C-Reactive Protein Levels at Diagnosis of Acute Graft-versus-Host Disease Predict Steroid-Refractory Disease,Treatment-Related Mortality,and Overall Survival after Allogeneic Hematopoietic Stem Cell Transplantation

Acute graft-versus-host disease (aGVHD) remains a cause of excessive morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Primary treatment consists of high-dose corticosteroids, but a small group of patients develop steroid-refractory disease, and their prognosis is especially poor. There is experimental evidence that coexisting inflammation aggravates aGVHD. Because C-reactive protein (CRP) is a systemic inflammatory marker, we aimed to investigate whether plasma CRP concentrations at the diagnosis of aGVHD can predict the risk of failing first-line therapy and developing steroid-refractory disease. We retrospectively studied 461 patients who underwent HSCT between 2010 and 2015. aGVHD grade II-IV was diagnosed in 148 patients (32%). CRP level and total white blood cell, lymphocyte, and neutrophil counts were available for all patients at the time of aGVHD diagnosis. According to local protocol, patients with failed response to high-dose steroid therapy (2?mg/kg) were treated with the TNF-α inhibitor infliximab and categorized as having steroid-refractory disease. Of 148 patients with grade II-IV aGVHD, 28 (19%) developed steroid-refractory disease. In these patients, plasma CRP concentration at diagnosis ranged between <1 and 253?mg/L. CRP levels were significantly higher in patients who developed steroid-refractory disease compared with those who responded to high-dose corticosteroid therapy (odds ratio, 1.50; 95% confidence interval, 1.18-1.93; P?=?.001). This translated into significantly increased transplantation-related mortality and decreased overall survival in the patients with high CRP levels. Total white blood cell, lymphocyte, and neutrophil counts were not associated with steroid resistance in the patients with aGVHD. These results suggest that CRP level at diagnosis is a valid predictor of the development of steroid-refractory disease in patients who develop grade II-IV aGVHD after HSCT.     

Mortality after cancer among patients with diabetes mellitus: effect of diabetes duration and treatment

Aims/hypothesis

The prognostic role of different diabetes treatment types has not been studied in detail. We compared mortality rates among cancer patients with and without diabetes, accounting for diabetes treatment and diabetes duration.

Methods

This register-based study included all cancer patients diagnosed in Denmark during 1995–2009. The patients were classified into four groups according to diabetes status at the time of cancer diagnosis: no diabetes, diabetes without medication, diabetes with only oral hypoglycaemic agent (OHA) or diabetes with insulin treatment. Poisson models were used to examine the association between pre-existing diabetes in cancer patients and mortality relative to the non-diabetic cancer population.

Results

Among 426,129 patients with incident cancer, we identified 42,205 patients with diabetes prior to cancer diagnosis. Overall, cancer patients with diabetes had higher mortality rates than non-diabetic cancer patients, highest among OHA- or insulin-treated patients. For all cancers combined and diabetes duration of 2 years at cancer diagnosis, insulin-treated patients experienced the highest mortality rate ratios starting from 3.7 (95% CI 2.7, 5.1) for men and 4.4 (3.1, 6.5) for women 1 year after cancer diagnosis, increasing to 5 (3.5, 7.0) for men and 6.5 (4.2, 9.3) for women 9 years after cancer diagnosis.

Conclusions/interpretation

Our study provides strong evidence that cancer patients with pre-existing diabetes experience higher mortality than cancer patients without diabetes. The higher mortality seen among cancer patients treated with OHAs or insulin is in accordance with the existing evidence that more intensive diabetes treatment reflects a larger degree of comorbidity at the time of cancer diagnosis, and hence poorer survival.     

How do line managers experience and handle the return to work of employees on sick leave due to work-related stress? A one-year follow-up study

Purpose: To examine how line managers experience and manage the return to work process of employees on sick leave due to work-related stress and to identify supportive and inhibiting factors.

Materials and methods: Semi-structured interviews with 15?line managers who have had employees on sick leave due to work-related stress. The grounded theory approach was employed.

