Cervix cytology samples revealed increased methylation of the human markers FAM19A4/miR124-2 up to 8 years before adenocarcinoma.

INTRODUCTION: Methylation analysis of the promoter region of tumor-suppressor genes has previously shown high sensitivity for detection of high-grade cervical intraepithelial neoplasia (CIN) and cancer. HPV-testing has a high sensitivity to identify women at risk to develop cancer, and has been implemented in cervical screening programs in several countries. But in most HPV-positive women the infection will clear and they will not develop cancer. Testing for methylation could help to identify women who have potentially progressive cervical disease and need closer follow-up. The goal of the present study was to investigate the potential use of methylation as a triage test of HPV-positive women in the screening program. MATERIAL AND METHODS: A collection of liquid-based cytology (LBC) samples from 106 women, collected between 4 months and 8 years before histologically confirmed cervical cancer or CIN3, was analyzed for hypermethylation of the human genes FAM19A4 and miR124-2. RESULTS: Methylation was detected in 45% (33/73) of normal LBC samples from women who later developed CIN3+, compared with 10% (3/31) of normal LBC samples from women without subsequent dysplasia (P = 0.0006). Overall, methylation was detected in 39% (14/36), 51% (19/37), 61% (14/23) and 70% (7/10) of LBC samples from women who later developed CIN3, adenocarcinoma in situ (AIS), squamous cell carcinoma (SCC) and adenocarcinoma (ADC), respectively. Positive methylation analysis was not significantly more frequent than abnormal cytology of atypical squamous cells of unclear significance or worse (ASCUS+) in LBC samples collected 4 months to 8 years before SCC or AIS; however, prior to the development of ADC, methylation was observed in 7/10 LBC samples, despite normal cytology. Overall, LBC samples collected before invasive cancer (ADC and SCC) were more frequently positive in the methylation analysis than in cytological analysis of ASCUS+ (P = 0.048). For LBC samples collected more than 2 years before the development of AIS, SCC or ADC, methylation analysis showed a higher positivity rate than cytology did. CONCLUSIONS: Testing for methylation of FAM19A4/miR124-2 as a triage for HPV-positive women would be useful to identify women at risk of cancer development, especially adenocarcinoma. Further studies are needed to estimate the cost-effectiveness before introducing methylation testing in the screening program.

Hyperlipidemia in children and adolescents with acute lymphoblastic leukemia: A systematic review and meta-analysis.

BACKGROUND: The established association between acute lymphoblastic leukemia (ALL) and hyperlipidemia has, in some studies, been linked to toxicities such as pancreatitis, thrombosis, and osteonecrosis. However, a systematic review investigating the incidence, management, and clinical implications of hyperlipidemia during childhood ALL treatment is lacking. OBJECTIVES: Systematically assess the incidence of hyperlipidemia during ALL treatment, explore associations with risk factors and severe toxicities (osteonecrosis, thrombosis, and pancreatitis), and review prevalent management strategies. METHODS: A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Data synthesis was descriptive, and a meta-analysis of hypertriglyceridemia and risk of severe toxicities was performed. RESULTS: We included 13 studies with 3,425 patients. Hyperlipidemia incidence varied widely (6.7%-85%) but with inconsistent definitions and screening strategies across studies. Evidence regarding risk factors was conflicting, but age (> 10 years) and treatment with asparaginase and glucocorticosteroids seem to be associated with hyperlipidemia. Hypertriglyceridemia (grade 3/4) increased the risk for osteonecrosis (odds ratio (OR): 4.27, 95% confidence interval (CI): 2.77-6.61). No association could be established for pancreatitis (OR: 1.60, 95% CI: 0.53-4.82) or thrombosis (OR: 2.45, 95% CI: 0.86-7.01), but larger studies are needed to confirm this. CONCLUSION: The overall evidence of this systematic review is limited by the small number of studies and risk of bias. Our review suggests that hypertriglyceridemia increases the risk for osteonecrosis. However, larger studies are needed to explore the clinical implications of hyperlipidemia and randomized trials investigating hyperlipidemia management and its impact on severe toxicities.

Circulating tumour HPV16 DNA quantification - A prognostic tool for progression-free survival in patients with HPV-related oropharyngeal carcinoma receiving curative chemoradiotherapy.

