Program on high value cost-conscious education in intensive care: Educational program on prediction of outcome and cost awareness on Intensive Care admission.

BACKGROUND: Intensive Care (ICU) involves extended and long lasting support of vital functions and organs. However, current training programs of ICU residents mainly focus on extended support of vital functions and barely involve training on cost-awareness and outcome. We incorporated an educational program on high-value cost-conscious care for residents and fellows on our ICU and measured the effect of education. METHODS: A cohort study with factorial survey design, in which ICU residents and fellows were asked to evaluate clinical vignettes, was performed on the mixed surgical-medical ICU of the Amsterdam University Medical Centre. Residents were offered an educational program focusing on outcome and costs of ICU care. Before and after the program they filled out a questionnaire, which consisted of 23 vignettes, in which known predictors of outcome of community acquired pneumonia (CAP), pancreatitis, acute respiratory distress syndrome (ARDS) and cardiac arrest were presented, together with varying patient factors (age, body mass index (BMI), acute kidney failure (AKI) and haemato-oncological malignancy). Participants were asked to either admit the patient or estimate mortality. RESULTS: BMI, haemato-oncological malignancy and severity of pancreatitis were discriminative for admission to ICU in clinical vignettes on pancreatitis and CAP. After education, only severity of pancreatitis was judged as discriminative. Before the intervention only location of cardiac arrest (in- vs out of hospital) was distinctive for mortality, afterwards this changed to presence of haemato-oncological malignancy. CONCLUSION: We incorporated an educational program on high-value cost-conscious care in the training of ICU physicians. Based on our vignette study, we conclude that the improvement of knowledge of costs and prognosis after this program was limited.

Melatonin improves development, mitochondrial function and promotes the meiotic resumption of sheep oocytes from in vitro grown secondary follicles.

The aim of this study was to evaluate follicular survival and development of ovine isolated secondary follicles cultured in medium containing fixed or sequential concentrations of melatonin and further oocyte maturation. Isolated secondary follicles were cultured for 18 days in α-MEM+ alone (control) or with different concentrations of melatonin (100, 500 or 1000 pg/mL) or sequential concentrations of melatonin (Mel Seq: Day 6 = 100; Day 12 = 500; Day 18 = 1000 pg/mL). The percentages of morphologically normal follicles and antral cavity formation increased significantly in 1000 pg/mL melatonin compared to the other treatments. After 18 days, 1000 pg/mL melatonin (Mel 100) showed a greater (P < 0.05) follicular diameter than α-MEM+, 100 and 500 pg/mL melatonin. In addition, the concentration of 500 pg/mL melatonin showed a higher (P < 0.05) percentage of fully grown oocytes than α-MEM+, Mel 100 and Mel Seq treatments. After oocyte maturation, the levels of ROS were lower (P < 0.05) in 1000 pg/mL melatonin (Mel 1000) than in other treatments. Both Mel 1000 and Mel Seq treatments showed significantly higher levels of mitochondrial activity than other treatments. There were no significant differences between 500 and 1000 pg/mL melatonin regarding meiotic stages. In conclusion, the concentration of 1000 pg/mL melatonin maintains survival, promotes follicular development and increases the levels of active mitochondria after in vitro culture of sheep secondary follicles. Moreover, this concentration promotes the meiotic competence of oocytes and decreases the production of ROS during oocyte maturation.

Effects of melatonin on the in vitro growth of early antral follicles and maturation of ovine oocytes.

This study aimed to evaluate the effect of melatonin on the in vitro culture and maturation of isolated sheep early antral follicles. Isolated early antral follicles were cultured for 12 d in α-minimum essential medium (MEM+) alone (control) or α-MEM+ added with fixed different concentrations (100, 500, or 1,000 pg/mL) or a sequential concentration of melatonin (MelSeq; day 6 = 100; day 12 = 500 pg/mL). The percentage of morphologically normal follicles was higher (P < 0.05) in 500 pg/mL melatonin than the other treatments at 6 d. Mel 500 also showed a higher rate of fully grown oocytes (P < 0.05) than other treatments. After in vitro culture, reactive oxygen species (ROS) levels in oocytes were similar between Mel 500 and MelSeq, with both being lower (P < 0.05) than other treatments. Oocytes cultured in both Mel 500 and Mel 1000 showed glutathione peroxidase levels similar (P > 0.05) to the control group and higher (P < 0.05) than other treatments. Mitochondrial activity was similar (P > 0.05) among control, Mel 500, and Mel 1000 treatments. Mel 500 treatment presented a higher percentage of germinal vesicle breakdown oocytes than the control group and similar percentages to the other treatments. Follicles cultured in melatonin followed by oocyte maturation with the addition of 500 pg/mL melatonin in maturation medium showed increased (P < 0.05) levels of mitochondrial activity compared to α-MEM+ alone. In conclusion, the concentration of 500 pg/mL of melatonin promotes development and decreases ROS levels of ovine oocytes from in vitro grown early antral follicles. Moreover, melatonin increases mitochondrial activity and promotes the acquisition of meiotic competence of these oocytes.

