Enhanced Risk Stratification for Children and Young Adults with B-Cell Acute Lymphoblastic Leukemia: A Children's Oncology Group Report.

Current strategies to treat pediatric acute lymphoblastic leukemia rely on risk stratification algorithms using categorical data. We investigated whether using continuous variables assigned different weights would improve risk stratification. We developed and validated a multivariable Cox model for relapse-free survival (RFS) using information from 21199 patients. We constructed risk groups by identifying cutoffs of the COG Prognostic Index (PICOG) that maximized discrimination of the predictive model. Patients with higher PICOG have higher predicted relapse risk. The PICOG reliably discriminates patients with low vs. high relapse risk. For those with moderate relapse risk using current COG risk classification, the PICOG identifies subgroups with varying 5-year RFS. Among current COG standard-risk average patients, PICOG identifies low and intermediate risk groups with 96% and 90% RFS, respectively. Similarly, amongst current COG high-risk patients, PICOG identifies four groups ranging from 96% to 66% RFS, providing additional discrimination for future treatment stratification. When coupled with traditional algorithms, the novel PICOG can more accurately risk stratify patients, identifying groups with better outcomes who may benefit from less intensive therapy, and those who have high relapse risk needing innovative approaches for cure.

Urban-rural disparities in old-age mortality vary systematically with age: evidence from Germany and England & Wales.

OBJECTIVES: Population aging - which tends to be more pronounced in rural than in urban areas - poses important challenges for facilitating equal opportunities for aging well and 'aging in place.' Unmet health care needs among the older rural population may result in poorer health and higher mortality, but the scientific evidence of a systematic rural mortality disadvantage at older ages is scarce. We argue that systematic urban-rural mortality differences by age may be found if the confounding effect of life expectancy is considered. STUDY DESIGN: Nationwide population-based study. METHODS: We draw on age- and sex-specific data for the population aged 60+ years in NUTS-3 regions in Germany (2016-2018) and LAU-1 regions in England & Wales (2017-2019). To account for the confounding effect of life expectancy, we compare age-specific mortality only across urban and rural regions with similar life expectancy levels. We quantify statistical uncertainty with bootstrapping. RESULTS: The results show a remarkable shift from higher mortality in urban regions to higher mortality in rural regions with increasing age, when controlling for the confounding effect of life expectancy. That is, the urban mortality disadvantage is strongest for the population aged 60-79 years, whereas the pattern shifts toward a rural mortality disadvantage for the population aged 80 years and older. This pattern is present at all levels of life expectancy, for both sexes and in both countries. CONCLUSION: The shift from urban to rural excess mortality over age suggests that regions may vary in their capability to respond to arising health issues across older ages. This systematic mortality disadvantage is of high public health relevance and should be considered in designing policies to reduce regional mortality disparities.

[Which typical foot fractures should the radiologist know?] / Welche typischen Fußfrakturen sollte der Radiologe kennen?

CLINICAL/METHODICAL ISSUE: Due to mechanical loading and the number of joints involved, fractures of the foot are among the most common fractures. STANDARD RADIOLOGICAL METHODS: X-ray is basis for diagnostic workup of all foot fractures. METHODICAL INNOVATIONS: For stress fractures, the additional use of magnetic resonance imaging (MRI) is indicated. Computed tomography (CT) can be used for preoperative imaging of intraarticular tarsal fractures. PERFORMANCE: Simple traumatic fractures can be reliably diagnosed by X­ray. On the other hand, there is a poor sensitivity for stress fractures. ACHIEVEMENTS: Using a combination of X­ray, MRI, and CT, it is possible to reliably diagnosis and classify foot fractures. PRACTICAL RECOMMENDATIONS: The first step to diagnose a foot fracture should be the X­ray. CT and MRI can also be used to detect intra-articular fractures and MRI can be used for stress fractures.

How long do centenarians survive? Life expectancy and maximum lifespan.

OBJECTIVES: The purpose of this study was to explore the pattern of mortality above the age of 100 years. In particular, we aimed to examine whether Scandinavian data support the theory that mortality reaches a plateau at particularly old ages. Whether the maximum length of life increases with time was also investigated. METHODS: The analyses were based on individual level data on all Swedish and Danish centenarians born from 1870 to 1901; in total 3006 men and 10 963 women were included. Birth cohort-specific probabilities of dying were calculated. Exact ages were used for calculations of maximum length of life. Whether maximum age changed over time was analysed taking into account increases in cohort size. RESULTS: The results confirm that there has not been any improvement in mortality amongst centenarians in the past 30 years and that the current rise in life expectancy is driven by reductions in mortality below the age of 100 years. The death risks seem to reach a plateau of around 50% at the age 103 years for men and 107 years for women. Despite the rising life expectancy, the maximum age does not appear to increase, in particular after accounting for the increasing number of individuals of advanced age. CONCLUSION: Mortality amongst centenarians is not changing despite improvements at younger ages. An extension of the maximum lifespan and a sizeable extension of life expectancy both require reductions in mortality above the age of 100 years.

