Investigating Stability in Subgroup Identification for Stratified Medicine.

Subgroup analysis may be used to investigate treatment effect heterogeneity among subsets of the study population defined by baseline characteristics. Several methodologies have been proposed in recent years and with these, statistical issues such as multiplicity, complexity, and selection bias have been widely discussed. Some methods adjust for one or more of these issues; however, few of them discuss or consider the stability of the subgroup assignments. We propose exploring the stability of subgroups as a sensitivity analysis step for stratified medicine to assess the robustness of the identified subgroups besides identifying possible factors that may drive this instability. After applying Bayesian credible subgroups, a nonparametric bootstrap can be used to assess stability at subgroup-level and patient-level. Our findings illustrate that when the treatment effect is small or not so evident, patients are more likely to switch to different subgroups (jumpers) across bootstrap resamples. In contrast, when the treatment effect is large or extremely convincing, patients generally remain in the same subgroup. While the proposed subgroup stability method is illustrated through Bayesian credible subgroups method on time-to-event data, this general approach can be used with other subgroup identification methods and endpoints.

CRISPR-Cas12a nucleases function with structurally engineered crRNAs: SynThetic trAcrRNA.

CRISPR-Cas12a systems are becoming an attractive genome editing tool for cell engineering due to their broader editing capabilities compared to CRISPR-Cas9 counterparts. As opposed to Cas9, the Cas12a endonucleases are characterized by a lack of trans-activating crRNA (tracrRNA), which reduces the complexity of the editing system and simultaneously makes CRISPR RNA (crRNA) engineering a promising approach toward further improving and modulating editing activity of the CRISPR-Cas12a systems. Here, we design and validate sixteen types of structurally engineered Cas12a crRNAs targeting various immunologically relevant loci in-vitro and in-cellulo. We show that all our structural modifications in the loop region, ranging from engineered breaks (STAR-crRNAs) to large gaps (Gap-crRNAs), as well as nucleotide substitutions, enable gene-cutting in the presence of various Cas12a nucleases. Moreover, we observe similar insertion rates of short HDR templates using the engineered crRNAs compared to the wild-type crRNAs, further demonstrating that the introduced modifications in the loop region led to comparable genome editing efficiencies. In conclusion, we show that Cas12a nucleases can broadly utilize structurally engineered crRNAs with breaks or gaps in the otherwise highly-conserved loop region, which could further facilitate a wide range of genome editing applications.

A perspective on the role of uncertainty in sustainability science and engineering.

The Trans-Atlantic Research and Development Interchange on Sustainability Workshop (TARDIS) is a meeting on scientific topics related to sustainability. The 2019 workshop theme was "On the Role of Uncertainty in Managing the Earth for Global Sustainability." This paper presents the perspectives on this topic derived from talks and discussions at the 2019 TARDIS workshop. There are four kinds of uncertainties encountered in sustainability ranging from clear enough futures to true surprises. The current state-of-the-art in assessing and mitigating these uncertainties is discussed.

Evidence that a deviation in the kynurenine pathway aggravates atherosclerotic disease in humans.

BACKGROUND: The metabolism of tryptophan (Trp) along the kynurenine pathway has been shown to carry strong immunoregulatory properties. Several experimental studies indicate that this pathway is a major regulator of vascular inflammation and influences atherogenesis. Knowledge of the role of this pathway in human atherosclerosis remains incomplete. OBJECTIVES: In this study, we performed a multiplatform analysis of tissue samples, in vitro and in vivo functional assays to elucidate the potential role of the kynurenine pathway in human atherosclerosis. METHODS AND RESULTS: Comparison of transcriptomic data from carotid plaques and control arteries revealed an upregulation of enzymes within the quinolinic branch of the kynurenine pathway in the disease state, whilst the branch leading to the formation of kynurenic acid (KynA) was downregulated. Further analyses indicated that local inflammatory responses are closely tied to the deviation of the kynurenine pathway in the vascular wall. Analysis of cerebrovascular symptomatic and asymptomatic carotid stenosis data showed that the downregulation of KynA branch enzymes and reduced KynA production were associated with an increased probability of patients to undergo surgery due to an unstable disease. In vitro, we showed that KynA-mediated signalling through aryl hydrocarbon receptor (AhR) is a major regulator of human macrophage activation. Using a mouse model of peritoneal inflammation, we showed that KynA inhibits leukocyte recruitment. CONCLUSIONS: We have found that a deviation in the kynurenine pathway is associated with an increased probability of developing symptomatic unstable atherosclerotic disease. Our study suggests that KynA-mediated signalling through AhR is an important mechanism involved in the regulation of vascular inflammation.