Results: Even though managers may accept the overall concept of work-related stress, they focus on personality and individual circumstances when an employee is sick-listed due to work-related stress. The lack of a common understanding of stress creates room for this focus. Line managers experience cross-pressure, discrepancies between strategic and human-relationship perspectives and a lack of organizational support in the return to work process.

Conclusion: Organizations should aim to provide support for line managers. Research-based knowledge and guidelines on work-related stress and return to work process are essential, as is the involvement of coworkers. A commonly accepted definition of stress and a systematic risk assessment is also important. Cross-pressure on line managers should be minimized and room for adequate preventive actions should be provided as such an approach could support both the return to work process and the implementation of important interventions in the work environment.

• Implication for rehabilitation

• Organizations should aim to provide support for line managers handling the return to work process.

• Cross-pressure on line managers should be minimized and adequate preventive actions should be provided in relation to the return to work process.

• Research-based knowledge and guidelines on work-related stress and return to work are essential.

• A common and formal definition of stress should be emphasized in the workplace.

     

Risk assessment tools to identify women with increased risk of osteoporotic fracture: Complexity or simplicity? A systematic review

A huge number of risk assessment tools have been developed. Far from all have been validated in external studies, more of them have absence of methodological and transparent evidence, and few are integrated in national guidelines. Therefore, we performed a systematic review to provide an overview of existing valid and reliable risk assessment tools for prediction of osteoporotic fractures. Additionally, we aimed to determine if the performance of each tool was sufficient for practical use, and last, to examine whether the complexity of the tools influenced their discriminative power. We searched PubMed, Embase, and Cochrane databases for papers and evaluated these with respect to methodological quality using the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS) checklist. A total of 48 tools were identified; 20 had been externally validated, however, only six tools had been tested more than once in a population‐based setting with acceptable methodological quality. None of the tools performed consistently better than the others and simple tools (i.e., the Osteoporosis Self‐assessment Tool [OST], Osteoporosis Risk Assessment Instrument [ORAI], and Garvan Fracture Risk Calculator [Garvan]) often did as well or better than more complex tools (i.e., Simple Calculated Risk Estimation Score [SCORE], WHO Fracture Risk Assessment Tool [FRAX], and Qfracture). No studies determined the effectiveness of tools in selecting patients for therapy and thus improving fracture outcomes. High‐quality studies in randomized design with population‐based cohorts with different case mixes are needed.     

Pharmacokinetics and dose proportionality of cefpimizole in normal humans after intramuscular administration.

The pharmacokinetics of cefpimizole (free acid equivalents of cefpimizole sodium), a broad-spectrum cephalosporin antibiotic, were evaluated after intramuscular administration of single doses (dose range, 100 to 1,000 mg) and multiple doses (dose range, 500 to 2,000 mg) given b.i.d. for 6 or 11 days. The kinetics after intramuscular administration correspond to a one-compartment model with first-order input. The apparent volume of distribution of the absorbed dose averaged 18.6 +/- 3.4 (standard deviation) liters for 58 individuals; the absorption-phase and elimination-phase rate constants averaged 2.53 +/- 1.16 h-1 (half-life, 0.27 h) and 0.338 +/- 0.041 h-1 (half-life, 2.05 h), respectively; and the mean residence time was 3.43 +/- 0.43 h. The total body clearance of the absorbed dose after single-dose intramuscular administration was 102 +/- 13 ml/min. The primary route of elimination was renal with 73 to 83% of the administered dose excreted in the urine as unchanged drug. Renal clearance averaged 81 +/- 13 ml/min. Dose proportionality was obtained from area under the plasma curve, concentration maximum in plasma, and cumulative urinary excretion levels. Multiple-dose evaluation of intramuscular administration of cefpimizole indicated no apparent change in the absorption or elimination phases after b.i.d. dosing for 6 or 11 days. The kinetic parameters determined from multiple-dose plasma and urine levels were in close agreement with the same parameters calculated from single-dose results. No apparent accumulation of cefpimizole occurred, and nondetectable levels of drug were observed in the 24-h plasma and 24- to 48-h urine specimen after administration of the last dose. The kinetics of cefpimizole after intramuscular administration were similar to the kinetics obtained after intravenous infusion.     