Predictors of short-term and long-term mortality in critically ill patients admitted to the intensive care unit following allogeneic stem cell transplantation.

Historically, the mortality of patients admitted to the ICU after allogeneic stem cell transplantation (alloSCT) is high. Advancements in transplantation procedures, infectious monitoring and supportive care may have improved the outcome. This study aimed to determine short-term and long-term mortality after ICU admission of patients after alloSCT and to identify prognostic clinical and transplantation-related determinants present at ICU admission for long-term outcome. A multicenter cohort study was performed to determine 30-day and 1-year mortality within 2 years following alloSCT. A total of 251 patients were included. The 30-day and 1-year mortality was 55% and 80%, respectively. Platelet count <25 × 109/L (OR: 2.26, CI: 1.02-5.01) and serum bilirubin >19 µmol/L (OR: 2.47 CI: 1.08-5.65) at admission, other donor than a HLA-matched-related or HLA-matched-unrelated donor (OR: 4.59, CI: 1.49-14.1) and vasoactive medication within 24 h (OR: 2.35, CI: 1.28-4.31) were associated with increased 30-day mortality. Other donor than a HLA-matched-related or HLA-matched-unrelated donor (OR: 1.9, CI: 1.13-3.19), serum bilirubin >77 (OR: 2.05, CI: 1.28-3.30) and vasoactive medication within 24 h (OR: 1.65, CI: 1.12-2.43) were associated with increased 1-year mortality. Neutropenia was associated with decreased 30-day and 1-year mortality (OR: 0.29, CI: 0.14-0.59 and OR: 0.70, CI: 0.48-0.98). Myeloablative conditioning and T cell-depleted transplantation were not associated with increased mortality.

Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML.

This corrects the article DOI: 10.1038/leu.2017.9.

The management of critically ill patients with haematological malignancies.

The management of critically ill patients with haematological malignancy (HM) still shows inter- and intra-regional differences. Our objective in this updated review was to address the evidence supporting the potential treatment options, based on multidisciplinary processes, of critically ill patients with HM. A stepwise approach to the critical care pathway of this patient population from the triage to ICU admission to ICU discharge was chosen to emphasise certain key findings. Our main focus relied on significant issues of decision-making in daily clinical routine. The plethora of studies shifted the pragmatic treatment policy into an evidence-based approach. The transfer of a patient with HM from the haematology ward to the ICU and vice versa should be based on a well-defined clinical care process in which the haematologists and intensivists are in close collaboration and direct communication. A protocolised clinical approach to treat a critically ill patient with HM seems helpful to optimise patient-oriented care and patient safety.

Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants.

Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.

[Using thromboelastography to measure coagulation following massive blood loss]. / Stolling meten met trombo-elastografie bij massaal bloedverlies.

Thromboelastography is becoming increasingly important for diagnosing coagulation disorders in patients with massive blood loss. This whole-blood measurement provides information about the speed of clot formation, clot strength, and degree of fibrinolysis. The result can be used as a basis for making a faster and better choice of a suitable blood product for the patient with severe blood loss. This technique can be carried out simply and quickly as a rapid test ('point-of-care test') or in a central laboratory. Use of thromboelastography in patients undergoing cardiac surgery results in reduced use of blood products and is proven to be cost effective. A reduction in the use of blood products was also seen in trauma patients and patients undergoing liver transplantation when this technique was used. Studies on other groups of patients with massive blood loss are being conducted at the moment.

Supplemented base medium containing Amburana cearensis associated with FSH improves in vitro development of isolated goat preantral follicles.