The positive influence of methotrexate on the mortality of patients with rheumatoid arthritis is partly independent of its effect on disease activity: results of a re-evaluation 18 years after baseline.

OBJECTIVES: Methotrexate (MTX) is the anchor drug in the treatment of patients with rheumatoid arthritis (RA). MTX shows effects on disease activity and mortality. However, it is unclear whether the effect of MTX on mortality depends on its effect on disease activity. METHODS: In a post-hoc analysis we analysed the data of our cohort established in Ratingen, Germany, and included all patients starting treatment with MTX (n=271) between 1980 and 1987. One year after baseline (BL), response to MTX treatment was assessed using a modified ACR 20 response. Follow-up data of 250 patients were available after 10 and 18 years. RESULTS: After 1 year, there were 66% responders and 20% non-responders; only 14% had discontinued MTX treatment due to side effects or lack of efficacy. Most patients continued MTX treatment irrespective of efficacy. Ten years after BL, 61% of the patients were still treated with MTX. After 18 years, the responder-group showed a standardised mortality ratio of 1.6 compared to 3.2 for the group of non-responders. However, when adjusting for age, gender, response to MTX treatment one year after BL, number of swollen joints and comorbidities after 10 years an independent association of continued MTX treatment with lower mortality was found for the period 10 to 18 years after BL (hazard ratio (HR): 0.63, 95% confidence interval: 0.43-0.92, p=0.015). CONCLUSIONS: In this cohort, the mortality lowering effect of continued MTX use was partly independent of its effect on disease activity. This finding may affect treatment decisions concerning RA patients with insufficient response to MTX.

[Association of work load and mental disorders: review of the data]. / Zusammenhang von Arbeitsbelastungen und psychischen Erkrankungen : Review der Datenlage.

Currently, the two faces of work as described by Kurt Lewin (The socialization of the Taylor system. A fundamental examination of work and vocational psychology 1920) are clearly pronounced. Thus, work can be beneficial to personal development and well-being as work is a possible source of learning opportunities, motivation and positive emotional states. On the other hand there are a growing number of complaints about stress and exhaustion because of high work load and working days lost due to incapacity to work because of mental ill health are increasing. The question arises whether there is a relationship between work load and mental health. This article presents information on the data and tries to clarify if the relationship between work load and mental health results more due to bad job design than a distorted response behavior due to mental illness.

Possible effects of anaesthetic management on the 1 yr followed-up risk of herpes zoster after Caesarean deliveries.

BACKGROUND: As general anaesthesia may compromise the immune system, it has been hypothesized that latent varicella-zoster virus is more likely to be reactivated and cause herpes zoster in mothers after Caesarean deliveries under general anaesthesia. Our study was thus aimed at investigating the risk of herpes zoster among women during the first year after Caesarean deliveries under either general or regional anaesthesia. METHODS: Two nationwide population-based data sets were utilized, including the Taiwan birth certificate registry and the Taiwan National Health Insurance Research Dataset. From 2001 to 2003, a total of 162 495 women underwent Caesarean delivery. Among them, 21 454 women received general anaesthesia, whereas 141 041 patients received regional anaesthesia. Each individual was followed for 1 yr to identify the subsequent occurrence of herpes zoster. Cox's proportional hazards regressions were performed for analysis. RESULTS: During the 1 yr follow-up period, 0.46% of the women receiving general anaesthesia experienced an episode of herpes zoster, compared with 0.34% of women receiving regional anaesthesia. In Caesarean deliveries, the use of general anaesthesia compared with regional anaesthesia was independently associated with a 1.29-fold (95% confidence interval=1.04-1.61) increase in the 1 yr risk of herpes zoster, after adjusting for maternal and infant characteristics. CONCLUSIONS: In this series, there was a small increased risk of herpes zoster in the year after Caesarean delivery with general anaesthesia. Future studies are needed to further investigate these findings.

