Effects of spatial variation in dose delivery: what can we learn from radon-related lung cancer studies?

Exposure to radon progeny results in heterogeneous dose distributions in many different spatial scales. The aim of this review is to provide an overview on the state of the art in epidemiology, clinical observations, cell biology, dosimetry, and modelling related to radon exposure and its association with lung cancer, along with priorities for future research. Particular attention is paid on the effects of spatial variation in dose delivery within the organs, a factor not considered in radiation protection. It is concluded that a multidisciplinary approach is required to improve risk assessment and mechanistic understanding of carcinogenesis related to radon exposure. To achieve these goals, important steps would be to clarify whether radon can cause other diseases than lung cancer, and to investigate radon-related health risks in children or persons at young ages. Also, a better understanding of the combined effects of radon and smoking is needed, which can be achieved by integrating epidemiological, clinical, pathological, and molecular oncology data to obtain a radon-associated signature. While in vitro models derived from primary human bronchial epithelial cells can help to identify new and corroborate existing biomarkers, they also allow to study the effects of heterogeneous dose distributions including the effects of locally high doses. These novel approaches can provide valuable input and validation data for mathematical models for risk assessment. These models can be applied to quantitatively translate the knowledge obtained from radon exposure to other exposures resulting in heterogeneous dose distributions within an organ to support radiation protection in general.

[Self-assessment of daily activities using the Duruöz Hand Index-Validation of the German translation]. / Selbstbeurteilung von Alltagsaktivitäten mittels Duruöz-Hand-Index ­ Validierung der deutschen Übersetzung.

BACKGROUND: Independence in activities of daily living depends to a large extent on the upper extremities; however, the instruments widely used in geriatrics to assess self-care abilities do not allow a focus on this body region. In order to map the fluctuating course of hand function-dependent daily living skills with a self-assessment instrument, rheumatologists have developed the Duruöz Hand Index (DHI). OBJECTIVE: The German translation authorized by Duruöz was tested for its applicability in the assessment of geriatric outpatient and day hospital patients and test quality criteria were determined. MATERIAL AND METHODS: Study participants completed the DHI three times. A postgraduate student blinded to the results performed an anamnesis and examination. The geriatric team made an inter-professional assessment of hand function-related daily living skills twice with at least 2­week intervals. RESULTS: Data collection was performed from 16 November 2016 to 27 April 2017 on 101 geriatric day hospital or outpatient patients. Retest reliability was high (0.937), as was internal consistency (Cronbach's α 0.949). Difficulty with activities of daily living correlated more closely with joint mobility (Keitel Index) and fine motor skills (20 cents test) than with hand strength. CONCLUSION: The DHI provides a survey of difficulties with activities of daily living that is focused on the upper extremities. Because about one in three patients required assistance (answering follow-up questions, reading aloud) despite the exclusion of patients with more severely impaired cognition and vision, the examiner should remain present.

Predictions of inter- and intra-lobar deposition patterns of inhaled particles in a five-lobe lung model.

OBJECTIVE: To develop a stochastic five-lobe lung model and to compute particle deposition fractions in the five lobes, considering anatomical as well as ventilatory asymmetry. MATERIALS AND METHODS: The stochastic five-lobe lung model was derived from an existing stochastic model for the whole lung, which implicitly contains information on the lobar airway structure. Differences in lobar ventilation and sequential filling of individual lobes were simulated by a stochastic lobar ventilation model. Deposition fractions of inhaled unit density particles in the five lobes were calculated by an updated version of the Monte Carlo deposition code Inhalation, Deposition, and Exhalation of Aerosols in the Lung (IDEAL). RESULTS: Simulations for defined exposure and breathing conditions revealed that the two lower lobes receive higher deposition and the two upper lobes lower deposition, compared to the average deposition for the whole lung. The resulting inter-lobar distribution of deposition fractions indicated that the non-uniform lung morphometry is the dominating effect, while non-uniform ventilation only slightly enhances the lobar differences. The relation between average lobe-specific deposition fractions and corresponding average values for the whole lung allowed the calculation of lobe-specific deposition weighting factors. DISCUSSION: Comparison with limited deposition measurements for upper vs. lower (U/L) and left vs. right (L/R) lobes revealed overall agreement between experimental and theoretical data. Calculations of the L/R deposition ratio for inhaled aerosol boli confirmed the hypothesis of Möller et al. that the right lung is less able to expand at the end of a breath because of the restrictive position of the liver.