Boom boom pow: Shock-facilitated aqueous alteration and evidence for two shock events in the Martian nakhlite meteorites.

Nakhlite meteorites are ~1.4 to 1.3 Ga old igneous rocks, aqueously altered on Mars ~630 Ma ago. We test the theory that water-rock interaction was impact driven. Electron backscatter diffraction demonstrates that the meteorites Miller Range 03346 and Lafayette were heterogeneously deformed, leading to localized regions of brecciation, plastic deformation, and mechanical twinning of augite. Numerical modeling shows that the pattern of deformation is consistent with shock-generated compressive and tensile stresses. Mesostasis within shocked areas was aqueously altered to phyllosilicates, carbonates, and oxides, suggesting a genetic link between the two processes. We propose that an impact ~630 Ma ago simultaneously deformed the nakhlite parent rocks and generated liquid water by melting of permafrost. Ensuing water-rock interaction focused on shocked mesostasis with a high density of reactive sites. The nakhlite source location must have two spatially correlated craters, one ~630 Ma old and another, ejecting the meteorites, ~11 Ma ago.

A novel, blocking, Fc-silent anti-CD40 monoclonal antibody prolongs nonhuman primate renal allograft survival in the absence of B cell depletion.

CD40-CD154 pathway blockade prolongs renal allograft survival in nonhuman primates (NHPs). However, antibodies targeting CD154 were associated with an increased incidence of thromboembolic complications. Antibodies targeting CD40 prolong renal allograft survival in NHPs without thromboembolic events but with accompanying B cell depletion, raising the question of the relative contribution of B cell depletion to the efficacy of anti-CD40 blockade. Here, we investigated whether fully silencing Fc effector functions of an anti-CD40 antibody can still promote graft survival. The parent anti-CD40 monoclonal antibody HCD122 prolonged allograft survival in MHC-mismatched cynomolgus monkey renal allograft transplantation (52, 22, and 24 days) with accompanying B cell depletion. Fc-silencing yielded CFZ533, an antibody incapable of B cell depletion but still able to potently inhibit CD40 pathway activation. CFZ533 prolonged allograft survival and function up to a defined protocol endpoint of 98-100 days (100, 100, 100, 98, and 76 days) in the absence of B cell depletion and preservation of good histological graft morphology. CFZ533 was well-tolerated, with no evidence of thromboembolic events or CD40 pathway activation and suppressed a gene signature associated with acute rejection. Thus, use of the Fc-silent anti-CD40 antibody CFZ533 appears to be an attractive approach for preventing solid organ transplant rejection.

New ischaemic brain lesions in cervical artery dissection stratified to antiplatelets or anticoagulants.

BACKGROUND AND PURPOSE: To determine the frequency of new ischaemic or hemorrhagic brain lesions on early follow-up magnetic resonance imaging (MRI) in patients with cervical artery dissection (CAD) and to investigate the relationship with antithrombotic treatment. METHODS: This prospective observational study included consecutive CAD patients with ischaemic or non-ischaemic symptoms within the preceding 4 weeks. All patients had baseline brain MRI scans at the time of CAD diagnosis and follow-up MRI scans within 30 days thereafter. Ischaemic lesions were detected by diffusion-weighted imaging (DWI), intracerebral bleeds (ICBs) by paramagnetic-susceptible sequences. Outcome measures were any new DWI lesions or ICBs on follow-up MRI scans. Kaplan-Meier statistics and calculated odds ratios with 95% confidence intervals were used for lesion occurrence, baseline characteristics and type of antithrombotic treatment (antiplatelet versus anticoagulant). RESULTS: Sixty-eight of 74 (92%) CAD patients were eligible for analysis. Median (interquartile range) time interval between baseline and follow-up MRI scans was 5 (3-10) days. New DWI lesions occurred in 17 (25%) patients with a cumulative 30-day incidence of 41.3% (standard error 8.6%). Occurrence of new DWI lesions was associated with stroke or transient ischaemic attack at presentation [7.86 (2.01-30.93)], occlusion of the dissected vessel [4.09 (1.24-13.55)] and presence of DWI lesions on baseline MRI [6.67 (1.70-26.13)]. The type of antithrombotic treatment had no impact either on occurrence of new DWI lesions [1.00 (0.32-3.15)] or on functional 6-month outcome [1.27 (0.41-3.94)]. No new ICBs were observed. CONCLUSION: New ischaemic brain lesions occurred in a quarter of CAD patients, independently of the type of antithrombotic treatment. MRI findings could potentially serve as surrogate outcomes in pilot treatment trials.