Cefotaxime monotherapy in septicemic patients with hematological malignancies

Cefotaxime at a dosage of 3 gm intravenously every eight hours was administered to 80 patients with hematological malignancies and suspected septicemia. Blood samples for culturing were taken before and during antibiotic therapy. Nineteen patients had verified bacteremia and ten of them responded completely to cefotaxime. Twelve of the 19 patients had granulocyte counts of less than 0.5 X 10(9)/L. Minimal inhibitory concentrations of cefotaxime, ceftazidime, moxalactam, cefsulodin, cefoxitin, cefuroxime, and cefamandole against the pathogens were measured: cefotaxime was the best cephalosporin against gram-negative isolates and was found acceptable against gram-positive bacteria. In 61 patients no bacteremia could be demonstrated, but specific pathogens were isolated in 11 patients: from the urine in five, from the sputum in five, and from a perianal abscess in one. Complete response was obtained with cefotaxime in seven of these 11 patients. Monotherapy with cefotaxime in septicemic patients with hematological malignancies appears to be a valuable alternative to other antibiotic regimens.     

Disability, pain, psychological factors and physical performance in healthy controls, patients with sub-acute and chronic low back pain: a case-control study.

OBJECTIVE: To compare measures of disability, psychological factors, pain and physical performance in healthy controls, and patients with sub-acute and chronic low back pain. To evaluate the concept of the deconditioning syndrome and to explore factors that may contribute to chronicity. DESIGN: Case-control study. SUBJECTS: Three age- and gender-matched groups were included in the study; healthy controls (n = 45), patients sick-listed 8-12 weeks (n = 46) and patients with chronic low back pain on a waiting list for lumbar instrumented fusion (n = 45). METHODS: Measures of disability, pain, psychological factors, and physical performance were obtained from the 3 groups using validated measures. RESULTS: Gender, age, body weight and height were not significantly different between the groups. Comparable scores were found for self-rated working ability, fear-avoidance beliefs for physical activity and aerobic capacity in the 2 patient groups. Oswestry Disability Index, pain, emotional distress, abdominal and back muscle endurance were significantly different between the 3 groups. Self-efficacy for pain and fear-avoidance beliefs for work was significantly different between the 2 patient groups. CONCLUSION: The results suggest a stepwise deterioration of impairment and disability from healthy controls to patients with chronic low back pain. Most variables distinguished between healthy controls and patients with sub-acute or chronic low back pain. Deconditioning was more related to psychophysical measures of abdominal and back muscle endurance than to cardiovascular fitness. Comparable scores for fear-avoidance and working ability in the 2 patient categories suggest that these factors appear at an early stage and contribute to the transition from acute to chronic low back pain.     

Typing of 30 insertion/deletions in Danes using the first commercial indel kit--Mentype® DIPplex

In this study, we tested the first commercial kit with insertion/deletion (indel) polymorphisms, the Mentype(?) DIPplex PCR Amplification Kit (DIPplex kit). A total of 30 biallelic autosomal indels and Amelogenin were amplified with the DIPplex kit. All loci were amplified in one PCR multiplex and all amplicon lengths were shorter than 160 bp. Full indel profiles were generated from as little as 100 pg of DNA. A total of 117 individuals from Danish paternity cases were successfully typed. No deviation from Hardy-Weinberg equilibrium was observed for any of the indels. The combined mean match probability was 3.3 × 10(-13), the mean paternity exclusion probability was 99.7% and the typical paternity indices for trios and duos were 2350 and 165, respectively. Furthermore, we typed five highly degraded DNA samples with the DIPplex kit, the AmpFlSTR(?) SGM Plus kit and the AmpFlSTR(?) SEfiler Plus kit. Full indel profiles were obtained with the DIPplex kit, whereas only partial profiles were obtained with the STR kits. In general, the DIPplex kit performed well and it would be a valuable assay for forensic genetic testing, especially in crime cases with partially degraded DNA or low amounts of template DNA. However, some difficulties with pull-ups were observed at DNA concentrations of 1000 pg. Rearrangement of the allele windows by changing the lengths of some of the PCR primers would greatly improve the assay, and more robustness towards higher amounts of DNA would allow the use of the DIPplex kit without prior quantification of the samples.