A dose of only 5 mg prednisolone daily retards radiographic progression in early rheumatoid arthritis - the Low-Dose Prednisolone Trial.

Glucocorticoids (GC) have been used to treat rheumatoid arthritis (RA) for more than 60 years. Despite this very long experience, there remains considerable debate concerning the adequate dosing and timing of these medications, primarily because of frequent and sometimes serious side effects, particularly in high doses. GCs are documented to provide immediate symptomatic relief and to decrease signs of inflammation in active disease. At the time when the Low-Dose Prednisolone Trial (LDPT) was designed, no clear evidence was available concerning whether low doses of GCs given over a long period add to slowing of structural damage in RA. The trial was therefore designed to test the hypothesis that even a low dose of prednisolone that was thought to cause no or only very limited harm could slow radiographic progression. The trial therefore included patients with active early RA (disease duration less than two years) who received either prednisolone 5 mg/day or placebo on concomitant DMARD therapy with parenteral gold or methotrexate for two years. Radiographs of hands and feet were taken at baseline, and at 6, 12 and 24 months. Structural damage was assessed using change in the Ratingen score (0-190 scale) as the primary outcome, and change in the Sharp/van der Heijde score (0-448 scale) for additional information concerning the same radiographs. Of 192 patients in the study, 166 were available for intention to treat analysis (ITT), and 76 completed the study per protocol (PP). Progression of the Ratingen score was significantly less at all consecutive time points in the prednisolone group compared to the control group, with the greatest difference after 6 months. At 24 months the increase in score in the prednisolone group was 1.2 ± 3.5, (95% CI 0.4-2.1) and in the placebo group 4.3 ± 6.8 (95% CI 2.7-5.9) (p=0.006, ITT-analysis). This was confirmed by the results of the Sharp/van der Heijde erosion and total score with an increase of the total score of 5.3 ± 10.7 units in the prednisolone compared to 11.4 ± 19.1 in the placebo group (p=0.022) at 24 months. The LDPT trial therefore confirmed that a very low daily dose of 5 mg prednisolone given over two years in combination with background DMARD therapy substantially decreases radiographically detectable damage in patients with early RA.

Glucocorticoid treatment in early rheumatoid arthritis.

Glucocorticoids (GCs) have been an invaluable tool in the treatment of patients with rheumatoid arthritis (RA) for decades, with a focus mainly on symptom management. In addition, several studies in the last 15 years have shown that GCs are also disease-modifying in patients with RA - which implies that they inhibit radiographic progression. These effects seem to be especially important in the early course of disease. Nonetheless, there is still a lack of knowledge concerning optimal therapeutic strategies with GCs, particularly regarding patient selection and optimal dosage schedules.

Efficacy of methotrexate in comparison to biologics in rheumatoid arthritis.

This paper reviews trials comparing the efficacy of MTX and biologic agents. So far, the clinical evaluations of 9 biologics have been published. Three TNF inhibitors - etanercept, adalimumab, golimumab - and the IL 6 receptor inhibitor tocilizumab have been investigated in MTX naïve patients using a parallel design. The trials had 3 treatment arms: monotherapies of MTX and of the biologic compound, and the combination of both. The other biologics - infliximab, certolizumab pegol, anakinra, rituximab, and abatacept - were investigated in patients who experienced inadequate response to MTX, and were treated with MTX + biologic agent versus MTX + placebo. That design does not provide a real comparison between MTX and the biologics but may indirectly give an indication of the relative efficacy of the different biologic agents. In all trials providing a head to head comparison, MTX and biologics were similarly effective as measured by ACR and EULAR response criteria including clinical remission. In general, improvement started earlier with biologic treatment than with MTX therapy. Inhibition of radiological progression was stronger with biologics probably since TNF inhibitors, in addition to their anti-inflammatory effect, directly reduce osteoclast activity. The efficacy of biologics was significantly potentiated when they were combined with MTX. Based on the trial results the efficacy of MTX may be underestimated: the initial dose of MTX was too low and was increased only gradually. The trial design with ITT analysis and LOCF may have been disadvantageous for MTX since more patients treated with MTX withdrew and thereby had less time under treatment. Folic acid supplementation may have reduced the efficacy of MTX by interfering with its mechanism of action. Nonetheless, all trials confirmed a surprisingly good performance of MTX in comparison with biologics.

Rheumatoid arthritis patients who smoke have a higher need for DMARDs and feel worse, but they do not have more joint damage than non-smokers of the same serological group.