Smoking alters circulating plasma microvesicle pattern and microRNA signatures.

Circulating plasma microvesicles (PMVs) and their microRNA content are involved in the development of atherosclerosis and could serve as biomarkers for cardiovascular disease (CVD) progression. However, little is known on how smoking influences the levels of PMVs and microRNA signatures in vivo. Therefore, we aimed to investigate the effects of smoking on circulating PMV levels and CVD-related PMV-derived microRNAs in young, healthy smokers. Twenty young (10 female, 10 male; 25 ± 4 years) healthy smokers (16 ± 6 cigarettes per day for 8 ± 4 years) and age- and sex-matched controls were included in this study. While complete blood count revealed no differences between both groups, smoking significantly enhanced intracellular reactive oxygen species in platelets and leukocytes as well as platelet-leukocyte aggregate formation. Total circulating PMV counts were significantly reduced in smokers, which could be attributed to decreased platelet-derived PMVs. While the number of endothelial PMVs remained unaffected, smoking propagated circulating leukocyte-derived PMVs. Despite reduced total PMVs, PMV-derived microRNA-profiling of six smoker/control pairs revealed a decrease of only a single microRNA, the major platelet-derived microRNA miR-223. Conversely, miR-29b, a microRNA associated with aortic aneurysm and fibrosis, and RNU6-2, a commonly used reference-RNA, were significantly up-regulated. Smoking leads to alterations in the circulating PMV profile and changes in the PMV-derived microRNA signature already in young, healthy adults. These changes may contribute to the development of smoking-related cardiovascular pathologies. Moreover, these smoking-related changes have to be considered when microRNA or PMV profiles are used as disease-specific biomarkers.

The joint contribution of tumor phenotype and education to breast cancer survival disparity between Hispanic and non-Hispanic white women.

Some studies suggest that Hispanic women are more likely to have ER- and triple-negative (ER-/PR-/HER2-) tumors and subsequently poorer prognosis than non-Hispanic white (NHW) women. In addition, only a handful of studies have examined period-specific effects of tumor phenotype and ethnicity on breast cancer survival, leaving the time-varying effects of hormonal status and ethnicity on breast cancer survival poorly defined. This study describes short and long-term breast cancer survival by ethnicity at 0-5 years and 5+ years post-diagnosis using data from the New Mexico Health, Eating, Activity, and Lifestyle cohort of Hispanic and NHW women ages 29-88 years newly diagnosed with stages I-IIIA breast cancer. The survival rate for Hispanics at 0-5 years was 82.2 % versus 94.3 % for NHW. Hispanics were more likely to have larger tumors, more advanced stage, and ER- phenotypes compared to NHW women. There was a significantly higher risk of breast cancer mortality in Hispanics over 5 years of follow-up compared to NHW (HR = 2.78, 95 % CI 1.39-5.56), adjusting for age, tumor phenotype, stage, and tumor size. This ethnic difference in survival, however, was attenuated and no longer statistically significant when additional adjustment was made for education, although a >1.5-fold increase in mortality was observed. In contrast, there was no difference between ethnic groups for survival after 5 years (HR = 1.08, 95 % CI 0.36-3.24). Our results indicate that the difference in survival between Hispanic and NHW women with breast cancer occurs in the first few years following diagnosis and is jointly associated with tumor phenotype and socio-demographic factors related to education.

[Chylothorax in an 87-year-old patient]. / Chylothorax bei einer 87-jährigen Patientin.

An 87-year-old woman presented with a left-sided pleural effusion. The milky aspirate fulfilled the criteria of a chylothorax. Thorax computed tomography (CT) showed characteristic multiple cysts and consequently the rare diagnosis of post-menopausal pulmonary lymphangioleiomyomatosis was made. In the diagnostic work-up of pleural effusion the determination of triglycerides should be considered to confirm the diagnosis of chylothorax. In the presence of a chylothorax the differential diagnosis of lymphangioleiomyomatosis should be included even in advanced age.