The effects of Amburana cearensis ethanolic extract, with or without addition of a mix of supplements associated or not with FSH, on in vitro morphology and development of caprine secondary follicles were evaluated. In experiment 1, isolated follicles (250 µm in diameter) were cultured for 12 days in alpha-modified minimal essential medium (α-MEM) alone (control) or in medium composed of different concentrations of A. cearensis extract (Amb 0.1; 0.2, or 0.4 mg/mL). In experiment 2, culture media were α-MEM or Amb 0.2 mg/mL (both without supplements), or these same media supplemented with BSA, insulin, transferrin, selenium, glutamine, hypoxanthine, and ascorbic acid (referred as α-MEM(+) and Amb 0.2(+), respectively), or these last groups also supplemented with sequential FSH (100 ng/mL from Day 0 to Day 6; 500 ng/mL from Day 6 to Day 12), constituting groups α-MEM(+) + FSH and Amb 0.2(+) + FSH. At the end of culture in experiment 1, control medium (α-MEM) and Amb 0.2 mg/mL had higher percentages (P < 0.05) of morphologically normal follicles and percentage of fully grown oocytes, i.e., oocyte greater than 110 µm, compared to the other A. cearensis extract concentrations. In experiment 2, all supplemented media had higher percentages (P < 0.05) of normal follicles and antrum formation than nonsupplemented media. In addition, follicles cultured in Amb 0.2(+) + FSH showed an average increase in diameter higher (P < 0.05) than the other treatments. Oocytes cultured in both treatments supplemented with FSH showed greater glutathione and active mitochondria levels than nonsupplemented media but similar to the other treatments. In conclusion, A. cearensis extract (0.2 mg/mL) added by supplements and FSH improves follicular growth. Therefore, it can be an alternative culture medium for goat preantral follicle development.

Secondary malignancies in chronic myeloid leukemia patients after imatinib-based treatment: long-term observation in CML Study IV.

Treatment of chronic myeloid leukemia (CML) has been profoundly improved by the introduction of tyrosine kinase inhibitors (TKIs). Long-term survival with imatinib is excellent with a 8-year survival rate of ∼88%. Long-term toxicity of TKI treatment, especially carcinogenicity, has become a concern. We analyzed data of the CML study IV for the development of secondary malignancies. In total, 67 secondary malignancies were found in 64 of 1525 CML patients in chronic phase treated with TKI (n=61) and interferon-α only (n=3). The most common malignancies (n⩾4) were prostate, colorectal and lung cancer, non-Hodgkin's lymphoma (NHL), malignant melanoma, non-melanoma skin tumors and breast cancer. The standardized incidence ratio (SIR) for all malignancies excluding non-melanoma skin tumors was 0.88 (95% confidence interval (0.63-1.20)) for men and 1.06 (95% CI 0.69-1.55) for women. SIRs were between 0.49 (95% CI 0.13-1.34) for colorectal cancer in men and 4.29 (95% CI 1.09-11.66) for NHL in women. The SIR for NHL was significantly increased for men and women. An increase in the incidence of secondary malignancies could not be ascertained. The increased SIR for NHL has to be considered and long-term follow-up of CML patients is warranted, as the rate of secondary malignancies may increase over time.

Frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the European ENEST1st study.

The Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study included 1089 patients with newly diagnosed chronic myeloid leukemia in chronic phase. The rate of deep molecular response (MR(4) (BCR-ABL1⩽0.01% on the International Scale or undetectable BCR-ABL1 with ⩾10,000 ABL1 transcripts)) at 18 months was evaluated as the primary end point, with molecular responses monitored by the European Treatment and Outcome Study network of standardized laboratories. This analysis was conducted after all patients had completed 24 months of study treatment (80.9% of patients) or discontinued early. In patients with typical BCR-ABL1 transcripts and ⩽3 months of prior imatinib therapy, 38.4% (404/1052) achieved MR(4) at 18 months. Six patients (0.6%) developed accelerated or blastic phase, and 13 (1.2%) died. The safety profile of nilotinib was consistent with that of previous studies, although the frequencies of some nilotinib-associated adverse events were lower (for example, rash, 21.4%). Ischemic cardiovascular events occurred in 6.0% of patients. Routine monitoring of lipid and glucose levels was not mandated in the protocol. These results support the use of frontline nilotinib, particularly when achievement of a deep molecular response (a prerequisite for attempting treatment-free remission in clinical trials) is a treatment goal.

Perioperative management and outcome of fracture treatment in patients with haemophilia without inhibitors.

