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author:("rogawski, A")
1.  Criteria for fairly allocating scarce health-care resources to genetic tests: which matter most? 
The use of genetic tests is expanding rapidly. Given limited health-care budgets throughout Europe and few national coverage decisions specifically for genetic tests, decisions about allocating scarce resources to genetic tests are frequently ad hoc and left to lower-level decision makers. This study assesses substantive ethical and economic criteria to prioritize genetic services in a reasonable and fair manner. Principles for allocating health-care resources can be classified into four categories: need-based allocation; maximizing total benefits; treating people equally; and promoting and rewarding social usefulness. In the face of scarcity, the degree of an individual's need for medical intervention is an important criterion. Also, different economic concepts of efficiency are of relevance in the theory and practice of prioritizing genetic tests. Equity concerns are most likely to be relevant in terms of avoiding undesirable inequities, which may also set boundaries to the use of efficiency as a prioritization criterion. The aim of promoting and rewarding social usefulness is unlikely to be relevant to the question of what priority a genetic test should have in clinical practice. Further work is needed to select an appropriate set of criteria; operationalize them; and assign weights before some kind of standardized priority information can be added to information sources for genetic services. Besides the substantive criteria, formal considerations like those pointed out in the framework of accountability for reasonableness need to be considered in decision making.
doi:10.1038/ejhg.2013.172
PMCID: PMC3865392  PMID: 23921536
health-care prioritization; genetic testing; costs and cost analysis; resource allocation; ethics
2.  Eliciting preferences for priority setting in genetic testing: a pilot study comparing best-worst scaling and discrete-choice experiments 
European Journal of Human Genetics  2013;21(11):1202-1208.
Given the increasing number of genetic tests available, decisions have to be made on how to allocate limited health-care resources to them. Different criteria have been proposed to guide priority setting. However, their relative importance is unclear. Discrete-choice experiments (DCEs) and best-worst scaling experiments (BWSs) are methods used to identify and weight various criteria that influence orders of priority. This study tests whether these preference eliciting techniques can be used for prioritising genetic tests and compares the empirical findings resulting from these two approaches. Pilot DCE and BWS questionnaires were developed for the same criteria: prevalence, severity, clinical utility, alternatives to genetic testing available, infrastructure for testing and care established, and urgency of care. Interview-style experiments were carried out among different genetics professionals (mainly clinical geneticists, researchers and biologists). A total of 31 respondents completed the DCE and 26 completed the BWS experiment. Weights for the levels of the six attributes were estimated by conditional logit models. Although the results derived from the DCE and BWS experiments differed in detail, we found similar valuation patterns in the DCE and BWS experiments. The respondents attached greatest value to tests with high clinical utility (defined by the availability of treatments that reduce mortality and morbidity) and to testing for highly prevalent conditions. The findings from this study exemplify how decision makers can use quantitative preference eliciting methods to measure aggregated preferences in order to prioritise alternative clinical interventions. Further research is necessary to confirm the survey results.
doi:10.1038/ejhg.2013.36
PMCID: PMC3798841  PMID: 23486538
resource allocation; priority setting; discrete-choice experiment; best-worst scaling; genetic testing
3.  Endoscopic lateral orbitotomy 
Acta Neurochirurgica  2014;156(10):1897-1900.
Background
Lateral orbitotomy can be minimalized using contemporary endoscopy.
Methods
Anatomy of the temporal fossa/orbital wall junction is described. The attachment of the temporal fascia is cut off from the orbital rim through a 1.5 cm skin incision in the lateral orbital wrinkle. The temporal muscle is detached from the bone to create a space for the telescope. An appropriate bone opening in the lateral orbital wall is created with the aid of neuronavigation to handle intraorbital pathology.
Conclusion
Endoscopic lateral orbitotomy is an original alternative to the microsurgical Krönlein approach and yields good functional and cosmetic results.
Electronic supplementary material
The online version of this article (doi:10.1007/s00701-014-2205-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s00701-014-2205-7
PMCID: PMC4166432  PMID: 25160850
Lateral orbitotomy; Endoscopy; Orbit
4.  Effects of the Racket Polar Moment of Inertia on Dominant Upper Limb Joint Moments during Tennis Serve 
PLoS ONE  2014;9(8):e104785.