BACKGROUND AND PURPOSE: Circulating tumour (ct) human papillomavirus (HPV) DNA is detectable in HPV-related oropharyngeal carcinoma (OPSCC) patients and has the potential to become an important clinical tool. This study aimed to evaluate the prognostic significance of ctHPV16-DNA kinetics during treatment with chemoradiotherapy in HPV-related OPSCC. Patients with p16-positive OPSCC recruited to the ARTSCAN III trial, comparing radiotherapy plus cisplatin with radiotherapy plus cetuximab, constituted the study cohort. MATERIALS AND METHODS: Blood samples before start and at the end of treatment of 136 patients were analysed. ctHPV16-DNA was quantified by real-time (q)PCR. The correlation between ctHPV16-DNA levels and tumour burden was investigated with Pearson regression analysis. The prognostic value of ctHPV16-DNA levels at baseline and decline during treatment was evaluated by area-under-the-curve (AUC) calculations and analysed with univariable and multivariable Cox proportional hazards models. RESULTS: ctHPV16-DNA was detectable with qPCR in 108/136 patients before start of treatment and cleared in 74% of these patients at the end of treatment. Disease burden was significantly correlated with baseline ctHPV16-DNA levels (R = 0.39, p=<0.001). Both lower baseline levels and AUC-ctHPV16DNA were associated with improved progression-free survival (p = 0.01 and p < 0.001), overall survival (p = 0.013 and p = 0.002), but not local tumour control (p = 0.12 and p = 0.2, respectively), with a stronger association for AUC-ctHPV16DNA (likelihood ratio test 10.5 vs 6.5 in Cox regression analyses of progression-free survival). In multivariable analysis including tumour volume (GTV-T) and treatment allocation (cisplatin vs cetuximab), AUC-ctHPV16DNA remained a significant prognostic marker of progression-free survival. CONCLUSION: ctHPV16-DNA is an independent prognostic factor in HPV-related OPSCC.

Differential Expression of the ß3 Subunit of Voltage-Gated Ca2+ Channel in Mesial Temporal Lobe Epilepsy.

The purpose of this study was to identify and validate new putative lead drug targets in drug-resistant mesial temporal lobe epilepsy (mTLE) starting from differentially expressed genes (DEGs) previously identified in mTLE in humans by transcriptome analysis. We identified consensus DEGs among two independent mTLE transcriptome datasets and assigned them status as "lead target" if they (1) were involved in neuronal excitability, (2) were new in mTLE, and (3) were druggable. For this, we created a consensus DEG network in STRING and annotated it with information from the DISEASES database and the Target Central Resource Database (TCRD). Next, we attempted to validate lead targets using qPCR, immunohistochemistry, and Western blot on hippocampal and temporal lobe neocortical tissue from mTLE patients and non-epilepsy controls, respectively. Here we created a robust, unbiased list of 113 consensus DEGs starting from two lists of 3040 and 5523 mTLE significant DEGs, respectively, and identified five lead targets. Next, we showed that CACNB3, a voltage-gated Ca2+ channel subunit, was significantly regulated in mTLE at both mRNA and protein level. Considering the key role of Ca2+ currents in regulating neuronal excitability, this suggested a role for CACNB3 in seizure generation. This is the first time changes in CACNB3 expression have been associated with drug-resistant epilepsy in humans, and since efficient therapeutic strategies for the treatment of drug-resistant mTLE are lacking, our finding might represent a step toward designing such new treatment strategies.

A Danish national, multicentre evaluation of the new donor vigilance system among different staff groups.

BACKGROUND AND OBJECTIVES: Two years after implementing a new national donor vigilance system, the Danish Haemovigilance Committee conducted a nationwide survey to evaluate the implementation among different staff groups. We present the results here. MATERIALS AND METHODS: The study was designed as an anonymous online survey to evaluate the satisfaction with the new registration, understanding of the parameters used and the user-friendliness. The REDCap platform was used. The questionnaire consisted of 22 questions. Ordinal variables were answered using five-point Likert scale (1 = strongly disagree to 5 = strongly agree). The data were analysed using descriptive statistics. Successful implementation was defined as mean overall satisfaction ≥4 and mean understanding of the individual components (adverse reaction category, severity and imputability) in the registration ≥4. RESULTS: In all, 104 staff members (77.9% donation staff) participated. The mean (SD) overall satisfaction among all participants was 3.96 (0.94), highest among medical doctors (4.43 (0.78)) and lowest for administrative or other personnel (2.78 (1.09)). The mean scores for understanding the adverse reaction categories, severity and imputability were 3.92 (0.94), 3.92 (0.94) and 3.88 (1.00), respectively. Experience with a previous donor vigilance system was associated with lower scores. The most successful implementation programme included a medical doctor for introduction and a contact person. CONCLUSION: The goal for successful implementation was not met. However, the overall attitude towards the new registration was positive and indicates that the system is suitable for different staff groups. Our results suggest that implementation could benefit from special attention to administrative staff and those accustomed to another donor vigilance system.