Zurich Fabry study - prevalence of Fabry disease in young patients with first cryptogenic ischaemic stroke or TIA.

BACKGROUND AND PURPOSE: The etiology of stroke in young patients remains undetermined in up to half of the cases. Data on prevalence of Fabry disease (FD) in young people with cryptogenic ischaemic stroke are limited and controversial. We aimed to evaluate the frequency of unrecognized FD in a cohort of stroke patients at a tertiary stroke center. METHODS: Patients suffering from first cryptogenic ischaemic stroke or transient ischaemic attack (TIA) at the age of 18-55 years were screened for the presence of FD. We measured the serum activity of α-galactosidase (α-GAL) in all patients. In addition, sequencing of α-GAL gene was performed in men with low enzyme activity and in all women. RESULTS: Between January, 2006, and October, 2009, we recruited 150 patients (102 men, 48 women) with a mean age of 43 ± 9 years at symptom onset (135 ischaemic stroke, 15 TIA). The α-GAL activity was low in nine patients (6%; six men and three women). Genetic sequencing in six men with low enzyme activity and all 48 women detected no α-GAL gene mutation. CONCLUSION: Our study suggests that the yield of screening for FD in patients with first cryptogenic ischaemic stroke or TIA is very low. Further large-scale studies are needed to investigate the importance of FD amongst patients with recurrent cryptogenic strokes.

[Upper leg amputation. Transfemoral amputation]. / Oberschenkelamputation. Transfemorale Amputation.

Objective. Amputation through the diaphysis of the femur at the most peripheral level possible. The stump, covered with soft tissue flaps, is free from pain. It can be fitted with a total contact prosthetic socket. The hip joint is preserved with its full range of motion.Indications. When no possibility to amputate at a more distal level through the tibia or the knee joint exists.Contraindications. When it is possible to amputate at a more distal level.Surgical technique. Symmetrical flaps in the frontal plane are recommended. Asymmetrical flaps and flaps in the sagittal plane can also be made. Their muscles are fixed to each other (myodesis) or the bone end by means of transosseous sutures (myopexy). The ischial nerve has to be shortened about 2 inches proximal to the end of the femur.In peripheral vascular diseases, this procedure is not suitable. An alternative technique is suggested.In chronic osteomyelitis (e.g., after intramedullary nailing), the ventral half of the femur can be removed and the medullary cavity cleansed and filled with a muscular flap in order to maintain length. Lengthening procedures of the femur are discussed.Postoperative management. Avoid active or passive movement of the stump for the first 2 weeks in order not to disturb healing of the muscle sutures. Physical therapy, prosthetic fitting after 4­6 weeks, according to the expected functional level 0­4. Aids: crutches, wheel chair, adjustable bed, modified hand-controlled automobile.The walking ability of a patient with a double amputation above the knee is severely limited and in patients with peripheral artery disease remains the exception.

[Transtibial amputation]. / Unterschenkelamputation.

OBJECTIVE: To make a transtibial stump as long as possible, free from local and phantom pain with a maximum of terminal load bearing. In order to preserve the knee joint, an ultra-short tibial stump of 5-6 cm may be indicated. INDICATIONS: A hindfoot amputation level is not possible to achieve. CONTRAINDICATIONS: In amputations for peripheral vascular diseases, amputations through the distal third of the tibia are not recommended. If they still heal, the level selection might have been too proximal. SURGICAL TECHNIQUE: According to Verduyn and Burgess, a long posterior muscular flap covering the stump is attached ventrally to a short anterior flap. Modifications: fibular bone bridge (Guedes), resection of the soleus muscle (Baumgartner), Myodesis (Bowker), and Brückner's procedure. Alternative: rotation plasty according to Borggreve-van Nes-Winkelmann. POSTOPERATIVE MANAGEMENT: Special diagonal elastic bandaging over the knee that must be changed daily. Early prosthetic fitting (in general after 4-6 weeks) after wound has healed. Physical therapy: gait training with 2 crutches or parallel bars with or without an inflatable "prosthesis". Isometric training of the quadriceps. A stump requires several months until it has achieved its final form. During this time, the prosthesis must be adjusted accordingly. Modifications in the home, workplace, and automobile must be made. Sport for the disabled! RESULTS: In order to preserve a maximum of stump length, wound healing problems are to be taken into consideration, requiring surgery and sometimes even reamputation through or above the knee joint. If it is possible to preserve the knee joint, the rehabilitation results, even with an ultra-short transtibial stump, are far superior to any more proximal amputation level.