This study examined the effect of the polar moment of inertia of a tennis racket on upper limb loading in the serve. Eight amateur competition tennis players performed two sets of 10 serves using two rackets identical in mass, position of center of mass and moments of inertia other than the polar moment of inertia (0.00152 vs 0.00197 kg.m2). An eight-camera motion analysis system collected the 3D trajectories of 16 markers, located on the thorax, upper limbs and racket, from which shoulder, elbow and wrist net joint moments and powers were computed using inverse dynamics. During the cocking phase, increased racket polar moment of inertia was associated with significant increases in the peak shoulder extension and abduction moments, as well the peak elbow extension, valgus and supination moments. During the forward swing phase, peak wrist extension and radial deviation moments significantly increased with polar moment of inertia. During the follow-through phase, the peak shoulder adduction, elbow pronation and wrist external rotation moments displayed a significant inverse relationship with polar moment of inertia. During the forward swing, the magnitudes of negative joint power at the elbow and wrist were significantly larger when players served using the racket with a higher polar moment of inertia. Although a larger polar of inertia allows players to better tolerate off-center impacts, it also appears to place additional loads on the upper extremity when serving and may therefore increase injury risk in tennis players.
doi:10.1371/journal.pone.0104785
PMCID: PMC4130553  PMID: 25117871
5.  Health Disparities in Mid-to-Late Life: The Role of Earlier Life Family and Neighborhood Socioeconomic Conditions 
Social science & medicine (1982)  2011;74(4):625-636.
The relationship between neighborhoods of residence in young adulthood and health in mid to late life in the United States are examined using the 1968-2005 waves of the Panel Study of Income Dynamics (PSID). The sample consists of persons who were aged 20-30 in 1968 and are followed for a period of 38 years (N=2,730). Four-level hierarchical random effects models of self-assessed general health status as a function of individual, family, and neighborhood factors are estimated. Using the original sampling design of the PSID, we analyze adult health trajectories of married couples and neighbors followed from young adulthood through elderly ages to assess the magnitudes of the possible causal effects of family and neighborhood characteristics in young adulthood on health in mid to late life. Estimates suggest disparities in neighborhood conditions in young adulthood account for one-quarter of the variation in mid-to-late-life health. Living in poor neighborhoods during young adulthood is strongly associated with negative health outcomes in later life. This result is robust even in the presence of a reasonably large amount of potential unobservable individual and family factors that may significantly affect both neighborhood of residence and subsequent health status. Racial differences in health status in mid to late life are also associated with family and neighborhood socioeconomic conditions earlier in life. Three quarters of the black-white gap in health status at ages over 55 can be accounted for by differences in childhood socioeconomic status and neighborhood and family factors in young adulthood.
doi:10.1016/j.socscimed.2011.10.021
PMCID: PMC4100798  PMID: 22212443
USA; self-assessed health; family; neighborhood effects; life course; racial & socioeconomic disparities; multilevel modeling
6.  The Laws of Natural Deduction in Inference by DNA Computer 
The Scientific World Journal  2014;2014:834237.
We present a DNA-based implementation of reaction system with molecules encoding elements of the propositional logic, that is, propositions and formulas. The protocol can perform inference steps using, for example, modus ponens and modus tollens rules and de Morgan's laws. The set of the implemented operations allows for inference of formulas using the laws of natural deduction. The system can also detect whether a certain proposition a can be deduced from the basic facts and given rules. The whole protocol is fully autonomous; that is, after introducing the initial set of molecules, no human assistance is needed. Only one restriction enzyme is used throughout the inference process. Unlike some other similar implementations, our improved design allows representing simultaneously a fact a and its negation ~a, including special reactions to detect the inconsistency, that is, a simultaneous occurrence of a fact and its negation. An analysis of correctness, completeness, and complexity is included.
doi:10.1155/2014/834237
PMCID: PMC4106178  PMID: 25133261
7.  Long-term cognitive function, neuroimaging, and quality of life in primary CNS lymphoma 
Neurology  2013;81(1):84-92.
Objective:
To describe and correlate neurotoxicity indicators in long-term primary CNS lymphoma (PCNSL) survivors who were treated with high-dose methotrexate–based regimens with or without whole-brain radiotherapy (WBRT).
Methods:
Eighty PCNSL survivors from 4 treatment groups (1 with WBRT and 3 without WBRT) who were a minimum of 2 years after diagnosis and in complete remission underwent prospective neuropsychological, quality-of-life (QOL), and brain MRI evaluation. Clinical characteristics were compared among treatments by using the χ2 test and analysis of variance. The association among neuroimaging, neuropsychological, and QOL outcomes was assessed by using the Pearson correlation coefficient.
Results:
The median interval from diagnosis to evaluation was 5.5 years (minimum, 2 years; maximum, 26 years). Survivors treated with WBRT had lower mean scores in attention/executive function (p = 0.0011), motor skills (p = 0.0023), and neuropsychological composite score (p = 0.0051) compared with those treated without WBRT. Verbal memory was better in survivors with longer intervals from diagnosis to evaluation (p = 0.0045). On brain imaging, mean areas of total T2 abnormalities were different among treatments (p = 0.0006). Total T2 abnormalities after WBRT were more than twice the mean of any non-WBRT group and were associated with poorer neuropsychological and QOL outcomes.