Positive association between social capital and the quality of health care service: A cross-sectional study.

BACKGROUND: Social capital is an acknowledged theoretical concept in work environment research focusing on collective resources that arise from social networks between employees in the workplace. Social capital is divided into bonding (in the work unit), bridging (between work units), and linking social capital (between the work units and management). However, only a few studies have investigated the relationship between social capital and the quality of health care, which is the key outcome of hospital services. OBJECTIVE: We investigated the associations between bonding, bridging and two types of linking social capital with the self-reported quality of health care services among Danish hospital employees. Next, we directly compared how social capital, workload and work pace each affected the quality of health care. DESIGN: A cross-sectional study at Regional Hospital West Jutland, Denmark. DATA: Questionnaire data were collected from 1589 Danish hospital employees. We used validated scales for social capital, workload, and work pace and self-developed scales for clinical quality, quality of patient involvement, and overall professional quality. METHODS: Binary logistic regression analyses were conducted. RESULTS: The analyses showed significant, positive associations of bonding and bridging social capital with all types of quality and negative associations between workload and all types of quality. The work pace was negatively associated with clinical quality. When covariates were included in the model, the associations remained statistically significant and showed no decrease in odds ratios. The marginal effects showed that when bonding and bridging social capital were increased by a single scale point, the predicted probability for a high clinical quality increased by an average of 0.5 percentage points. This increase corresponds to a change in the predicted probability of self-reported high clinical quality from 10% for the lowest reported bridging social capital to 54% for the highest reported bridging social capital. For workload and work pace, the effects were -0.2 and -0.3 percentage points, respectively. DISCUSSION & CONCLUSIONS: This study adds to the literature on positive work environment factors by focusing on social capital and the importance of well-functioning relationships within and especially between hospital units for high-quality health care. Hence, bridging and bonding social capital should be included in theoretical frameworks, as well as in hospital strategies and work environment guidelines to potentially improve the quality of health care services. However, further studies are needed to develop and test the effects of specific social capital interventions on the quality of health care services.

Reference intervals for platelet large cell ratio, platelet distribution width, plateletcrit and standard haematological parameters determined on the Sysmex XN-10 in a cohort of 30,917 Danish blood donors.

With the introduction of the Sysmex XN-10, new platelet indices reflecting platelet maturity can be obtained alongside with a full blood count. Therefore, the need for verified reference intervals is present. The purpose of this study was to establish reference intervals for the platelet indices: platelet large cell ratio (P-LCR), platelet distribution width (PDW) and plateletcrit (PCT) in a large Scandinavian cohort. Furthermore, we aimed to verify previously established reference intervals of haematological parameters included in a full blood count. Blood samples were obtained from healthy Danish blood donors and analysed by use of the Sysmex XN-10 analyser (Sysmex, Kobe, Japan). Non-parametric 95% reference intervals were determined as the 2.5 and 97.5 percentile and presented with 90% confidence intervals (CI). In total, 30,917 blood donors were included and the following reference intervals were established: P-LCR, ratio: 17.3 (90% CI: 17.2 - 17.5) - 46.2 (90% CI:45.9 - 46.4); P DW, fL:9.5 (90% CI: 9.5 - 9.5) - 17.2 (90% CI: 17.2 - 17.3) and PCT, fraction: 0.18 (0.18 - 0.18) - 0.38 (0.38 - 0.39). The reference intervals were stable across age and sex. Furthermore, reference intervals for the remaining haematological parameters included in a full blood count were verified and found in line with the previously established reference intervals.

The new donor vigilance system in Denmark reveals regional differences in adverse reactions supposedly caused by variation in the registration.