[Forefoot and midfoot amputations]. / Amputationen an Vor- und Mittelfuß

OBJECTIVE: Partial foot amputations are feasible regardless of the causal condition, including peripheral vascular disease with a few exceptions. Compared to higher amputation levels, a good foot stump permits full end bearing and enables the patient, even with a hindfoot stump, to walk without the need for a prosthesis. The more peripheral the amputation level selected, the greater the need for gentle tissue handling and meticulous postoperative care, but also the greater the risk of a breakdown requiring stump revision surgery. In the forefoot, partial amputation of the metatarsals preserves the length of the stump and, thus, minimizes the loss of weight-bearing surface. The resection of metatarsal and midfoot bones without removing the toes, called a "hidden" amputation, is more acceptable to the patient who does not feel as if he/she has become an amputee. In addition, no neuroma or phantom pain is experienced. Biomechanically, this amputation hardly differs from a classical amputation. INDICATIONS: Amputation cannot be avoided by any conservative or operative means. CONTRAINDICATIONS: Absolute: rapidly progressing peripheral arterial diseases, i.e., Buerger-Winiwarter's disease. Relative: renal failures requiring dialysis or kidney transplantation. SURGICAL TECHNIQUE: Patient in prone position, keep foot and calf free, protect heel from pressure. Mark the skin incisions. A long plantar flap covers the bones and is sutured to the short dorsal flap at the dorsum of the foot. Begin with the dorsal incision down to the bones. After separating the bones, turn the distal part down and separate the plantar soft tissue flap. The bones are well aligned and shaped. Longitudinal amputations preserve a larger load-bearing surface and, therefore, are preferred, if possible. Another alternative is the "hidden" amputation. Except for amputations in peripheral vascular diseases, the digits and their neurovascular supplies are preserved. Only the bones are resected, from transmetatarsal to Chopart. The toes will retract within a few weeks. The patients do not feel as if she/he has become an amputee, although the biomechanics of the foot are about the same as after a total amputation. In case of infection, wound debridement, open wound treatment, and delayed primary closure are recommended. POSTOPERATIVE MANAGEMENT: Full plantar weight bearing in plaster cast or walker is possible 4-6 weeks after surgery. In the case of diabetic foot, healing can require weeks. Total contact prosthesis without limiting the range of motion (ROM) of the ankle and the subtalar joint after 6 weeks. Best results are obtained with prostheses using the silicone technique. Alternative: orthopedic footwear. RESULTS: It is desirable to maintain the greatest length possible; wound healing disorders are observed in over half of all cases. Operative stump corrections are justified in 20-30%; a transtibial amputation is seldom necessary.

[Knee disarticulation and through-knee amputation]. / Knieexartikulation und transgenikuläre Amputation.

OBJECTIVE: A knee disarticulation or a through-knee stump is superior compared to a transfemoral stump. The thigh muscles are all preserved, and the muscle balance remains undisturbed. The range of motion of the hip joint is not limited. The bulbous shape of the stump allows full weight bearing at the stump end and can easily be fitted with a prosthesis. An amputee with a bilateral knee disarticulation is able to walk "barefoot". INDICATIONS: A more distal amputation level, e.g., an ultra-short transtibial amputation, is not possible. Important alternative to transfemoral amputations. Possible for any etiology except for Buerger-Winiwarter's disease. New indications are infected and loosened total knee replacements. CONTRAINDICATIONS: Preservation of the knee joint is possible. SURGICAL TECHNIQUE: Knee disarticulation is a very atraumatic procedure, compared to transfemoral amputations. Neither bones nor muscles have to be severed, just skin, ligaments, vessels, and nerves. Even the meniscal cartilages may be left in place to act as axial shock absorbers. The cartilage of the femur is not resected, but only bevelled in case of osteoarthritis. There are no tendon attachments or myoplastic procedures necessary. The patella remains in place and is held in position only by the retinacula. Skin closure must be performed without the slightest tension, and if possible not in the weight-bearing area. Transcondylar amputations across the femoral condyles only are indicated when there are not sufficient soft tissues for wound closure of a knee disarticulation. Alternatives as the techniques of Gritti, Klaes, and Eigler, the shortening of the femur and the Sauerbruch's rotation plasty [14] are presented and discussed. POSTOPERATIVE MANAGEMENT: The risk of decubital ulcers is rather high. Correct bandaging of the stump is, therefore, particularly important. Prosthetic fitting is possible 3-6 weeks after surgery. The type of prosthesis depends on the amputee's activity level. RESULTS: The superior performance of amputees with knee disarticulations in sports prove the superiority of that amputation level compared to transfemoral amputees. However, because less than 5% of amputations are knee disarticulations, statements about statistical significance cannot be made. On the other hand, one should do everything to preserve an ultra-short transtibial stump.