Conclusions:
Our results suggest that in patients treated for PCNSL achieving complete remission and surviving at least 2 years, the addition of WBRT to methotrexate-based chemotherapy increases the risk of treatment-related neurotoxicity. Verbal memory may improve over time.
Classification of evidence:
This study provides Class III evidence that in patients treated for PCNSL achieving complete remission and surviving at least 2 years, the addition of WBRT to methotrexate-based chemotherapy increases the risk of treatment-related neurotoxicity.
doi:10.1212/WNL.0b013e318297eeba
PMCID: PMC3770201  PMID: 23685932
8.  Funding Decisions for Newborn Screening: A Comparative Review of 22 Decision Processes in Europe 
Decision-makers need to make choices to improve public health. Population-based newborn screening (NBS) is considered as one strategy to prevent adverse health outcomes and address rare disease patients’ needs. The aim of this study was to describe key characteristics of decisions for funding new NBS programmes in Europe. We analysed past decisions using a conceptual framework. It incorporates indicators that capture the steps of decision processes by health care payers. Based on an internet survey, we compared 22 decisions for which answers among two respondents were validated for each observation. The frequencies of indicators were calculated to elicit key characteristics. All decisions resulted in positive, mostly unrestricted funding. Stakeholder participation was diverse focusing on information provision or voting. Often, decisions were not fully transparent. Assessment of NBS technologies concentrated on expert opinion, literature review and rough cost estimates. Most important appraisal criteria were effectiveness (i.e., health gain from testing for the children being screened), disease severity and availability of treatments. Some common and diverging key characteristics were identified. Although no evidence of explicit healthcare rationing was found, processes may be improved in respect of transparency and scientific rigour of assessment.
doi:10.3390/ijerph110505403
PMCID: PMC4053875  PMID: 24852389
coverage; reimbursement; decision-making; internet survey; European Union; tandem mass spectronomy
9.  Thoracic endovascular aortic repair with left subclavian artery coverage without prophylactic revascularisation—early and midterm results 
Langenbeck's Archives of Surgery  2014;399(5):619-627.
Background
The management of the left subclavian artery when coverage is necessary during thoracic aorta endografting remains a matter of debate.
Materials and methods
A retrospective analysis of a single-centre experience with thoracic endovascular aorta repair (TEVAR) was performed. Between April 2004 and October 2012, 125 cases of TEVAR were performed. The analysis focused on patients who required coverage of the left subclavian artery (LSA). We analysed mortality and morbidity with special attention to the rates of cerebrovascular accidents (CVAs) and spinal cord ischaemia (SCI) in the early and midterm.
Results
Of the 125 patients, 53 (42 %, group A) required an intentional coverage of the LSA to obtain an adequate proximal seal for the endograft; the remaining patients constituted group B. None of the patients in group A had protective LSA revascularisation prior to TEVAR. The primary technical success rate was 79.2 vs. 90.3 % (group A vs. group B, p = 0.08), and the primary clinical success rate was 77.4 vs. 82 % (group A vs. group B, p = 0.53). The 30-day mortality rate was 11.3 vs. 11.1 % (group A vs. group B, p = 0.97). The 30-day morbidity was 7.5 vs. 13.9 % (group A vs. group B, p = 0.4). CVA occurred in 1.9 % of group A patients, compared to 1.4 % of patients from group B (p = 0.82). The SCI incidence rate was 0 vs. 1.4 % (p = 0.39). The mean follow-up of group A was 24.1 months (range 2–64.6 months, SD = 19). Additionally, the 1-year estimated survival was 85.5 %, and the 3-year estimated survival was 78 %. There were no midterm CVAs; one event of SCI occurred in the seventh post-operative month in group A.
Conclusion
Our analysis, although retrospective and based on one institution experience, shows a realistic population of TEVAR patients. We prove that TEVAR with coverage of LSA origin can be accomplished with minimal neurological morbidity in this patient population. The study shows that LSA revascularisation is not mandatory before endograft deployment, especially in emergency settings. We also prove that although zone 2 TEVAR extends the proximal landing zone, it does not prevent type IA endoleaks from appearing. A multicentre randomised control trial with higher number of patients is necessary for proper, robust conclusion to be established.
doi:10.1007/s00423-014-1186-6
PMCID: PMC4050290  PMID: 24770837
TEVAR; Thoracic endovascular aortic repair; Aorta; Aneurysm; Dissection; Left subclavian artery
10.  The cost-utility of open prostatectomy compared with active surveillance in early localised prostate cancer 
Background
There is an on-going debate about whether to perform surgery on early stage localised prostate cancer and risk the common long term side effects such as urinary incontinence and erectile dysfunction. Alternatively these patients could be closely monitored and treated only in case of disease progression (active surveillance). The aim of this paper is to develop a decision-analytic model comparing the cost-utility of active surveillance (AS) and radical prostatectomy (PE) for a cohort of 65 year old men with newly diagnosed low risk prostate cancer.