The degree of inhomogeneity of the absorbed cell nucleus doses in the bronchial region of the human respiratory tract.

Inhalation of short-lived radon progeny is an important cause of lung cancer. To characterize the absorbed doses in the bronchial region of the airways due to inhaled radon progeny, mostly regional lung deposition models, like the Human Respiratory Tract Model (HRTM) of the International Commission on Radiological Protection, are used. However, in this model the site specificity of radiation burden in the airways due to deposition and fast airway clearance of radon progeny is not described. Therefore, in the present study, the Radact version of the stochastic lung model was used to quantify the cellular radiation dose distribution at airway generation level and to simulate the kinetics of the deposited radon progeny resulting from the moving mucus layer. All simulations were performed assuming an isotope ratio typical for an average dwelling, and breathing mode characteristic of a healthy adult sitting man. The study demonstrates that the cell nuclei receiving high doses are non-uniformly distributed within the bronchial airway generations. The results revealed that the maximum of the radiation burden is at the first few bronchial airway generations of the respiratory tract, where most of the lung carcinomas of former uranium miners were found. Based on the results of the present simulations, it can be stated that regional lung models may not be fully adequate to describe the radiation burden due to radon progeny. A more realistic and precise calculation of the absorbed doses from the decay of radon progeny to the lung requires deposition and clearance to be simulated by realistic models of airway generations.

Internal microdosimetry of alpha-emitting radionuclides.

At the tissue level, energy deposition in cells is determined by the microdistribution of alpha-emitting radionuclides in relation to sensitive target cells. Furthermore, the highly localized energy deposition of alpha particle tracks and the limited range of alpha particles in tissue produce a highly inhomogeneous energy deposition in traversed cell nuclei. Thus, energy deposition in cell nuclei in a given tissue is characterized by the probability of alpha particle hits and, in the case of a hit, by the energy deposited there. In classical microdosimetry, the randomness of energy deposition in cellular sites is described by a stochastic quantity, the specific energy, which approximates the macroscopic dose for a sufficiently large number of energy deposition events. Typical examples of the alpha-emitting radionuclides in internal microdosimetry are radon progeny and plutonium in the lungs, plutonium and americium in bones, and radium in targeted radionuclide therapy. Several microdosimetric approaches have been proposed to relate specific energy distributions to radiobiological effects, such as hit-related concepts, LET and track length-based models, effect-specific interpretations of specific energy distributions, such as the dual radiation action theory or the hit-size effectiveness function, and finally track structure models. Since microdosimetry characterizes only the initial step of energy deposition, microdosimetric concepts are most successful in exposure situations where biological effects are dominated by energy deposition, but not by subsequently operating biological mechanisms. Indeed, the simulation of the combined action of physical and biological factors may eventually require the application of track structure models at the nanometer scale.

[Hyponatremia in older persons (II)-A clear treatment : How to detect tricks and avoid pitfalls]. / Hyponatriämie im Alter (II) ­ eine klare Therapie : Tücken erkennen und Fallstricke umgehen.

The aim of this continuing medical education (CME) article (part II) is to describe the particular challenge of the treatment of hyponatremia, which occurs in older patients. This part II follows on from part I concerning the diagnosis in the previous volume. A staged approach is necessary. The best treatment is always when the underlying cause can be eliminated. Hyponatremia in older patients is mainly induced by the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. The authors use a concept for the first, second and third line strategy: (1) changing or discontinuation of drugs, (2) fluid restriction and (3) tolvaptan medication. The algorithm for treatment should be simple. It also contains recommendations for the correction rate. Caution is also needed in order to avoid the occurrence of an osmotic demyelination syndrome (ODS).

