin, Germany including adult patients with sepsis. Three different scoring systems were compared using patient characteristics to classify the population according to all cause hospital mortality risk (Moreno- PIRO, Rubulotta- PIRO and Howell-PIRO). RESULTS: Two-hundred-seventy-eight sepsis patients were included and reclassified using different PIRO models. All cause hospital mortality was 16.2%. Hospital mortality increased with higher PIRO scores with odds ratios of 1.070 (95% CI 1.041-1.100) for Moreno-PIRO, 1.282 (95% CI 1.079-1.524) for Rubulotta-PIRO and 1.256 (95% CI 1.146-1.367) for Howell-PIRO. Area under the curves for Moreno-PIRO was 0.743 (95% CI: 0.687-0.793), for Rubulotta-PIRO 0.646 (95% CI: 0.587-0.702) and for Howell-PIRO 0.751 (95% CI: 0.696-0.801). Moreno-PIRO and Howell-PIRO were statistically different compared with Rubulotta-PIRO (P=0.046 and P=0.035). CONCLUSION: Proposed PIRO classifications demonstrated slight differences between models without prioritization of one approach and all seemed feasible for patient classification. Future PIRO-development is needed to straighten predisposition, infection, and especially the response category.

Unlocking the potential of retinoic acid in anticancer therapy.

All-trans-retinoic acid (ATRA) is a physiologically active metabolite of vitamin A. Its antitumour activities have been extensively studied in a variety of model systems and clinical trials; however, to date the only malignancy responsive to ATRA treatment is acute promyelocytic leukaemia (APL) where it induces complete remission in the majority of cases when administered in combination with light chemotherapy and/or arsenic trioxide. After decades of studies, the efficacy of ATRA to treat other acute myeloid leukaemia (AML) subtypes and solid tumours remains poor. Recent studies directed to improve ATRA responsiveness in non-APL AML seem to indicate that the lack of effective ATRA response in these tumours may be primarily due to aberrant epigenetics, which negatively affect ATRA-regulated gene expression and its antileukaemic activity. Epigenetic reprogramming could potentially restore therapeutic effects of ATRA in all AML subtypes. This review discusses the current progresses in the understanding how ATRA can be utilised in the therapy of non-APL AML and other cancers.

Dose-response effect of exercise frequency on bone mineral density in post-menopausal, osteopenic women.

The purpose of this study was to determine the long-term dose-response relationship of exercise frequency on areal bone mineral density (aBMD) in early post-menopausal women with osteopenia. Based on the 12-year results of the consequently supervised exercise group (EG) of the Erlangen Fitness and Osteoporosis Prevention Study, we retrospectively structured two exercise groups according to the overall exercise frequency. Changes in aBMD at lumbar spine and proximal femur as assessed by dual-energy x-ray absorptiometry technique were compared between a low-frequency exercise group (LEF-EG, n = 16) with 1.5-<2 sessions/week and a high-frequency exercise group (HEF-EG, n = 25) with ≥ 2-3.5 sessions/week. Changes in aBMD at the lumbar spine and proximal femur were significantly more favorable in the HEF-EG compared with the LEF-EG; lumbar spine: (mean value ± standard deviation) 1.1 ± 4.7% vs -4.1 ± 3.0%; P = 0.001, ES: d' = 1.26; total hip: -4.4 ± 3.9% vs -6.7 ± 3.5%, P = 0.045, ES: d' = 0.70). BMD results of the LEF-EG did not significantly differ from the data of the non-training control group (lumbar spine: -4.4 ± 5.2%, total hip: -6.9 ± 5.0%). Although this result might not be generalizable across all exercise types and cohorts, it indicates that to impact bone, an overall exercise frequency of at least 2 sessions/week may be crucial, even if exercise is applied with high intensity/impact.

Effects of exercise on fracture reduction in older adults: a systematic review and meta-analysis.