Methods
A Markov model comparing PE and AS over a lifetime horizon was programmed in TreeAge from a German societal perspective. Comparative disease specific mortality was obtained from the Scandinavian Prostate Cancer Group trial. Direct costs were identified via national treatment guidelines and expert interviews covering in-patient, out-patient, medication, aids and remedies as well as out of pocket payments. Utility values were used as factor weights for age specific quality of life values of the German population. Uncertainty was assessed deterministically and probabilistically.
Results
With quality adjustment, AS was the dominant strategy compared with initial treatment. In the base case, it was associated with an additional 0.04 quality adjusted life years (7.60 QALYs vs. 7.56 QALYs) and a cost reduction of €6,883 per patient (2011 prices). Considering only life-years gained, PE was more effective with an incremental cost-effectiveness ratio of €96,420/life year gained. Sensitivity analysis showed that the probability of developing metastases under AS and utility weights under AS are a major sources of uncertainty. A Monte Carlo simulation revealed that AS was more likely to be cost-effective even under very high willingness to pay thresholds.
Conclusion
AS is likely to be a cost-saving treatment strategy for some patients with early stage localised prostate cancer. However, cost-effectiveness is dependent on patients’ valuation of health states. Better predictability of tumour progression and modified reimbursement practice would support widespread use of AS in the context of the German health care system. More research is necessary in order to reliably quantify the health benefits compared with initial treatment and account for patient preferences.
doi:10.1186/1472-6963-14-163
PMCID: PMC4022451  PMID: 24721557
Economic evaluation; Cost-utility analysis; Cost-effectiveness; Prostate cancer; Active surveillance; Decision analysis; Early evaluation
12.  Influence of baseline left ventricular function on the clinical outcome of surgical ventricular reconstruction in patients with ischaemic cardiomyopathy 
European Heart Journal  2012;34(1):39-47.
Aims
The Surgical Treatment for Ischemic Heart Failure (STICH) trial demonstrated no overall benefit when surgical ventricular reconstruction (SVR) was added to coronary artery bypass grafting (CABG) in patients with ischaemic cardiomyopathy. The present analysis was to determine whether, based on baseline left ventricular (LV) function parameters, any subgroups could be identified that benefited from SVR.
Methods and results
Among the 1000 patients enrolled, Core Lab measures of baseline LV function with adequate quality were obtained in 710 patients using echocardiography, in 352 using cardiovascular magnetic resonance, and in 344 using radionuclide imaging. The relationship between LV end-systolic volume index (ESVI), end-diastolic volume index, ejection fraction (EF), regional wall motion abnormalities, and outcome were first assessed only by echocardiographic measures, and then by 13 algorithms using a different hierarchy of imaging modalities and their quality. The median ESVI and EF were 78.0 (range: 22.8–283.8) mL/m2 and 28.0%, respectively. Hazard ratios comparing the randomized arms by subgroups of LVESVI and LVEF measured by echocardiography found that patients with smaller ventricles (LVESVI <60 mL/m2) and better LVEF (≥33%) may have benefitted by SVR, while those with larger ventricles (LVESVI >90 mL/m2) and lower LVEF (≤25%) did worse with SVR. Algorithms using all three imaging modalities found a weaker relationship between LV global function and the effects of SVR. The extent of regional wall motion abnormality did not influence the effects of SVR.
Conclusions
Subgroup analyses of the STICH trial suggest that patients with less dilated LV and better LVEF may benefit from SVR, while those with larger LV and poorer LVEF may do worse.
Clinical Trial Registration #: NCT00023595.
doi:10.1093/eurheartj/ehs021
PMCID: PMC3533917  PMID: 22584648
STICH; Surgical ventricular reconstruction; Coronary disease; Heart failure
13.  What is personalized medicine: sharpening a vague term based on a systematic literature review 
BMC Medical Ethics  2013;14:55.
Background
Recently, individualized or personalized medicine (PM) has become a buzz word in the academic as well as public debate surrounding health care. However, PM lacks a clear definition and is open to interpretation. This conceptual vagueness complicates public discourse on chances, risks and limits of PM. Furthermore, stakeholders might use it to further their respective interests and preferences. For these reasons it is important to have a shared understanding of PM. In this paper, we present a sufficiently precise as well as adequate definition of PM with the potential of wide acceptance.
Methods
For this purpose, in a first step a systematic literature review was conducted to understand how PM is actually used in scientific practice. PubMed was searched using the keywords “individualized medicine”, “individualised medicine”, “personalized medicine” and “personalised medicine” connected by the Boolean operator OR. A data extraction tabloid was developed putting forward a means/ends-division. Full-texts of articles containing the search terms in title or abstract were screened for definitions. Definitions were extracted; according to the means/ends distinction their elements were assigned to the corresponding category. To reduce complexity of the resulting list, summary categories were developed inductively from the data using thematic analysis. In a second step, six well-known criteria for adequate definitions were applied to these categories to derive a so-called precising definition.
