Lamellar split osteotomy: a new craniofacial technique

Craniofacial osteotomies have by convention been bilamellar translocations of the entire substance of the dysmorphic bone. This approach limits the surgeon by reducing the stable bone mass available for fixation, creating dependence on concave surfaces. Most important, it changes the bony topography that determines the preoperative plan. This paper presents a new craniofacial concept and technique used in 26 patients with various dysmorphic syndromes who were reconstructed by performing a lamellar split osteotomy. This technique maintains the internal lamella in its native position, thereby allowing it to act as a reference for the bony topography and providing a stable facial framework for rigid fixation. This interlamellar osteotomy has led to improved aesthetic results in the orthomorphic reconstructions of congenital and other deformities. It can be used in any aesthetic patient in whom contour changes or augmentation of form is desired. It is recommended as a preferred method for achieving quantitative contour improvement in patients over 3 years of age.     

Moral dilemmas in (not) treating patients who feel they are a burden

Working as clinical ethicists in an academic hospital, we find that practitioners tend to take a principle‐based approach to moral dilemmas when it comes to (not) treating patients who feel like a burden, in which respect for autonomy tends to trump other principles. We argue that this approach insufficiently deals with the moral doubts of professionals with regard to feeling that you are a burden as a motive to decline or withdraw from treatment. Neither does it take into adequately account the specific needs of the patient that might underlie their feeling of being a burden to others. We propose a care ethics approach as an alternative. It focuses on being attentive and responsive to the caring needs of those involved in the care process—which can be much more specific than either receiving or withdrawing from treatment. This approach considers these needs in the context of the patient's identity, biography and relationships, and regards autonomy as relational rather than as individual. We illustrate the difference between these two approaches by means of the case of Mrs K. Furthermore, we show that a care ethics approach is in line with interventions that are found to alleviate feeling a burden and maintain that facilitating moral case deliberation among practitioners can supports them in taking a care ethics approach to moral dilemmas in (not) treating patients who feel like a burden.     

Statistical guidance for experimental design and data analysis of mutation detection in rare monogenic mendelian diseases by exome sequencing

Recently, whole-genome sequencing, especially exome sequencing, has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases. However, it is unclear whether this approach can be generalized and effectively applied to other Mendelian diseases with high locus heterogeneity. Moreover, the current exome sequencing approach has limitations such as false positive and false negative rates of mutation detection due to sequencing errors and other artifacts, but the impact of these limitations on experimental design has not been systematically analyzed. To address these questions, we present a statistical modeling framework to calculate the power, the probability of identifying truly disease-causing genes, under various inheritance models and experimental conditions, providing guidance for both proper experimental design and data analysis. Based on our model, we found that the exome sequencing approach is well-powered for mutation detection in recessive, but not dominant, Mendelian diseases with high locus heterogeneity. A disease gene responsible for as low as 5% of the disease population can be readily identified by sequencing just 200 unrelated patients. Based on these results, for identifying rare Mendelian disease genes, we propose that a viable approach is to combine, sequence, and analyze patients with the same disease together, leveraging the statistical framework presented in this work.     

Incorporating historical information in biosimilar trials: Challenges and a hybrid Bayesian‐frequentist approach

For the approval of biosimilars, it is, in most cases, necessary to conduct large Phase III clinical trials in patients to convince the regulatory authorities that the product is comparable in terms of efficacy and safety to the originator product. As the originator product has already been studied in several trials beforehand, it seems natural to include this historical information into the showing of equivalent efficacy. Since all studies for the regulatory approval of biosimilars are confirmatory studies, it is required that the statistical approach has reasonable frequentist properties, most importantly, that the Type I error rate is controlled—at least in all scenarios that are realistic in practice. However, it is well known that the incorporation of historical information can lead to an inflation of the Type I error rate in the case of a conflict between the distribution of the historical data and the distribution of the trial data. We illustrate this issue and confirm, using the Bayesian robustified meta‐analytic‐predictive (MAP) approach as an example, that simultaneously controlling the Type I error rate over the complete parameter space and gaining power in comparison to a standard frequentist approach that only considers the data in the new study, is not possible. We propose a hybrid Bayesian‐frequentist approach for binary endpoints that controls the Type I error rate in the neighborhood of the center of the prior distribution, while improving the power. We study the properties of this approach in an extensive simulation study and provide a real‐world example.     