[Hyponatremia in older persons (part I)-keep diagnosis simple : How to detect tricks and avoid pitfalls]. / Hyponatriämie im Alter (Teil I) ­ Diagnose leicht gemacht : Tücken erkennen und Fallstricke umgehen.

Old age is a strong independent risk factor for hyponatremia. Dizziness, fatigue, reduced vigilance, cognitive impairment, gait deficits, nausea, vomiting, headache, falls, osteoporosis and fractures, coma and seizures are more frequent and severe than in middle-aged patients. Hyponatremia is mainly caused by the syndrome of inappropriate antidiuretic hormone (SIADH) secretion and also including drugs. Hyponatremia is multifactorial in a significant proportion of older patients. Hyponatremia requires a staged diagnostic approach to identify the underlying cause. The aim of this continuing medical education (CME) report (part I) is to emphasize the special challenges in the diagnostics of hyponatremia, which occur in older patients. Diagnostics should be kept simple. A special algorithm is presented. Part II concerning treatment will follow.

[Diagnosis and treatment of vascular dementia]. / Vaskulär bedingte Demenzen erkennen und behandeln.

Vascular dementias (VD, due to the various expressions of VD the plural form is used) are the second most common form of dementia after Alzheimer's dementia. These dementias play an important role especially in geriatric patients. They can occur due to acute events (e.g. stroke) and due to slowly progressive cerebrovascular damage. This article focuses on VD due to cortical and strategic infarcts, microangiopathic infarcts with lacunae as well as intracerebral bleeding. In addition to the clinical description and radiological findings, a special focus is on education, prevention and rehabilitation aspects.

Neurogeriatrics-a vision for improved care and research for geriatric patients with predominating neurological disabilities.

Geriatric medicine is a rapidly evolving field that addresses diagnostic, therapeutic and care aspects of older adults. Some disabilities and disorders affecting cognition (e.g. dementia), motor function (e.g. stroke, Parkinson's disease, neuropathies), mood (e.g. depression), behavior (e.g. delirium) and chronic pain disorders are particularly frequent in old subjects. As knowledge about these age-associated conditions and disabilities is steadily increasing, the integral implementation of neurogeriatric knowledge in geriatric medicine and specific neurogeriatric research is essential to develop the field. This article discusses how neurological know-how could be integrated in academic geriatric medicine to improve care of neurogeriatric patients, to foster neurogeriatric research and training concepts and to provide innovative care concepts for geriatric patients with predominant neurological conditions and disabilities.

Functional movement disorders in neurogeriatric inpatients : Underdiagnosed, often comorbid to neurodegenerative disorders and treatable.

BACKGROUND: The proportion of patients with functional movement disorders (FMD) is particularly high in neurology clinics. Treatment options have not been consistently developed, not well evaluated and not validated. This article presents the preliminary data on the prevalence and treatment response of patients with FMD who were treated within the framework of an early rehabilitative geriatric complex treatment at a university hospital for neurology. METHODS: From July 2017 to November 2018 the prevalence, demographic and clinical parameters, and response to treatment of FMD patients were documented and compared to non-FMD patients treated at the neurogeriatric ward of the University Hospital Schleswig-Holstein, in Kiel. Clinical endpoints were the Short Physical Performance Battery (SPPB) for mobility and the Barthel index for instrumented activity of daily life (iADL). RESULTS: The prevalence of FMD was 11% (19/175) and predominantly observed in women (74%). Of the FMD patients nine also had a diagnosis of either idiopathic Parkinson's disease (N = 7), dementia with Lewy bodies (N = 1) or progressive supranuclear palsy (N = 1). At admission, neither the SPPB nor the iADL differed significantly between FMD and non-FMD patients. The treatment response was comparable between the groups: SPPB change was +0.3±1.8 (mean, standard deviation) in FMD and +0.4±1.9 in non-FMD patients (p = 0.83). The iADL change was +19±15 in FMD and +18±17 in non-FMD (p = 0.83). CONCLUSION: The prevalence of FMD was unexpectedly high in the neurogeriatric ward of a German university hospital. There were comparable impairments and responses to multidisciplinary treatment in mobility and iADL between FMD and non-FMD geriatric patients, suggesting that specific and informed treatment provided by a multidisciplinary geriatric team is effective in geriatric FMD patients. Further studies of this underdiagnosed disorder in older age are warranted.