INTRODUCTION: Fractures in persons with haemophilia (PWH) are not uncommon and require an interdisciplinary approach to maintain haemostasis during surgical treatment. AIM: The aim of this study was to evaluate the perioperative management and outcome in PWH following fracture fixation compared to a matched non-haemophilic control group. METHODS: A cohort of 44 PWH who underwent 46 surgical fracture fixations was retrospectively compared to 46 non-haemophilic patients (matched-pair controls). Patients were classified according to the fracture localization: (i) proximal upper extremity (PrUEx; n = 7), (ii) distal upper extremity (DiUEx; n = 12), (iii) proximal lower extremity (PrLEx; n = 13) and (iv) distal lower extremity (DiLEx; n = 14). Both groups were assessed for length of hospital stay, duration of surgery, drainage use and complication rates. RESULTS: There was no significant difference regarding the duration of the preoperative hospital stay between PWH and controls. Only PWH who were operated at the DiUEx stayed significantly longer in hospital (4.8 ± 3.7 days) than controls (2.2 ± 2.3 days; P = 0.039). Operation time was significantly longer in PWH with fractures treated at the DiLEx (64.9 ± 26.6 min) compared to the controls (49.8 ± 37.9 min; P = 0.035). Neither frequency nor duration of surgical drainage placement differed significantly between the two groups. The overall complication rate in both groups was low without a statistically significant difference. CONCLUSION: An optimal interdisciplinary perioperative management provided the surgical treatment of fractures in PWH can be performed safely with a low complication rate.

[The "Muffplastik"--a Fasciocutaneous Reconstruction Technique in a Case of Extensive Soft Tissue Defect of the Distal Forearm--Historical Technique or Salvage Procedure?]. / Die "Muffplastik": fasziokutane Bauchhautlappenplastik zur Deckung eines ausgeprägten Defekts an der Hand und am distalen Unterarm--historischer Eingriff oder Rückzugsoption?

We present a case of a distant pedicled flap to reconstruct a defect at the distal upper extremity. We used this flap as a salvage procedure to treat a patient in the intensive care unit who was in a reduced general condition with numerous comorbidities that made regional or free microvascular flaps hazardous.

Identification of invasive fungal diseases in immunocompromised patients by combining an Aspergillus specific PCR with a multifungal DNA-microarray from primary clinical samples.

The increasing incidence of invasive fungal diseases (IFD), most of all invasive aspergillosis (IA) in immunocompromised patients emphasises the need to improve the diagnostic tools for detection of fungal pathogens. We investigated the diagnostic performance of a multifungal DNA-microarray detecting 15 different fungi [Aspergillus, Candida, Fusarium, Mucor, Rhizopus, Scedosporium and Trichosporon species (spp.)] in addition to an Aspergillus specific polymerase chain reaction (PCR) assay. Biopsies, bronchoalveolar lavage and peripheral blood samples of 133 immunocompromised patients (pts) were investigated by a multifungal DNA-microarray as well as a nested Aspergillus specific PCR assay. Patients had proven (n = 18), probable (n = 29), possible (n = 48) and no IFD (n = 38) and were mostly under antifungal therapy at the time of sampling. The results were compared to culture, histopathology, imaging and serology, respectively. For the non-Aspergillus IFD the microarray analysis yielded in all samples a sensitivity of 64% and a specificity of 80%. Best results for the detection of all IFD were achieved by combining DNA-microarray and Aspergillus specific PCR in biopsy samples (sensitivity 79%; specificity 71%). The molecular assays in combination identify genomic DNA of fungal pathogens and may improve identification of causative pathogens of IFD and help overcoming the diagnostic uncertainty of culture and/or histopathology findings, even during antifungal therapy.

[Impact of Preoperative Knee Stiffness on the Postoperative Outcome after Total Knee Arthroplasty in Patients with Haemophilia]. / Einfluss der präoperativen Kniesteife auf das postoperative Ergebnis nach Knieendoprothetik bei Patienten mit Hämophilie.