Results
We identified 2457 articles containing the terms PM in title or abstract. Of those 683 contained a definition of PM and were thus included in our review. 1459 ends and 1025 means were found in the definitions. From these we derived the precising definition: PM seeks to improve stratification and timing of health care by utilizing biological information and biomarkers on the level of molecular disease pathways, genetics, proteomics as well as metabolomics.
Conclusions
Our definition includes the aspects that are specific for developments labeled as PM while, on the other hand, recognizing the limits of these developments. Furthermore, it is supported by the quantitative analysis of PM definitions in the literature, which suggests that it it is widely acceptable and thus has the potential to avoid the above mentioned issues.
doi:10.1186/1472-6939-14-55
PMCID: PMC3878093  PMID: 24359531
Biomarkers; Conceptual vagueness; Definition; Individualized medicine; Stratification; Timing
14.  Evidence That GH115 α-Glucuronidase Activity, Which Is Required to Degrade Plant Biomass, Is Dependent on Conformational Flexibility* 
Background: The structure of GH115 glucuronidases that remove glucuronic acid from xylan chains is unknown.
Results: Bacteroides ovatus GH115 glucuronidase is a dimeric enzyme that contains a flexible active site pocket.
Conclusion: The assembly of the catalytic apparatus of the glucuronidase requires substantial conformational changes.
Significance: Conformational changes are highly unusual in glycoside hydrolases.
The microbial degradation of the plant cell wall is an important biological process that is highly relevant to environmentally significant industries such as the bioenergy and biorefining sectors. A major component of the wall is glucuronoxylan, a β1,4-linked xylose polysaccharide that is decorated with α-linked glucuronic and/or methylglucuronic acid (GlcA/MeGlcA). Recently three members of a glycoside hydrolase family, GH115, were shown to hydrolyze MeGlcA side chains from the internal regions of xylan, an activity that has not previously been described. Here we show that a dominant member of the human microbiota, Bacteroides ovatus, contains a GH115 enzyme, BoAgu115A, which displays glucuronoxylan α-(4-O-methyl)-glucuronidase activity. The enzyme is significantly more active against substrates in which the xylose decorated with GlcA/MeGlcA is flanked by one or more xylose residues. The crystal structure of BoAgu115A revealed a four-domain protein in which the active site, comprising a pocket that abuts a cleft-like structure, is housed in the second domain that adopts a TIM barrel-fold. The third domain, a five-helical bundle, and the C-terminal β-sandwich domain make inter-chain contacts leading to protein dimerization. Informed by the structure of the enzyme in complex with GlcA in its open ring form, in conjunction with mutagenesis studies, the potential substrate binding and catalytically significant amino acids were identified. Based on the catalytic importance of residues located on a highly flexible loop, the enzyme is required to undergo a substantial conformational change to form a productive Michaelis complex with glucuronoxylan.
doi:10.1074/jbc.M113.525295
PMCID: PMC3879575  PMID: 24214982
Bioenergy; Enzyme Structure; Glycoside Hydrolases; Plant Cell Wall; X-ray Crystallography
15.  Prognostic indicators of survival in patients with compensated and decompensated cirrhosis 
Background/Aims
Patients with cirrhosis are classified in a compensated and a decompensated stage. Portal hypertension is responsible for most of the complications of cirrhosis that mark the transition from compensated to decompensated cirrhosis. The objectives of this study were (a) to analyse survival of the different stages and substages of cirrhosis and (b) to examine the prognostic value of the hepatic venous pressure gradient (HVPG) at each of the stages.
Methods
A total of 729 patients with suspected cirrhosis underwent routine measurement of portal pressure and systemic haemodynamics between 11/1995 and 12/2004. The primary end-point of the study was death, collected until November 30th, 2006. Multivariable analysis was performed using two models to determine predictors of death at each stage.
Results
A total of 443 patients were included in the study. The 1-year mortality was 5.4% in compensated and 20.2% in decompensated patients. Compensated patients in stage 1 (no varices) had a longer survival than stage 2 patients (varices present) (P = 0.015). In decompensated patients, survival was not different between stage 3 (ascites, with or without varices) and stage 4 (variceal haemorrhage, with or without ascites). Age and HVPG (cut-off 10 mmHg) were independent predictors of death in compensated patients, whereas MELD was in decompensated patients.