BACKGROUND AND OBJECTIVES: In recent years, there has been an increased focus among blood bank professionals on the health and safety of blood donors. In 2019, the Danish Haemovigilance Committee designed a national donor vigilance system to improve the registration of adverse reactions (AR) in blood donors. The new donor vigilance system was implemented on 1 January 2020 and we here present the results from the first year of registration. MATERIALS AND METHODS: AR categories, severity level and imputability score were defined based on the definitions from the International Society of Blood Transfusion, AABB and the European Commission directive 2005/61/EC, respectively. RESULTS: Across all severity levels, AR in Danish blood donors were found to be rare (1498 per 100,000 donations). Only 0.2% of the registered reactions were classified as serious (2.7 per 100,000 donations). Large regional differences were seen in the registration of citrate reactions and haematomas. CONCLUSION: Significant differences across regions in what to categorize as an AR were persistent even when including a severity score in the reporting. The Danish Haemovigilance Committee will commence a national work to align the definitions but suggests that this matter is raised to an international level as part of the current work to agree upon definitions for assessment of donor AR.

Persistent Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Immunocompromised Host Displaying Treatment Induced Viral Evolution.

We report a coronavirus disease 2019 case with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persisting beyond 333 days in an immunocompromised patient with chronic lymphocytic leukemia, asymptomatically carrying infectious SARS-CoV-2 at day 197 postdiagnosis. In addition, viral sequencing indicates major changes in the spike protein over time, temporally associated with convalescent plasma treatment.

Deep learning reveals 3D atherosclerotic plaque distribution and composition.

Complications of atherosclerosis are the leading cause of morbidity and mortality worldwide. Various genetically modified mouse models are used to investigate disease trajectory with classical histology, currently the preferred methodology to elucidate plaque composition. Here, we show the strength of light-sheet fluorescence microscopy combined with deep learning image analysis for characterising and quantifying plaque burden and composition in whole aorta specimens. 3D imaging is a non-destructive method that requires minimal ex vivo handling and can be up-scaled to large sample sizes. Combined with deep learning, atherosclerotic plaque in mice can be identified without any ex vivo staining due to the autofluorescent nature of the tissue. The aorta and its branches can subsequently be segmented to determine how anatomical position affects plaque composition and progression. Here, we find the highest plaque accumulation in the aortic arch and brachiocephalic artery. Simultaneously, aortas can be stained for markers of interest (for example the pan immune cell marker CD45) and quantified. In ApoE-/- mice we observe that levels of CD45 reach a plateau after which increases in plaque volume no longer correlate to immune cell infiltration. All underlying code is made publicly available to ease adaption of the method.

Streptococcal toxic shock syndrome in a patient with community-acquired pneumonia. Impact of rapid diagnostics on patient management.

Here we describe a community-acquired pneumonia with Streptococcus pyogenes , group A following a common cold caused by human metapneumovirus. The patient, a 58-year-old woman with no prior medical history, developed respiratory failure and multi-organ dysfunction caused by streptococcal toxic shock syndrome. The patient was admitted to the intensive care unit and treated with supportive care. The definitive diagnosis was made by BioFire FilmArray by Biomerieux (multiplex PCR) 12 h before positive blood culture, thus enabling the clinician to add clindamycin and intravenous immunoglobulin to the treatment. The patient was discharged fully recovered after 23 days. Streptococci group A is a rare pathogen of severe pneumonia and rapid diagnostics by syndromic testing, potentially performed in a near patient setting, is crucial for early implementation of targeted antimicrobial treatment.

Inner histopathologic changes and disproportionate zone volumes in foetal growth plates following gestational hypoglycaemia in rats.