Alemtuzumab depletion failure can occur in multiple sclerosis.

Alemtuzumab is a lymphocyte-depleting antibody and one of the most effective treatments for relapsing multiple sclerosis. However, it also causes loss of immune-tolerance leading to secondary autoimmunity and marked anti-drug antibody responses. Although these anti-drug responses have been reported to be of no significance, we hypothesized that they will affect the depleting capacity and treatment response in some individuals. This was found following analysis of the regulatory submission of the pivotal phase III trials, which was obtained from the European Medicines Agency. At the population level there was lack of influence of 'ever-positive' alemtuzumab-specific antibody responses on lymphocyte depletion, clinical efficacy and adverse effects during the 2-year trial. This was not surprising as no one before the first infusion, and only 0·6% of people before the second-infusion, had pre-infusion, neutralizing antibodies (NAbs). However, at the individual level, NAbs led to poor lymphocyte depletion. Importantly, it was evident that 31% of people had NAbs and 75% had binding antibodies at the end of treatment-cycle 2, which suggests that problems may occur in people requiring additional alemtuzumab cycles. In addition, we also identified individuals, following 'post-marketing' alemtuzumab use, whose lymphocyte level was never effectively depleted after the first infusion cycle. Hence, although alemtuzumab depletes lymphocytes in most individuals, some people fail to deplete/deplete poorly, probably due to biological-response variation and NAbs, and this may lead to treatment failure. Monitoring depletion following infusion and assessment of the neutralizing response before re-infusion may help inform the decision to retreat or switch therapy to limit treatment failure.

VCSEL mode and polarization control by an elliptic dielectric mode filter.

In this paper, we demonstrate the effectiveness of polarization mode control in vertical-cavity surface-emitting lasers (VCSELs) with integrated elliptic dielectric mode filters. The single-mode single-polarization laser operation is obtained by an irregularly shaped oval dielectric mode filter, aimed at cost-effective mass production. The orthogonal polarization suppression ratio was measured to be 16.7 dB, and the side-mode suppression ratio exceeded 30 dB. A single fundamental mode power of 0.55 mW was achieved at a bias current of 4 mA. We compared the spectra and near-field intensities of the dielectric mode filter VCSEL with a reference device. The comparison clearly indicates the effectiveness of our dielectric mode filter in controlling the transverse- and polarization-mode properties of VCSELs.

High single-fundamental-mode power VCSEL integrated with alternating aluminum content micro-lens.

The patterned top-emitting vertical-cavity surface-emitting laser (VCSEL) with a fixed diameter etching window was etched in hydrobromic acid solution with anisotropic etching. An all-semiconductor micro-lens that consisted of alternating aluminum content was directly formed on the output window. The etched curved surface with designed curvature radius makes the mirror loss located at the convex region differ from the edge region. Higher-order modes experience larger mirror loss and are therefore filtered out. The VCSEL with the designed micro-lens reaches a 3.14 mW single-mode power with side-mode suppression ratio >25 dB, which is over 50 times higher than the 0.06 mW single-mode power of the reference VCSEL.

OPSR enhancement of high-temperature operating shallow-surface grating VCSELs.

A polarization-stable single-mode 894 nm vertical cavity surface emitting laser (VCSEL) with an orthogonal polarization suppression ratio of 30 dB, even at a temperature up to 80°C, was achieved for atomic clock applications by utilizing shallow-surface gratings. An improved grating VCSEL fabrication technology for mass production was also proposed by taking advantage of the displacement Talbot lithography. The multi-mode grating VCSEL was also measured for other applications that need polarization stability, such as doubled-data-rate polarization multiplexed free-space links.