The Changing Face of P300 BCIs: A Comparison of Stimulus Changes in a P300 BCI Involving Faces,Emotion, and Movement

Background

One of the most common types of brain-computer interfaces (BCIs) is called a P300 BCI, since it relies on the P300 and other event-related potentials (ERPs). In the canonical P300 BCI approach, items on a monitor flash briefly to elicit the necessary ERPs. Very recent work has shown that this approach may yield lower performance than alternate paradigms in which the items do not flash but instead change in other ways, such as moving, changing colour or changing to characters overlaid with faces.

Methodology/Principal Findings

The present study sought to extend this research direction by parametrically comparing different ways to change items in a P300 BCI. Healthy subjects used a P300 BCI across six different conditions. Three conditions were similar to our prior work, providing the first direct comparison of characters flashing, moving, and changing to faces. Three new conditions also explored facial motion and emotional expression. The six conditions were compared across objective measures such as classification accuracy and bit rate as well as subjective measures such as perceived difficulty. In line with recent studies, our results indicated that the character flash condition resulted in the lowest accuracy and bit rate. All four face conditions (mean accuracy >91%) yielded significantly better performance than the flash condition (mean accuracy = 75%).

Conclusions/Significance

Objective results reaffirmed that the face paradigm is superior to the canonical flash approach that has dominated P300 BCIs for over 20 years. The subjective reports indicated that the conditions that yielded better performance were not considered especially burdensome. Therefore, although further work is needed to identify which face paradigm is best, it is clear that the canonical flash approach should be replaced with a face paradigm when aiming at increasing bit rate. However, the face paradigm has to be further explored with practical applications particularly with locked-in patients.     

Fractal analysis of leaf-texture properties as a tool for taxonomic and identification purposes: a case study with species from Neotropical Melastomataceae (Miconieae tribe)

Melastomataceae is a common and dominant family in Neotropical vegetation, with high species diversity which leads to a large variation in some morphological structures. Despite this, some species of Melastomataceae are very similar in their external leaf morphology, leading to difficulties in their identification without the presence of reproductive organs. Here we have proposed and tested a computer-aided texture-based approach used to correctly identify and distinguish leaves of some species of Melastomataceae that occur in a region of Neotropical savanna in Southeastern Brazil, also comparing it with other previously proposed approaches. The results demonstrated that our approach may clearly separate the studied species, analyzing the patterns of leaf texture (both adaxial and abaxial surfaces), and achieving better accuracy (100%) than other methods. Our work has suggested that leaf texture properties can be used as a new characteristic for identification, and as an additional source of information in taxonomic and systematic studies. As the method may be supervised by experts, it is also suitable for discrimination of species with high morphological plasticity, improving the automated discrimination task. This approach can be very useful for identification of species in the absence of reproductive material, and is a rapid and powerful tool for plant identification.     

Analysis of cell surface light chain immunoglobulin expression by flow cytometry in normal controls: a new mathematical approach

It has been observed in flow cytometric studies that in normal individuals there are proportionally more kappa+ than lambda+ bearing light chain B-cells. Overt predominance of one type of light chain bearing cell over the other is a characteristic of B-cell neoplasias, a phenomenon called clonal excess (CE). A mathematical model using the Weibull distribution is proposed for studying such an excess. The new approach is desirable for two reasons: First, it is parametric and hence offers a more sensitive and versatile analysis than its nonparametric counterparts. Second, it utilizes only the relevant information from the upper tails of the distributions of the fluorescence intensity of the kappa+ and lambda+ cells. Two measures of CE based on the Weibull model are proposed, and a normal range of variability was determined for each measure using a random sample of 48 normal controls. Such normal ranges are particularly useful in detecting cancer patients with minimal B-cell neoplasias. A comparative study of the new measures, Ault's maximum difference measure, and a measure based on Ligler's method showed that the parametric approach provides much more sensitivity than both the nonparametric ones.     