Maternal hypoglycaemia throughout gestation until gestation day (GD)20 delays foetal growth and skeletal development. While partially prevented by return to normoglycaemia after completed organogenesis (GD17), underlying mechanisms are not fully understood. Here, we investigated the pathogenesis of these changes and significance of maternal hypoglycaemia extending beyond organogenesis in non-diabetic rats. Pregnant rats received insulin-infusion until GD20 or GD17, with sacrifice on GD20. Hypoglycaemia throughout gestation increased maternal corticosterone levels, which correlated with foetal levels. Growth plates displayed central histopathologic changes comprising disrupted cellular organisation, hypertrophic chondrocytes, and decreased cellular density; expression of pro-angiogenic factors, HIF-1α and VEGF-A increased in surrounding areas. Disproportionately decreased growth plate zone volumes and lower expression of the structural protein MATN-3 were seen, while bone ossification parameters were normal. Ending maternal/foetal hypoglycaemia on GD17 reduced incidence and severity of histopathologic changes and with normal growth plate volume. Compromised foetal skeletal development following maternal hypoglycaemia throughout gestation is hypothesised to result from corticosterone-induced hypoxia in growth plates, where hypoxia disrupts chondrocyte maturation and growth plate structure and volume, decreasing long bone growth. Maternal/foetal hypoglycaemia lasting only until GD17 attenuated these changes, suggesting a pivotal role of glucose in growth plate development.

Urinary incontinence in women: treatment barriers and significance for Danish and German GPs.

BACKGROUND: Female urinary incontinence (UI) is common. Only scant information exists on the significance of UI for GPs' consultations. OBJECTIVES: (i) To assess the significance of female UI for GPs and to look at barriers that could be detrimental to treatment by comparing GPs from Denmark and Germany, with different health systems and access to UI guidelines. (ii) To assess whether GPs' gender and age were relevant to the discussion of UI. METHODS: We conducted a cross-sectional survey. In the Fehmarn belt-region, a Danish-German border region, a self-developed questionnaire was sent to all the GPs (n = 930). RESULTS: In total, 407 GPs returned the questionnaire (43%); 403 questionnaires were analysed. Using a scale from 0 (never) to 10 (always), addressing UI was reported with an average score of 3.8 (SD: 2.1) among Danish and 3.5 (SD: 2.1) among German GPs. The topic was discussed more frequently with female (4.2; SD 2.2) than with male GPs (3.2; SD 2.0). Danish GPs estimated the prevalence among their female patients at 10% (SD: 8.0) and German GPs at 14% (SD: 11.2). 61% of the Danish and 19% of the German GPs used UI guidelines. German GPs significantly more often reported the barrier 'uncertainty of how to treat UI' [OR = 5.39 (95% CI: 2.8; 10.4)]. CONCLUSIONS: In consultations with female GPs, UI was discussed significantly more frequently than with male GPs. Compared with the Danish GPs, German GPs stated significantly more uncertainties regarding UI treatment measures, and tended not to use UI guidelines.

A survey on client-centered practice among danish occupational therapists.

BACKGROUND: In Denmark, the cost of healthcare services comprise 12% of the gross domestic product. A recommended method for optimizing effectiveness of and enhance client satisfaction with healthcare is client-centred practice (CCP), a central component of occupational therapy ideology. However, Danish occupational therapists' perceptions of CCP, including the facilitators and barriers that may contribute to CCP, have never been examined. AIM: To examine Danish occupational therapists' perceptions of CCP. METHODS: A survey was conducted using an electronic questionnaire in a small, but representative sample of Danish occupational therapists from all regions and practices. RESULTS: Three hundred and forty-six occupational therapists (5%) responded. Of these, 98% rated CCP as important, 97% considered their work client-centred, and 92% were satisfied with their level of CCP. Having time to conduct self-directed work, using assessments to identify clients' priorities, and CCP education, but not fixed regimes, were positively correlated with CCP. CONCLUSION: Danish occupational therapists perceive to practice CCP and appear to have adopted the beliefs, theory and ideals of CCP, perhaps influenced by the egalitarian Danish culture. Self-directed work, means to identify and evaluate their clients' wishes, and education facilitated CCP. Possible absence of occupational therapists not compliant with CCP makes further research warranted.

Predictors and reasons for help-seeking behavior among women with urinary incontinence.