OBJECTIVES: To investigate the influence of smoking on disease activity, drug need and radiographic joint damage in RF-positive and -negative patients with early RA. METHODS: Baseline and 3-yr follow-up data of 896 patients of an early RA cohort comprised clinical and radiographic parameters (Ratingen Score). Information about disease severity, treatment and smoking were obtained by questionnaires. Univariate and multivariate analyses were used to show the influence of smoking on drug use, ACR improvement and joint damage. Smokers and non-smokers were compared according to RF serology. RESULTS: Fifty per cent of the patients were never, 23% past and 27% current smokers. Current smokers were significantly more often RF-positive (71%) than past (66%) or never smokers (53%), but neither the RF-positive nor the RF-negative current smokers had higher 28-joint disease activity score (DAS28) or radiographic scores than never or past smokers. Within 3 yrs, current smokers had taken significantly more DMARD combinations or biologics. Non-smokers and those with <20 pack-years (PYs) had a 2-fold higher probability to reach ACR improvement than heavy smokers (>20 PYs). However, smokers did not differ in radiographic joint damage when compared with non-smokers of the same serological group. CONCLUSIONS: The higher use of DMARDs may indicate that smoking weakens the potency of anti-rheumatic drugs and/or is needed to control an otherwise higher disease activity. Since the risk of adverse events increases with the amount of drugs taken, this is another reason to persuade RA patients to quit smoking.

[Imaging in ankylosing spondylitis]. / Bildgebung bei Spondylitis ankylosans.

In addition to the typical clinical symptoms, conventional x-rays and magnetic resonance imaging (MRI) are important for the diagnosis and management of ankylosing spondylitis (AS). While radiography is mainly useful for detecting chronic structural changes, MRI is, in addition, able to detect active inflammation. The detection of structural changes in the sacroiliac joints and, in part, the spine, remains the gold standard for the diagnosis of AS. The detection of active sacroiliitis or spondylitis in early disease stages is only possible using MR techniques such as STIR and T1 post-gadolinium sequences. Lateral radiographs of the spine are useful for detecting shiny corners and the characteristic syndesmophytes and ankylosis. The modified Stoke Anklyosing Spondylitis Spine Score (SASSS) is the best scoring method for quantifying such changes, allthough only the cervical and the lumber spine are evaluated with this method. MRI changes can also be quantified. New scoring methods are sensitive to change only 3 months after initiation of therapy with anti-TNF agents.

Is remission in rheumatoid arthritis associated with radiographic healing?

The precondition for joint damage in rheumatoid arthritis (RA) is inflammation, and the precondition for healing is absence of inflammation. A systematic search for healing phenomena in RA patients in remission has not yet been undertaken. In reports of patients in whom healing was observed, clinical and laboratory data have not been published in part due to space restrictions. However, this preliminary review of the existing literature about repair supports the thesis that a strong association may exist between remission and repair. Several reports indicate that patients in whom radiographic repair was seen were in clinical remission. In most reports clinical response to treatment was very good, and in groups of patients in which scoring was done, evidence of repair was seen in patients with strong inhibition or halt of radiographic progression. In contrast, healing is unlikely to be detected in patients with persistent clinically active disease and/or moderate or strong radiographic progression. In most reports clinical response to treatment was very good, and in groups of patients in which scoring was done, evidence of repair was seen in patients with strong inhibition or halt of radiographic progression. In contrast, healing is unlikely to be detected in patients with persistent clinically active disease and/or moderate or strong radiographic progression.

[Community knowledge about stroke. A survey in the District of Wesel, Germany (2002)]. / Schlaganfallwissen der Bevölkerung. Survey im Kreis Wesel (2002).

Community knowledge of stroke signs and risk factors in Germany is poor, while lacking knowledge is an important cause for delays in hospital admission. In the Wesel district (North Rhine-Westphalia) the local health conference put this issue on its agenda and initiated a phone survey. The aim was to assess community knowledge of stroke symptoms and risk factors as well as self-reported prevalence of established risk factors; in addition, the role of information on stroke risk provided to patients by the general practitioner (GP) was to be estimated. The study population was defined as comprising all residents in the district of Wesel between 18 and 87 years of age (approx. 385,000 people). The sample of 1,089 persons was drawn randomly and the telephone survey was carried out by the CATI-Laboratory (Computer Assisted Telephone Interviews) at the Institute of Public Health (lögd, Bielefeld) between 18 February and 28 March 2002. A total of 1,089 people were interviewed, of whom 31.9% knew no symptom, 25.7% could name one symptom, 23.8% two symptoms and 18.6% knew three or more correct signs. Weakness/paralysis was named most frequently by 43.6% of the respondents. The majority of respondents named smoking as a risk factor (59.6%), while hypertension was mentioned by 39.4% of the participants. Among 555 respondents aged 45 years and older, 75.1% said they had never received a GP's advice on stroke risk, while 75.3% among these persons reported to have at least one risk factor. The present study shows a persistent lack of community knowledge about stroke. It is recommended that knowledge be improved especially with regard to (a) proper action: "stroke is a medical emergency-call the emergency telephone code 112", (b) symptoms and warning signs and (c) major stroke risk factors, especially high blood pressure. Moreover, information and advice on stroke should play a bigger part in the doctor's daily practice; patients should be made aware of their stroke risks and ways of prevention.