雄激素性脱发的发病机制与激光治疗

雄激素性脱发(androgenetic alopecia,AGA)是皮肤科的常见病与多发病,雄激素性脱发的药物综合治疗及手术治疗的部分患者取得了一定的效果,但都存在副作用大、患者依从性差等问题,有研究表明低功率激光能够促进动物毛发的生长,因而可能在改善雄激素性脱发的症状方面具有重要的应用前景。本文回顾近年来对雄激素性脱发的可能发病机制、治疗现状及激光治疗的研究情况和进展,旨在为雄激素性脱发的治疗奠定科学依据。     

Development of a vaccine against haemonchus contortus

Haemonchus contortus is an economically important nematode parasite of sheep and the occurrence worldwide of strains resistant to anthelmintic chemicals has emphasized the need to develop a vaccine against it. Here, Ed Munn describes the approach to this problem adopted in his laboratory. The principle developed should be applicable to other gastrointestinal parasites.     

Self-care program for inpatients in a mental hospital.

Summary: A self-care program for selected inpatients in a mental hospital has been developed and has been in operation for more than a year. The 12-bed unit operates without any nursing or other professional staff during the night and weekend. Certain factors, including the mental hospital as an organization, tend to hamper the development of this type of program as well as the progress and growth of other programs in psychiatric hospitals. It is suggested that the much needed progress in the mental hospital would be facilitated by an open-systems approach to its organization. Mental hospitals should consider the introduction of self-care programs for selected patients, mainly in view of their therapeutic potential, but also because of the financial savings such programs offer.     

Action observation treatment: a novel tool in neurorehabilitation

This review focuses on a novel rehabilitation approach known as action observation treatment (AOT). It is now a well-accepted notion in neurophysiology that the observation of actions performed by others activates in the perceiver the same neural structures responsible for the actual execution of those same actions. Areas endowed with this action observation–action execution matching mechanism are defined as the mirror neuron system. AOT exploits this neurophysiological mechanism for the recovery of motor impairment. During one typical session, patients observe a daily action and afterwards execute it in context. So far, this approach has been successfully applied in the rehabilitation of upper limb motor functions in chronic stroke patients, in motor recovery of Parkinson''s disease patients, including those presenting with freezing of gait, and in children with cerebral palsy. Interestingly, this approach also improved lower limb motor functions in post-surgical orthopaedic patients. AOT is well grounded in basic neuroscience, thus representing a valid model of translational medicine in the field of neurorehabilitation. Moreover, the results concerning its effectiveness have been collected in randomized controlled studies, thus being an example of evidence-based clinical practice.     

The Marker State Space (MSS) Method for Classifying Clinical Samples

The development of accurate clinical biomarkers has been challenging in part due to the diversity between patients and diseases. One approach to account for the diversity is to use multiple markers to classify patients, based on the concept that each individual marker contributes information from its respective subclass of patients. Here we present a new strategy for developing biomarker panels that accounts for completely distinct patient subclasses. Marker State Space (MSS) defines “marker states” based on all possible patterns of high and low values among a panel of markers. Each marker state is defined as either a case state or a control state, and a sample is classified as case or control based on the state it occupies. MSS was used to define multi-marker panels that were robust in cross validation and training-set/test-set analyses and that yielded similar classification accuracy to several other classification algorithms. A three-marker panel for discriminating pancreatic cancer patients from control subjects revealed subclasses of patients based on distinct marker states. MSS provides a straightforward approach for modeling highly divergent subclasses of patients, which may be adaptable for diverse applications.     