INTRODUCTION AND HYPOTHESIS: The aim of the study was to evaluate the predictors and reasons for help-seeking behavior among women with urinary incontinence (UI) in Germany and Denmark. METHODS: This international postal survey was conducted in 2014. In each country, 4,000 women of at least 18 years of age were randomly selected. The questionnaires included validated items regarding help-seeking behavior and the ICIQ-UI SF. UI was defined as any involuntary loss of urine. Binary logistic regression analysis was used to assess factors predicting help-seeking behavior. Reasons for seeking or not seeking help were evaluated in terms of the severity of UI and as the most frequently reported. RESULTS: Of 1,063 Danish women with UI, 25.3% had consulted a physician compared with 31.4% of 786 German women with UI (p = 0.004). The severity and duration of UI, and actively seeking information regarding UI, were significant independent predictors of help-seeking behavior. Women with slight/moderate UI did not seek help because they did not consider UI as a problem, whereas of women with severe/very severe UI, German women reported that other illnesses were more important and Danish women reported that they did not have enough resources to consult a physician. CONCLUSIONS: Only a small proportion of women with UI had consulted a physician, and the driving forces for help-seeking behavior were severity and duration of UI and actively seeking information regarding UI. Public information campaigns might enhance consultation rates providing that passively receiving and actively seeking information have the same effects on help-seeking behavior. We show for the first time that reasons for not consulting a physician for UI vary depending on the severity of the UI.

Prevalence of urinary incontinence among women and analysis of potential risk factors in Germany and Denmark.

INTRODUCTION: Urinary incontinence (UI) is a prevalent condition that interferes with women's health-related quality of life. Prevalence rates from earlier studies are wide-ranging, due to heterogeneity in methodology, definition of UI and the populations included. We aimed to determine the prevalence of UI and associated risk factors in Germany and Denmark using the same methodology, definition and population. MATERIAL AND METHODS: A postal survey was conducted in two regions in Germany and Denmark, including 8000 women aged 18+ years. UI was defined as any complaint of involuntary loss of urine. The questionnaire contained socio-demographic questions and the International Consultation on Incontinence Modular Questionnaire Urinary Incontinence Short Form (ICIQ-UI SF). RESULTS: The response rate in Germany and Denmark was 46.2 and 66.6% (p < 0.001) and the prevalence rate of UI was 48.3 and 46.4% (p = 0.188), respectively. Stress urinary incontinence dominated among younger women, and urgency urinary incontinence and mixed urinary incontinence among women 80+ years in Germany and Denmark, respectively. The subgroup of women with body mass index (BMI) ≥35 had the highest prevalence of UI (67.3%). The subgroup of women with BMI <35 were more likely to have stress urinary incontinence, and the subgroup of women with BMI ≥35 were more likely to have mixed urinary incontinence. UI was significantly associated with age as with BMI, vaginal delivery, chronic obstructive pulmonary disease, and having at least one co-morbidity. CONCLUSIONS: Prevalence rates in the two regions in Germany and Denmark were similar, despite significantly different response rates. This difference may reflect various attitudes towards answering a questionnaire, but the response rate on questions concerning UI seemed consistent.

Differences in global DNA methylation of testicular seminoma are not associated with changes in histone modifications, clinical prognosis, BRAF mutations or gene expression.

Testicular germ cell tumours of young adults are comprised of a heterogeneous group of non-seminomas and a homogeneous group of seminomas. While the majority of seminomas retain a hypo-methylated genome, a small fraction displays a highly methylated genome, resembling hyper-methylated non-seminomas. It is well established from e.g. melanoma, colorectal and thyroid cancer that a methylated phenotype can be correlated to prognosis and can be related to BRAF mutations. In the present study we investigated the global methylation level in 67 seminomas and classified them as hypo-methylated, intermediate, patchy and hyper-methylated, respectively. A selected subset representing each level of DNA methylation and the TCam2 seminoma cell line were subsequently analysed for a range of other epigenetic marks (6 histone marks and 5-hydroxymethylcytosine), the presence of the BRAF V600E de novo mutation, differences in the transcriptome and finally correlated to the clinical outcome. We did not identify any histone marks or hydroxymethylation levels that correlated with the methylation level of the genome. Some histone marks, however, showed a great variation while others were found at the same level in all the investigated seminomas. We did not identify any tumours with the BRAF V600E mutation and transcriptome analysis revealed no significant differences between hypo- and hyper-methylated seminomas. Similarly, no obvious differences in the clinical manifestation of the patients representing hypo- or hyper-methylated seminomas were identified. The level of DNA methylation in testicular seminomas consequently seems secondary to the manifestation of the tumour phenotype.

Vaccine Targeting of Subdominant CD8+ T Cell Epitopes Increases the Breadth of the T Cell Response upon Viral Challenge, but May Impair Immediate Virus Control.