Conclusion
Survival rates and predictors of death are different between patients with compensated and decompensated cirrhosis. Unlike the Italian cohort staging system, ascites is a better stratifying clinical event than variceal haemorrhage in patients with decompensated cirrhosis. The presence of clinically significant portal hyper-tension has prognostic value in compensated cirrhosis.
doi:10.1111/j.1478-3231.2012.02830.x
PMCID: PMC3713489  PMID: 22679906
ascites; cirrhosis; oesophageal varices; variceal haemorrhage
16.  Association of Angiotensin-Converting Enzyme Inhibitor Therapy Initiation With a Reduction in Hemoglobin Levels in Patients Without Renal Failure 
Mayo Clinic Proceedings  2012;87(12):1189-1195.
Objective
To investigate whether treatment initiated with an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin II receptor blocker (ARB) for patients with ischemic heart disease, hypertension, or diabetes causes a reduction in hemoglobin (Hb) levels.
Patients and Methods
This was a retrospective cohort analysis using the computerized database of a large health maintenance organization. Included were all adults with a first purchase of an ACE-I, an ARB, or a calcium channel blocker (CCB) between January 1, 2004, and December 31, 2009, defined as the index date. Measures of Hb levels before and 1 year after the index date were reviewed, and the change was calculated. All the analyses were stratified by pharmaceutical class. The main exposure variables were the proportion of days covered (PDC) by these drugs and the mean enalapril dosage (for enalapril users only).
Results
Levels of Hb before and after treatment were available for 14,754 patients taking ACE-Is, 751 taking ARBs, and 3087 taking CCBs. A high PDC was significantly associated with greater yearly reductions in Hb levels compared with a low PDC for CCB use, but was more pronounced for ACE-I and ARB use. A high PDC was also associated with a higher odds of developing anemia in ACE-I users (odds ratio [OR], 1.59; P<.001) and ARB users (OR, 2.21; P=.05). In nonanemic enalapril users, every 10-mg increment in daily dose was associated with an OR of 1.45 for the development of anemia (P<.001). The association remained after excluding nonadherent patients.
Conclusion
Levels of Hb are reduced during the first year of use of ACE-Is and to a lesser extent with use of ARBs. This association is dose dependent and is not explained by patient adherence.
doi:10.1016/j.mayocp.2012.07.020
PMCID: PMC3547548  PMID: 23141116
ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; Hb, hemoglobin; IHD, ischemic heart disease; MHS, Maccabi Healthcare Services; OR, odds ratio; PDC, proportion of days covered; WHO, World Health Organization
17.  Motor Imagery and Tennis Serve Performance: The External Focus Efficacy 
There is now ample evidence that motor imagery (MI) contributes to enhance motor performance. Previous research also demonstrated that directing athletes’ attention to the effects of their movements on the environment is more effective than focusing on the action per se. The present study aimed therefore at evaluating whether adopting an external focus during MI contributes to enhance tennis serve performance. Twelve high-level young tennis players were included in a test-retest procedure. The effects of regular training were first evaluated. Then, players were subjected to a MI intervention during which they mentally focused on ball trajectory and specifically visualized the space above the net where the serve can be successfully hit. Serve performance was evaluated during both a validated serve test and a real match. The main results showed a significant increase in accuracy and velocity during the ecological serve test after MI practice, as well as a significant improvement in successful first serves and won points during the match. Present data therefore confirmed the efficacy of MI in combination of physical practice to improve tennis serve performance, and further provided evidence that it is feasible to adopt external attentional focus during MI. Practical applications are discussed.
Key PointsMotor imagery contributes to enhance tennis serve performance.Data provided evidence of the benefits of adopting an external focus of attention during imagery.Results showed significant improvement in successful first serves and won points during a real match.
PMCID: PMC3761826  PMID: 24149813
Movement imagery; motor performance; focus of attention; safety window
18.  Joint Kinetics to Assess the Influence of the Racket on a Tennis Player’s Shoulder 
This study aimed at investigating the influence of three rackets on shoulder net joint moments, power and muscle activity during the flat tennis serve under field- conditions. A 6-camera Eagle® motion analysis system, operating at 256 Hz, captured racket and dominant upper limb kinematics of the serve in five tennis players under three racket conditions (A: low mass, high balance and polar moment, B: low three moments of inertia, and C: high mass, swingweight and twistweight). The electromyographic activity of six trunk and arm muscles was simultaneously recorded. Shoulder net joint moments and power were computed by 3D inverse dynamics. The results showed that greater shoulder joint power and internal/external rotation peak moments were found to accelerate and decelerate racket A in comparison with the racket C. Moreover, serving with the racket A resulted in less activity in latissimus dorsi muscle during the acceleration phase, and biceps brachii muscle during the follow-through phase when compared with racket C. These initial findings encourage studying the biomechanical measurements to quantify the loads on the body during play in order to reduce them, and then prevent shoulder injuries. Racket specifications may be a critical point for coaches who train players suffering from shoulder pain and chronic upper limb injuries should be considered in relation to the racket specifications of the players.