Phylogenetic approach reveals that virus genotype largely determines HIV set-point viral load

HIV virulence, i.e. the time of progression to AIDS, varies greatly among patients. As for other rapidly evolving pathogens of humans, it is difficult to know if this variance is controlled by the genotype of the host or that of the virus because the transmission chain is usually unknown. We apply the phylogenetic comparative approach (PCA) to estimate the heritability of a trait from one infection to the next, which indicates the control of the virus genotype over this trait. The idea is to use viral RNA sequences obtained from patients infected by HIV-1 subtype B to build a phylogeny, which approximately reflects the transmission chain. Heritability is measured statistically as the propensity for patients close in the phylogeny to exhibit similar infection trait values. The approach reveals that up to half of the variance in set-point viral load, a trait associated with virulence, can be heritable. Our estimate is significant and robust to noise in the phylogeny. We also check for the consistency of our approach by showing that a trait related to drug resistance is almost entirely heritable. Finally, we show the importance of taking into account the transmission chain when estimating correlations between infection traits. The fact that HIV virulence is, at least partially, heritable from one infection to the next has clinical and epidemiological implications. The difference between earlier studies and ours comes from the quality of our dataset and from the power of the PCA, which can be applied to large datasets and accounts for within-host evolution. The PCA opens new perspectives for approaches linking clinical data and evolutionary biology because it can be extended to study other traits or other infectious diseases.     

Use of cell therapy as a means of targeting chemotherapy to inoperable pancreatic cancer

Although approved for the treatment of pancreatic cancer, the chemotherapeutic agent ifosfamide is not an effective therapy for this type of tumour. Ifosfamide must be activated by cytochrome P450 (P450) enzymes in the liver, initially to a short lived intermediate and then to toxic metabolites that are subsequently distributed by the circulatory system. Particularly for pancreatic cancer, this liver-mediated conversion results in relatively high systemic toxicities and poor therapeutic concentrations at the liver-distant site of the tumour. Activation of ifosfamide at the site of the tumour may allow lower doses to be used, while increasing the therapeutic index due to the resultant active concentrations generated locally. A cell-based therapy has been conceived where encapsulated, 293-derived cells genetically modified to overexpress a cytochrome P450 enzyme, are implanted near solid tumours. The cells are encapsulated in polymers of cellulose sulphate in order to provide a means of immunoprotection in vivo as well as to physically constrain them to the vicinity of the tumour. A major advantage of this strategy is that it allows one standard cell line to be applied to all patients and this approach can be extended to the treatment of other tumour types. After proof of principle studies in animal models, a phase I/II clinical trial was initiated in patients with stage III/IV nonresectable pancreatic cancer. Encapsulated cells were angiographically placed into the tumour vasculature of 14 patients and followed by systemic low dose ifosfamide treatment. Angiographic delivery of encapsulated cells proved feasible in all but one patient, and was well tolerated with no capsule or ifosfamide treatment-related adverse events. Four of the treated patients showed tumour regressions after capsule delivery and ifosfamide treatment in computer-tomography scans. The other 10 patients showed no further tumour growth (i.e. stable disease) during 20 weeks observation period. The median life expectancy of the patient collective was extended two fold as compared to age and status matched historical controls, with a 3-fold improvement in one year survival being attained. Evidence for a clinical benefit of the treatment was also obtained on the basis of standard parameters for quality of life. This approach has been evaluated by the European Medicines Evaluation Agency (EMEA) and orphan drug status has been granted. A pivotal clinical trial is now being planned with the help of the EMEA. Taken together, the data from this clinical trial suggest that encapsulated cytochrome P450-expressing cells combined with chemotherapy may be useful for the local treatment of a number of solid tumours and support the performance of further clinical studies of this new treatment.     

Selective ozone concentrations may reduce the ischemic damage after a stroke

Abstract Stroke is one of the most debilitating diseases, and it is unfortunate that only a small percentage of patients can be treated with thrombolytic agents. Consequently, there is an urgent need of finding an alternative procedure for reoxygenating the so-called penumbra at the earliest time as possible for reducing morbidity and disability. A preliminary, preclinical study has been carried out by using rat hippocampal and cortical brain slices subjected to oxygen-glucose deprivation. Oxygen-ozone gaseous mixture appeared to be effective in reverting damage of brain tissues, supporting the evaluation of this approach in well-designed clinical trials in stroke patients.     