Outcome of intravenous thrombolysis in stroke patients weighing over 100 kg.

BACKGROUND: Intravenous thrombolysis with alteplase for ischemic stroke is fixed at a maximal dose of 90 mg for safety reasons. Little is known about the clinical outcomes of stroke patients weighing >100 kg, who may benefit less from thrombolysis due to this dose limitation. METHODS: Prospective data on 1,479 consecutive stroke patients treated with intravenous alteplase in six Swiss stroke units were analyzed. Presenting characteristics and the frequency of favorable outcomes, defined as a modified Rankin scale (mRS) score of 0 or 1, a good outcome (mRS score 0-2), mortality and symptomatic intracranial hemorrhage (SICH) were compared between patients weighing >100 kg and those weighing ≤100 kg. RESULTS: Compared to their counterparts (n = 1,384, mean body weight 73 kg), patients weighing >100 kg (n = 95, mean body weight 108 kg) were younger (61 vs. 67 years, p < 0.001), were more frequently males (83 vs. 60%, p < 0.001) and more frequently suffered from diabetes mellitus (30 vs. 13%, p < 0.001). As compared with patients weighing ≤100 kg, patients weighing >100 kg had similar rates of favorable outcomes (45 vs. 48%, p = 0.656), good outcomes (58 vs. 64%, p = 0.270) and mortality (17 vs. 12%, p = 0.196), and SICH risk (1 vs. 5%, p = 0.182). After multivariable adjustment, body weight >100 kg was strongly associated with mortality (p = 0.007) and poor outcome (p = 0.007). CONCLUSION: Our data do not suggest a reduced likehood of favorable outcomes in patients weighing >100 kg treated with the current dose regimen. The association of body weight >100 kg with mortality and poor outcome, however, demands further large-scale studies to replicate our findings and to explore the underlying mechanisms.

IV thrombolysis and statins.

OBJECTIVE: To examine whether prior statin use affects outcome and intracranial hemorrhage (ICH) rates in stroke patients receiving IV thrombolysis (IVT). METHODS: In a pooled observational study of 11 IVT databases, we compared outcomes between statin users and nonusers. Outcome measures were excellent 3-month outcome (modified Rankin scale 0-1) and ICH in 3 categories. We distinguished all ICHs (ICH(all)), symptomatic ICH based on the criteria of the ECASS-II trial (SICH(ECASS-II)), and symptomatic ICH based on the criteria of the National Institute of Neurological Disorders and Stroke (NINDS) trial (SICH(NINDS)). Unadjusted and adjusted odds ratios (OR) with 95% confidence intervals were calculated. RESULTS: Among 4,012 IVT-treated patients, 918 (22.9%) were statin users. They were older, more often male, and more frequently had hypertension, hypercholesterolemia, diabetes, coronary heart disease, and concomitant antithrombotic use compared with nonusers. Fewer statin users (35.5%) than nonusers (39.7%) reached an excellent 3-month outcome (OR(unadjusted) 0.84 [0.72-0.98], p = 0.02). After adjustment for age, gender, blood pressure, time to thrombolysis, and stroke severity, the association was no longer significant (0.89 [0.74-1.06], p = 0.20). ICH occurred by trend more often in statin users (ICH(all) 20.1% vs 17.4%; SICH(NINDS) 9.2% vs 7.5%; SICH(ECASS-II) 6.9% vs 5.1%). This difference was statistically significant only for SICH(ECASS-II) (OR = 1.38 [1.02-1.87]). After adjustment for age, gender, blood pressure, use of antithrombotics, and stroke severity, the OR(adjusted) for each category of ICH (ICH(all) 1.15 [0.93-1.41]; SICH(ECASS-II) 1.32 [0.94-1.85]; SICH(NINDS) 1.16 [0.87-1.56]) showed no difference between statin users and nonusers. CONCLUSION: In stroke patients receiving IVT, prior statin use was neither an independent predictor of functional outcome nor ICH. It may be considered as an indicator of baseline characteristics that are associated with a less favorable course.