Key PointsLight racket required more joint power than heavy one to achieve similar post impact ball velocity.Serving with a light racket resulted in higher shoulder internal and external rotation moments than using a heavy one for similar performance.Chronic shoulder pain should encourage coaches to check for potentially inappropriate racket specifications of their players.
PMCID: PMC3761829  PMID: 24149804
EMG; inverse dynamics; joint power; joint moment; tennis serve
19.  Operative field temperature during transnasal endoscopic cranial base procedures 
Acta Neurochirurgica  2013;155(5):903-908.
Background
Data regarding the safety of endoscopic skull base exploration are very scarce. With this method, fragile vital structures (cranial nerves, the optic complex, brainstem, hypothalamus or cerebral ventricles) are exposed to direct illumination within a closed space. Also, high-speed drills, cauterization and ultrasonic aspiration deliver a significant load of thermal energy. The aim of this study was to record the temperature close to the structures of the skull base and in the intradural space during the procedures performed using extended endoscopic transnasal approaches.
Methods
The temperature of the skull base was continuously recorded during six transnasal endoscopic procedures. Implantable copper-constantan thermocouples were inserted: one into the esophagus and another through the nostril to reach the operative field at the skull base.
Results
At the beginning of the procedure, the temperature of the operative field was on average 36.8 °C ± 0.80 °C, i.e. only 1 °C higher than the esophageal temperature. Then it grew continuously during the whole procedure, to eventually reach a level of 42–43 °C at the final stage, whereas the esophageal temperature remained stable. Occasionally, the temperature increased up to 45 °C during cauterization and ultrasonic aspiration, and even up to 62 °C during high-speed drilling.
Conclusion
Endoscopic skull base surgery is associated with an incessant increase of the temperature of the intraoperative field. The temperature can peak suddenly to levels which can potentially harm neural structures and influence the rate of postoperative complications.
doi:10.1007/s00701-013-1674-4
PMCID: PMC3627044  PMID: 23494137
Endoscopy; Transnasal; Extended approach; Cranial base; Temperature
20.  A randomised, double-blind, placebo-controlled phase 2 study of trebananib (AMG 386) in combination with FOLFIRI in patients with previously treated metastatic colorectal carcinoma 
British Journal of Cancer  2013;108(3):503-511.
Background:
This phase 2 study evaluated trebananib (AMG 386), an investigational peptide-Fc fusion protein that neutralises the interaction between angiopoietins-1/2 and the Tie2 receptor, plus FOLFIRI as second-line treatment for patients with metastatic colorectal cancer.
Methods:
Patients had adenocarcinoma of the colon or rectum with progression within 6 months of receiving only one prior fluoropyrimidine/oxaliplatin-based chemotherapy regimen for metastatic disease. All patients received FOLFIRI and were randomised 2 : 1 to also receive intravenous trebananib 10 mg kg−1 once weekly (QW) (Arm A) or placebo QW (Arm B). The primary end point was investigator-assessed progression-free survival (PFS).
Results:
One hundred and forty-four patients were randomised (Arms A/B, n=95/49). Median PFS in Arms A and B was 3.5 and 5.2 months (hazard ratio (HR) 1.23; 95% CI, 0.81–1.86; P=0.33) and median overall survival (OS) was 11.9 and 8.8 months, respectively (HR 0.90; 95% CI; 0.53–1.54; P=0.70). Objective response rate (ORR) was 14% and 0% in Arms A and B, respectively. Incidence of grade ⩾3 adverse events was similar between treatment arms (Arm A, 61% Arm B, 65%) and included pulmonary embolism (1%/4%), deep vein thrombosis (5%/2%), and hypertension (1%/0%).
Conclusion:
Administration of trebananib plus FOLFIRI did not prolong PFS compared with placebo plus FOLFIRI. Toxicities were manageable and consistent with those known for FOLFIRI and trebananib.
doi:10.1038/bjc.2012.594
PMCID: PMC3593550  PMID: 23361051
AMG 386; trebananib; angiopoietin inhibitor; metastatic colorectal carcinoma
21.  Efficacy and safety of ipilimumab therapy in patients with metastatic melanoma: a retrospective multicenter analysis 
Contemporary Oncology  2013;17(3):257-262.
Aim of the study
The Patient Assistance Program, a type of expanded access program, was initiated for compassionate purposes to provide ipilimumab to patients with unresectable stage III or IV melanoma with failed previous treatment. The aim of this analysis is to evaluate efficacy, safety, and tolerability of ipilimumab therapy in daily clinical practice.
Material and methods
We analyzed 50 patients (29 males, 21 females) aged 21 to 76 years (median: 49 years). An ipilimumab dose of 3 mg/kg was administered intravenously every 3 weeks for a total of 4 doses. Patients were assessed for response rate, progression-free survival and overall survival, and monitored for adverse events.