Drought as a challenge for the plant breeder

Since agriculture began, drought has been on of the major plagues affecting crop production causing famine and death. Despite many decades of research, drought continues to be a major challenge to agricultural scientists. This is due to the unpredictability of its occurrence, severity, timing and duration; and to the interaction of drought with other abiotic stresses, particularly extremes of temperature and variations in nutrients availability; and with biotic stresses. Breeding has not been as effective in improving crop production under drought-stress conditions as it has in their absence — or where the stress can be alleviated by irrigation. This paper argues that the relative lack of success of breeding for stress conditions in general, and for drought-stress conditions in particular, can be partly attributed to use of the same breeding approach that is successful for favourable environments. A different breeding approach for drought-stress conditions is discussed in relation to the environment in which selection should be conducted, the germplasm to be used, and the experimental designs and plot techniques to be employed.     

Augmentation mammaplasty: a comparative analysis

With the continuation of augmentation mammaplasty as a desirable operation for a large segment of the female population in the United States, the problem of fibrous capsular contracture that has been present since the inception of the operation has persisted. Various approaches to the problem have been entertained, and a lessening of the incidence has occurred as reviewed in our earlier report, which follows augmentation mammaplasty in our clinic from 1962 through 1979. In this retrospective study, no significant difference in contracture rate was seen based on patient smoking habits, operative approach used, or implant type. It is important to note that the total experience with the low-bleed implant was significantly lower in terms of number of patients meeting the criteria of this retrospective study than the standard gel mammary implant. Greater follow-up time and number of patients will be evaluated in future retrospective studies. We have demonstrated in this study that placement of the implant beneath the pectoral muscle has significantly diminished the incidence of capsular contracture both as Baker grades II, III, and IV and as Baker grades III and IV. The retropectoral site has become the preferred location for the prosthesis in our clinic. There is no appreciable alteration in the overall shape of the breasts from this approach, and therefore, it will continue to be the preferred method. Rates of incidence of hematoma, the most frequent adverse reaction after contracture, were not significantly different between the retropectoral and retromammary implant sites.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ethical considerations in African traditional medicine: a response to Nyika

Like other so-called 'parallel' practices in medicine, traditional medicine (TM) does not avoid criticism or even rejection. Nyika's article 'Ethical and Regulatory Issues Surrounding African Traditional Medicine in the Context of HIV/AIDS' looks at some of the issues from a traditional Western ethical perspective and suggests that it should be rejected. I respond to this article agreeing with Nyika's three major criticisms: lack of informed consent, confidentiality and paternalism. However, as traditional healers are consulted by over 70% of South Africans before any other type of healthcare professional, a blanket negation of TM is not possible, nor is it politically feasible. A pragmatic approach would be to work within the current structures for positive change. I point out that, as all cultural practices do, TM will change over time. Yet, until some regulations and change occur, the problem of harm to patients remains a major concern.     

Beyond and within public engagement: a broadened approach to engagement in biobanking

Social studies on biobanking have traditionally focused on public engagement, that is, engagement with donors, patients and the general public as an important factor of sustainability. In this article, we claim that, in order to fully understand the way biobanks work, it is necessary to pay attention to a number of other actors, which have an equal, if not greater, impact on their practices and strategies. This means taking a broadened approach to biobank engagement. By using data collected from interviews with different biobank experts based in five different countries (UK, Canada, Finland, Spain and Iceland), we identify seven communities, including the public, that emerge as relevant. Such relationships condition the way biobanks develop, act and plan. The discussion illustrates how the relationships with those seven communities are articulated. We conclude that there is a need for a broadened approach to biobank engagement in order to understand biobank sustainability.