[The Medical Expert in the Physician Liability Process: What has Changed Since the Enactment of the Patient Rights Act (PatRG)?] / Der ärztliche Sachverständige im Arzthaftungsprozess: Was hat sich seit Inkrafttreten des Patientenrechtegesetzes geändert?

In February 2013, the law on the improvement of the rights of patients enacted a whole series of legal regulations for different areas of health care. In terms of physician liability, the Patient Rights Act and the introduction of sections 630a-h in the Civil Code (BGB) brought a transparency-oriented representation of general contractual aspects, a comprehensive legal regulation regarding patient education and consent, standardization of the treatment documentation, and a new basis for the right of access to the treatment file. The specificities of the treatment contract developed in the framework of supreme judicial jurisprudence were translated into legal form, and the presumed facts known from established case law and considered favorable to the patient under certain conditions were then summarized as exceptions to the principle of the objective burden of proof. In this paper the regulations in the new sections 630a-h of the Civil Code are presented and examined with regard to the consequences to be taken into account by the medical expert in the physician liability process.

[Chameleon spondylodiscitis : Challenge for geriatricians]. / Chamäleon Spondylodiszitis : Herausforderung für den Geriater.

The incidence of spondylodiscitis is increasing and attributable to an aging population with multimorbidities. Spondylodiscitis represents a life-threatening disease. Typical clinical manifestations often involve nonspecific symptoms with back pain; however, due to the frequent absence of fever the disease is often overlooked. Pathogen detection and spinal imaging with magnetic resonance imaging (MRI) are essential for the diagnosis. Identification of the causative pathogen is particularly important for initiating targeted antibiotic treatment. Debridement and stabilization are the mainstays of surgical management, even though foreign material must be implanted into the focus of inflammation.

Comparison of airway deposition distributions of particles in healthy and diseased workers in an Egyptian industrial site.

The objective of this study is the prediction and comparison of airway deposition patterns of an industrial aerosol in healthy workers and workers suffering from silicosis. Mass concentrations and related size distributions of particulate matter were measured in the industrial area of Samalut in Minia, Egypt. A novel stochastic lung deposition model, simulating the symptoms of silicosis by chronic bronchial (Br) obstruction and emphysema in the acinar (Ac) region, was applied to compute mass deposition fractions, deposition density, deposition rate and deposition density rate distributions in healthy and diseased workers. In the case of healthy workers, both mass deposition fractions and deposition rates are highest in the first half of the Ac region of the lung, while the corresponding deposition density and deposition density rate distributions exhibit a maximum in the large Br airways. In the case of diseased lungs, bullous emphysema causes a large deposition peak in the region of the bronchioli respiratorii. Regional mass deposition fractions adopt maximum values in the extrathoracic region, except during mouth breathing for bullous emphysema, where Ac deposition can be the most prominent. In general, lung deposition is significantly higher in diseased than in healthy lungs. Indeed, workers suffering from silicosis receive significantly higher Ac doses than healthy workers exposed to the same aerosol. Thus, this illness may progress faster if a diseased worker remains in a strongly polluted area.

[Chameleon spondylodiscitis : Challenge for geriatricians]. / Chamäleon Spondylodiszitis : Herausforderung für den Geriater.

The incidence of spondylodiscitis is increasing and attributable to an aging population with multimorbidities. Spondylodiscitis represents a life-threatening disease. Typical clinical manifestations often involve nonspecific symptoms with back pain; however, due to the frequent absence of fever the disease is often overlooked. Pathogen detection and spinal imaging with magnetic resonance imaging (MRI) are essential for the diagnosis. Identification of the causative pathogen is particularly important for initiating targeted antibiotic treatment. Debridement and stabilization are the mainstays of surgical management, even though foreign material must be implanted into the focus of inflammation.