Results
The objective response (complete or partial response) rate was 12%. Median overall survival was 8 months and median progression-free survival was 3 months. In patients with ECOG-PS 0, the median overall survival was 16 months. Immune-related adverse events (irAEs) occurred in 48% of the patients, grade 3 or 4 irAEs were reported in 8% of the patients, and there were no toxic deaths.
Conclusions
Ipilimumab demonstrated clinical benefit in previously treated advanced melanoma patients. Although clinical benefit is limited to a minority of the patients, there is a benefit in terms of overall survival in this group of patients.
doi:10.5114/wo.2013.35785
PMCID: PMC3934064  PMID: 24596511
melanoma; ipilimumab; CTLA-4; immunotherapy; outcome
22.  Understanding How Noncatalytic Carbohydrate Binding Modules Can Display Specificity for Xyloglucan* 
The Journal of Biological Chemistry  2012;288(7):4799-4809.
Background: Carbohydrate binding modules (CBMs) contribute to the enzymatic degradation of complex polysaccharide structures.
Results: New CBMs display specificity for decorated glucans through an extensive hydrophobic platform that interacts with both backbone and side chain structures.
Conclusion: CBMs that bind to complex β-glucans exploit different components of these ligands as specificity determinants.
Significance: CBMs can utilize the side chains of decorated glucans as specificity determinants.
Plant biomass is central to the carbon cycle and to environmentally sustainable industries exemplified by the biofuel sector. Plant cell wall degrading enzymes generally contain noncatalytic carbohydrate binding modules (CBMs) that fulfil a targeting function, which enhances catalysis. CBMs that bind β-glucan chains often display broad specificity recognizing β1,4-glucans (cellulose), β1,3-β1,4-mixed linked glucans and xyloglucan, a β1,4-glucan decorated with α1,6-xylose residues, by targeting structures common to the three polysaccharides. Thus, CBMs that recognize xyloglucan target the β1,4-glucan backbone and only accommodate the xylose decorations. Here we show that two closely related CBMs, CBM65A and CBM65B, derived from EcCel5A, a Eubacterium cellulosolvens endoglucanase, bind to a range of β-glucans but, uniquely, display significant preference for xyloglucan. The structures of the two CBMs reveal a β-sandwich fold. The ligand binding site comprises the β-sheet that forms the concave surface of the proteins. Binding to the backbone chains of β-glucans is mediated primarily by five aromatic residues that also make hydrophobic interactions with the xylose side chains of xyloglucan, conferring the distinctive specificity of the CBMs for the decorated polysaccharide. Significantly, and in contrast to other CBMs that recognize β-glucans, CBM65A utilizes different polar residues to bind cellulose and mixed linked glucans. Thus, Gln106 is central to cellulose recognition, but is not required for binding to mixed linked glucans. This report reveals the mechanism by which β-glucan-specific CBMs can distinguish between linear and mixed linked glucans, and show how these CBMs can exploit an extensive hydrophobic platform to target the side chains of decorated β-glucans.
doi:10.1074/jbc.M112.432781
PMCID: PMC3576085  PMID: 23229556
Carbohydrate-binding Protein; Isothermal Titration Calorimetry; Plant Cell Wall; Protein Structure; X-ray Crystallography
25.  Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence 
British Journal of Cancer  2011;105(6):796-806.
Background:
We reported that Notch-1, a potent breast oncogene, is activated in response to trastuzumab and contributes to trastuzumab resistance in vitro. We sought to determine the preclinical benefit of combining a Notch inhibitor (γ-secretase inhibitor (GSI)) and trastuzumab in both trastuzumab-sensitive and trastuzumab-resistant, ErbB-2-positive, BT474 breast tumours in vivo. We also studied if the combination therapy of lapatinib plus GSI can induce tumour regression of ErbB-2-positive breast cancer.
Methods:
We generated orthotopic breast tumour xenografts from trastuzumab- or lapatinib-sensitive and trastuzumab-resistant BT474 cells. We investigated the antitumour activities of two distinct GSIs, LY 411 575 and MRK-003, in vivo.
Results:
Our findings showed that combining trastuzumab plus a GSI completely prevented (MRK-003 GSI) or significantly reduced (LY 411 575 GSI) breast tumour recurrence post-trastuzumab treatment in sensitive tumours. Moreover, combining lapatinib plus MRK-003 GSI showed significant reduction of tumour growth. Furthermore, a GSI partially reversed trastuzumab resistance in resistant tumours.
Conclusion:
Our data suggest that a combined inhibition of Notch and ErbB-2 signalling pathways could decrease recurrence rates for ErbB-2-positive breast tumours and may be beneficial in the treatment of recurrent trastuzumab-resistant disease.
doi:10.1038/bjc.2011.321
PMCID: PMC3171020  PMID: 21847123
ErbB-2; trastuzumab; Notch-1; GSI; recurrence; resistance

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