[Imaging methods in rheumatology: imaging in psoriasis arthritis (PsA)]. / Bildgebende Verfahren in der Rheumatologie: Bildgebung bei der Psoriasisarthritis (PsA).

Conventional radiography is still the standard method of imaging in PsA since it displays many joints at the same time, thereby allowing different types of joint involvement to be recognized. Moreover, thanks to the high resolution of radiography, bony changes in a single joint are depicted in a brilliant way. Several features of psoriatic arthritis allow the distinction from rheumatoid arthritis, including the frequent involvement of the distal interphalangeal joints, asymmetry of joint involvement, axial involvement of finger joints, oligoarticular involvement; however, symmetric polyarthritis is also possible. At the level of the single joint, there are signs of severe destructive changes potentially leading to mutilation and at the same time signs of periostal bone proliferation and ankylosis may be present. Bony proliferation and/or osteolysis are not restricted to the joint region but can affect also the total phalanx with bone apposition or concentric osteolysis which may lead to a complete disappearance of phalanxes. For purposes of quantification of radiographic changes scoring methods are used that were originally developed for rheumatoid arthritis. So far, there is only one validated scoring method that was specifically designed for PsA and that takes into account both features of PsA, damage as well as proliferation of bone. In contrast to conventional radiography, MRI and sonography are able to visualize inflammatory processes within the soft tissue (joint capsules, tendon sheaths, tendon insertions, etc.), allowing an estimation of disease activity. Scintigraphy is nonspecific and can only be used to detect clinically silent inflammatory spots. The relatively frequent spinal (axial) involvement is similar to that seen in ankylosing spondylitis. However, unilateral sacroiliitis, asymmetry of syndesmophytes and development of parsyndesmophytes may distinguish PsA from ankylosing spondylitis. While conventional radiography demonstrates the bony consequences of inflammation in the spine, MRI also shows the active inflammatory changes in sacroiliacal joints and vertebrae.

Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data.

Adverse effects of glucocorticoids have been abundantly reported. Published reports on low dose glucocorticoid treatment show that few of the commonly held beliefs about their incidence, prevalence, and impact are supported by clear scientific evidence. Safety data from recent randomised controlled clinical trials of low dose glucocorticoid treatment in RA suggest that adverse effects associated with this drug are modest, and often not statistically different from those of placebo.

[Imaging procedures in rheumatology. Differential diagnosis using various imaging procedures in rheumatoid arthritis (RA)]. / Bildgebende Verfahren in der Rheumatologie Differenzialindikation der verschiedenen bildgebenden Verfahren bei der rheumatoiden Arthritis (RA).

Conventional radiography, ultrasonography (US), magnetic resonance imaging (MRI), computed tomography, and scintigraphy are imaging techniques in use for rheumatoid arthritis (RA). Conventional radiography of the hands and the forefeet should be performed every 6 to 12 months in the first two years, and every 12 to 24 months after two years, in search of erosions. If radiography fails to detect erosions, radiography using a second plane should be done. US or MRI may be used to detect earlier erosions if therapeutic consequences exist. In severe RA, radiography of the cervical spine in the neutral position and with inclination should be performed every 3 to 4 years. MRI should be done, if the distance between atlas and dens is >4 mm. Scintigraphy is indicated if arthralgia occurs in many joints. US may detect or exclude inflammatory changes if arthralgia occurs in a few joints. Single symptomatic joints may be assessed by US to differentiate pathologies. Radiography aids in establishing a differential diagnosis, e. g., to detect osteoarthritis. MRI is indicated if the radiography or US is equivocal. It is indicated to diagnose osteonecrosis or meniscal lesions. Arthrocenthesis may be done without imaging or under radiographic or sonographic guidance.