As a result of the difficulties in making efficient vaccines against genetically unstable viruses such as HIV, it has been suggested that future vaccines should preferentially target subdominant epitopes, the idea being that this should allow a greater breadth of the induced T cell response and, hence, a greater efficiency in controlling escape variants. However, to our knowledge the evidence supporting this concept is limited at best. To improve upon this, we used the murine lymphocytic choriomeningitis virus model and adenoviral vectors to compare a vaccine expressing unmodified Ag to a vaccine expressing the same Ag without its immunodominant epitope. We found that removal of the dominant epitope allowed the induction of CD8(+) T cell responses targeting at least two otherwise subdominant epitopes. Importantly, the overall magnitude of the induced T cell responses was similar, allowing us to directly compare the efficiency of these vaccines. Doing this, we observed that mice vaccinated with the vaccine expressing unmodified Ag more efficiently controlled an acute viral challenge. In the course of a more chronic viral infection, mice vaccinated using the vaccine targeting subdominant epitopes caught up with the conventionally vaccinated mice, and analysis of the breadth of the CD8(+) T cell response revealed that this was notably greater in the former mice. However, under the conditions of our studies, we never saw any functional advantage of this. This may represent a limitation of our model, but clearly our findings underscore the importance of carefully weighing the pros and cons of changes in epitope targeting before any implementation.

Randomized trial of the effects of individual nutritional counseling in cancer patients.

BACKGROUND & AIMS: Cancer-related malnutrition is multifactorial and related to a bad prognosis. The aim of this study was to investigate the effect of intensive, individual dietary counseling of patients in radiotherapy and/or chemotherapy for gynecologic-, gastric-, or esophageal cancer. METHODS: 61 outpatients were stratified by diagnoses and randomly assigned to one of two groups (G1; n = 32 and G2; n = 29). The basic regimen, applied to both groups, included measurement of body weight, 24-h dietary recall interview, micronutrient status and quality of life. In addition G1 received intensive, individual dietary counseling one hour per week and, if the patient accepted, a daily oral nutritional supplement containing 2531 kJ, 33.8 g protein and 2.2 g EPA. RESULTS: At the end of the treatment period, significantly fewer patients had lost weight in the intervention group (mean: 44% vs. 72%, p < 0.05), and the fulfillment of estimated energy requirements was better during treatment (mean: 107% vs. 95%, p < 0.05). A significant positive effect was observed on the fulfillment of protein requirement, both during the treatment period (mean: 92% vs. 71%, p < 0.001) and at follow-up (mean: 86% vs. 71%, p < 0.05). CONCLUSION: In these cancer patients, intensive, individual dietary counseling was associated with a better weight maintenance and a higher provision of adequate amounts of protein and energy. The intervention had no significant effects on patients' quality of life, incidence of treatment-related side effects or appearance of micronutrient deficiencies.

Wearing an active spinal orthosis improves back extensor strength in women with osteoporotic vertebral fractures.

BACKGROUND: Vertebral fractures are the most common clinical manifestations of osteoporosis. Vertebral fractures and reduced back extensor strength can result in hyperkyphosis. Hyperkyphosis is associated with diminished daily functioning and an increased risk of falling. Improvements in back extensor strength can result in decreased kyphosis and thus a decreased risk of falls and fractures. OBJECTIVES: The aim was to examine the effects of an active spinal orthosis - Spinomed III - on back extensor strength, back pain and physical functioning in women with osteoporotic vertebral fractures. STUDY DESIGN: Experimental follow-up. METHODS: The women used the active spinal orthosis for 3 months. Outcomes were changes in isometric back extensor strength, changes in back pain and changes in physical functioning. RESULTS: A total of 13 women were included in the trial. Wearing the orthosis during a 3-month period was associated with an increase in back extensor strength of 50% (p = 0.01). The study demonstrated a 33% reduction in back pain and a 6.5-point improvement in physical functioning. The differences in pain and physical functioning were borderline significant. CONCLUSION: The women demonstrated a clinically relevant improvement in the back extensor strength. The differences in pain and physical functioning were clinically relevant and borderline significant. CLINICAL RELEVANCE: The results imply that Spinomed III could be recommended for women with vertebral fractures as a supplement to traditional back strengthening exercises. It is essential that the orthosis is adjusted correctly and that there is an individual programme concerning the amount of time the orthosis has to be worn every day.