Advantages of dietary, exercise-related, and therapeutic interventions to prevent and treat sarcopenia in adult patients: an update.

Sarcopenia is the loss of skeletal muscle mass and function with aging. Although the term sarcopenia was first coined in 1989, its etiology is still poorly understood. Moreover, a consensus for defining sarcopenia continues to elude us. Sarcopenic changes in the muscle include losses in muscle fiber quantity and quality, alpha-motor neurons, protein synthesis rates, and anabolic and sex hormone production. Other factors include basal metabolic rate, increased protein dietary requirements, and chronic inflammation secondary to age-related changes in cytokines and oxidative stress. These changes lead to decreased overall physical functioning, increased frailty, falls risk, and ultimately the loss of independent living. Because the intertwining relationships of these factors are complex, effective treatment options are still under investigation. The published data on sarcopenia are vast, and this review is not intended to be exhaustive. The aim of this review is to provide an update on the current knowledge of the definition, etiology, consequences, and current clinical trials that may help address this pressing public health problem for our aging populations.

[Progressive dyspnoea in two patients with carcinoid syndrome]. / Progrediente Dyspnoe bei Karzinoidsyndrom.

In patients with carcinoid syndrome, there has always to be considered cardiac impairment. We report about two patients with hepatic and bone metastases of a neuroendocrine tumor of the midgut, who suffered from progressive dyspnea. This was caused in both cases by a right-to-left atrial shunt, in case 1 based on a patent foramen ovale (PFO), in case 2 based on a secundum atrial septal defect. Symptoms were significantly reduced by percutaneous closure of PFO and ASD, respectively. Right-to-left atrial shunt was facilitated by right-sided carcinoid induced endocardial fibrosis with the consequence of severe tricuspid regurgitation, leading to an increase of right atrial pressure.

The safety and efficacy of arformoterol and formoterol in COPD.

This study evaluated the safety and efficacy of arformoterol and formoterol over 6-months in subjects with COPD. In a multi-center, 6-month randomized, double-blind, double-dummy trial, subjects with COPD (mean FEV(1) 1.21 L, approximately 41.0% predicted) were randomized to receive either nebulized arformoterol (15 microg BID [n = 149][ARF 15], 25 microg BID [n = 147][ARF 25]), or racemic formoterol (12 microg BID [n = 147][FORM]) delivered by DPI. The proportion of subjects with any post-treatment adverse event for ARF 15, ARF 25 microg, and FORM was 67.8%, 76.2% and 66.7%, respectively, and those with at least one COPD exacerbation was 32.2%, 30.6%, and 22.4%, respectively. Pulmonary function improved for all treatment groups and was maintained throughout the study. Mean change from baseline at 6-months for ARF 15, ARF 25 and FORM in peak FEV(1) was 0.30L, and 0.34L, and 0.26L, respectively, in 24-hour trough FEV(1) was, 0.10L, 0.14L, and 0.09L, and in inspiratory capacity was, 0.20L, 0.37L, and 0.23L. Dyspnea, (mean Transition Dypsnea Index (TDI) focal score) improved in all treatment arms (ARF 15: 1.4, ARF 25: 1.5, and FORM: 1.4) at 6 months, as did rescue short-acting beta(2)-agonists use (mean range: -1.1 to -1.3 actuations/day) and ipratropium bromide (mean range: -0.3 to -0.8 actuations/day). Health status, measured by St George's Respiratory Questionnaire, improved from baseline at 6-months in all treatment groups (mean change: -3.7 to -6.8). In this 6-month study, arformoterol and formoterol were well-tolerated, and their use was associated with improvement in pulmonary function and health status in subjects with COPD with no apparent development of tolerance.