UNLABELLED: In this meta-analysis, we evaluated the effect of exercise on fracture reduction in the elderly. Our results determined a significantly positive effect on overall fractures, whereas the possibility of a publication bias indicates the need for well-designed (multi-center) trials that generate enough power to focus on osteoporotic fractures. INTRODUCTION: The preventive effect of exercise on fracture incidence has not been clearly determined yet. Thus, the purpose of this study is to evaluate the effectiveness of exercise in preventing overall and vertebral fractures in older adults by meta-analyses technique. METHODS: This study followed the PRISMA recommendations for systematic reviews and meta-analyses. A systematic review of English articles between 1980 and March 2012 was performed. Terms used were: "exercise", "fractures", "bone", "falls", "osteoporosis", "BMD", "BMC", "bone turnover", while the search was limited to "clinical trial" and "humans". Controlled exercise trials that reported fracture number as endpoint or observation in subjects 45 years and older were included. RESULTS: Ten controlled exercise trials that reported overall fractures and three exercise trials that reported vertebral fractures met our inclusion criteria. Overall fracture number in the exercise group was 36 (n = 754) compared with 73 fractures in the CG (n = 670) (relative risk [RR] = 0.49; 95 % confidence interval [CI], 0.31-0.76). No significant heterogeneity of trial results (p = 0.28; I (2) = 17) was determined; however, there was some evidence to suggest a publication bias. The overall RR for vertebral fracture number (0.56; 95 % CI, 0.30-1.04) (EG: 19 fractures/103 subjects vs. CG: 31 fractures/102 subjects) was borderline non-significant while the heterogeneity of trial results also cannot be ruled out. CONCLUSION: Although there is evidence that exercise reduces overall and, to a lesser degree, vertebral fractures in the elderly, the possibility of publication bias weakens our result and demonstrates the imperative for large exercise studies with dedicated exercise protocols that focus on fractures as a primary endpoint.

Effect of block-periodized exercise training on bone and coronary heart disease risk factors in early post-menopausal women: a randomized controlled study.

The purpose of this 12 month randomized exercise intervention was to determine the effect of a block-periodized multipurpose exercise program on bone mineral density (BMD) and parameters of the metabolic syndrome (MetS) in early post-menopausal women. Eighty-five subjects (52.3 ± 2.4 years) living in the area of Erlangen (Germany) were randomly assigned into an exercise (EG, n=43) or a wellness-control group (CG: n=42). The EG performed a periodized multipurpose exercise program with 4-6-week blocks of high-intensity bone-specific exercise intermitted by 10-12 weeks of exercise dedicated to increase endurance and reduce cardiac and metabolic risk factors. The CG performed a low-volume/low-intensity "wellness" program to increase well-being. After 12 months, significant exercise effects were observed for the lumbar spine (LS) BMD as assessed by quantitative computed tomography [total BMD (EG: -0.3 ± 2.1% vs CG: -2.1 ± 2.2%, P=0.015); trabecular BMD (EG: -0.7 ± 3.4% vs CG: -4.7 ± 4.9%, P=0.001) and dual-energy x-ray absorptiometry (DXA) (EG: -0.1 ± 2.2% vs CG: -2.0 ± 2.0%, P=0.002)]. However, no significant effects were observed for total hip BMD as assessed by DXA (P=0.152). Although all MetS parameters were favorably affected among the EG, only the effect for waist circumference was significant. In summary, short periods of bone-specific intervention embedded in longer periods of exercises dedicated to improve cardiovascular and metabolic risk factors positively affected BMD at the LS.

Exercise and fractures in postmenopausal women: 12-year results of the Erlangen Fitness and Osteoporosis Prevention Study (EFOPS).

UNLABELLED: This trial is the first exercise study that focuses on fracture incidence as a primary study endpoint. Although we marginally failed to determine significant effects on "overall" fracture risk (p = .074) or rate ratio (p = .095), our findings further increased the evidence that exercise relevantly prevents fractures in the elderly. INTRODUCTION: The purpose of this study is to determine the effect of strictly supervised long-term exercise training on "overall" fracture incidence and bone mineral density (BMD) in postmenopausal osteopenic women. METHODS: Eighty-five early postmenopausal (1-8 years), osteopenic women living in the area of Erlangen-Nuremberg, Germany without any medication or diseases affecting bone metabolism were assessed after 12 years of supervised exercise (EG) or unvarying lifestyle (control, CG). Exercisers were encouraged to perform two group sessions/week and two home training sessions/week. Calcium and vitamin D supplementation was provided for both groups. "Overall" fractures were determined by questionnaires and structured interviews. The BMD was assessed at lumbar spine and proximal femur by dual-energy X-ray absorptiometry. RESULTS: "Overall" fracture risk ratio in the EG was 0.32 (95% confidence interval (CI), 0.08 to 1.05; p = .074), and the rate ratio for "overall" fractures was 0.38 (95% CI, 0.11 to 1.15; p = .095). BMD changes at lumbar spine (EG, -0.8%; 95% CI, 0.8% to -2.7% vs. CG, -4.0%; 95% CI, -2.4% to -5.7%; p = .011) and femoral neck (EG, -3.7%; 95% CI, -2.4% to -5.0% vs. CG, -6.7%; 95% CI, -5.3% to -8.2%; p = .003) significantly differed between both groups. CONCLUSION: Although we marginally failed to determine significant effects on overall fracture risk or rate ratio, our study increased the body of evidence for the fracture prevention efficiency of exercise programs, with special regard on bone strength (as assessed by bone mineral density measurement). Future studies should focus on subjects more prone to fractures to generate enough statistical power to clearly determine this issue.