INTRODUCTION: Total knee arthroplasty (TKA) is an effective treatment option for patients with end-stage haemophilic arthropathy of the knee. However, the procedure is technically challenging, as knee motion is often restricted before the operation and complication rates are then thought to be higher than for patients with a normal range of motion (ROM). There is very limited information on the outcome of TKA in haemophilic patients presenting with stiff knees. The objective of the present study was to retrospectively analyse and compare the clinical results after TKA in haemophiliacs with stiff and non-stiff knees. PATIENTS AND METHODS: The results of 50 TKA procedures in 41 haemophilic patients were retrospectively evaluated at a mean follow-up of 7.2 ± 4.9 years (range 2-25 years). 20 patients presenting with 23 stiff knees - defined by a preoperative ROM of 50° or less - were compared with 21 patients with 27 non-stiff knees. Knee motion (ROM, flexion, extension), Knee Society Score (KSS/KSS function), pain status (visual analogue scale, VAS), number of bleedings and patient satisfaction were evaluated. RESULTS: The complication rate was 12 %, including two haematomas, one aseptic loosening, and three periprosthetic infections. The overall mean ROM increased from 58.6 ± 34.2° (range 0-120°) preoperatively to 85.9 ± 23.4 (35-130°) postoperatively (p < 0.005). Mean KSS and KSS function improved from 30.6 ± 11.0 points (range 10-49) and 43.4 ± 9.3 points (range 15-65) to 79.3 ± 9.6 points (range 49-95) and 68.9 ± 11.0 points (45-90), respectively (p < 0.005). The mean VAS score decreased significantly from 7.9 ± 0.8 points (range 6-9) to 1.8 ± 1.1 points (range 0-4; p < 0.005). In comparison to the non-stiff group, patients with stiff knees showed a significantly greater mean improvement in ROM (46.3 ± 21.8° [range - 10-85°] vs. 9.4 ± 16.9° [range - 30-35°]), flexion (32.8 ± 19.6° [range - 10-85°] vs. 5.2 ± 16.2° [range - 40-35°]), and flexion contracture (13.5 ± 9.6° [range 5-30°] vs. 5.9 ± 6.7° [range 5-20°]). Both KSS and KSS function were significantly inferior in stiff knees than with non-stiff knees. Nine patients with knee stiffness who underwent additional v-y quadricepsplasty to lengthen the extensor mechanism developed a mean extensor lag of 7-0° ± 4-8° (range 5-15°). At final follow-up, 37/41 patients were satisfied or very satisfied with the surgical result. CONCLUSION: TKA in haemophilic patients presenting with haemophilic arthropathy of the knee results in significant improvements in function and reduced pain. Although the ultimate clinical outcome in stiff knees is inferior to that with non-stiff knees, joint replacement surgery can be successfully performed in patients with restricted preoperative range of motion. Vy-quadricepsplasty for to facilitate exposure is associated with the development of a postoperative extensor lag and should therefore be performed restrictively. Patient satisfaction after TKA was equally high in the two groups.

Outcome after total knee arthroplasty in haemophilic patients with stiff knees.

INTRODUCTION: Advanced haemophilic arthropathy of the knee is associated with progressive joint stiffness. Results after total knee arthroplasty (TKA) in stiff knees are considered to be inferior compared to those with less restricted preoperative range of motion (ROM). There is only very limited data on the results of primary TKA in haemophilic patients with stiff knees. AIM: The purpose of this retrospective study was to evaluate the clinical outcome after TKA performed in haemophilic patients with preoperative ROM of 50° or less. METHODS: Twenty one patients (23 knees) undergoing TKA with stiff knees were retrospectively evaluated. Mean follow-up was 8.3 years (range, 2-25). Clinical assessment included ROM, degree of flexion contracture and complication rate. Functional evaluation and pain status were assessed using the Knee Society's Scoring System (KSS). RESULTS: Range of motion improved from 26.7° preoperatively to 73.0° postoperatively. Flexion contracture decreased from 21.7° to 8.3°. KSS increased from 22.9 to 72.9 points. Evaluation of pain revealed a decrease from 8.4 points preoperatively to 2.1 points postoperatively. All these differences were statistically significant (P < 0.005). The complication rate was 8.7% including one late periprosthetic infection, and one aseptic implant loosening. Nine patients who required VY-quadricepsplasty for knee exposure developed a mean postoperative extensor lag of 7°. CONCLUSION: Total knee arthroplasty in haemophilic patients presenting with stiff knees results in significant improvement of function and reduction in pain. Although the clinical outcome is inferior compared to nonstiff knees reported in the literature, joint replacement surgery can be successfully performed in this particular group of patients.

Interferon alpha 2 maintenance therapy may enable high rates of treatment discontinuation in chronic myeloid leukemia.

A minority of chronic myeloid leukemia (CML) patients is capable of successfully discontinuing imatinib. Treatment modalities to increase this proportion are currently unknown. Here, we assessed the role of interferon alpha 2a (IFN) on therapy discontinuation in a previously reported cohort of 20 chronic phase CML patients who were treated upfront with IFN alpha plus imatinib followed by IFN monotherapy to maintain cytogenetic or molecular remission (MR) after imatinib discontinuation. After a median follow-up of 7.9 years (range, 5.2-12.2), relapse-free survival was 73% (8/11 patients) and 84% (5/6 patients) for patients who discontinued imatinib in major MR (MMR) and MR4/MR4.5, respectively. Ten patients discontinued IFN after a median of 4.5 years (range, 0.24-9.3). After a median of 2.8 years (range, 0.7-5.1), nine of them remain in ongoing treatment-free remission with MR5 (n=6) and MR4.5 (n=3). The four patients who still administer IFN are in stable MR5, MR4.5, MR4, and MMR, respectively. In conclusion, an IFN/imatinib induction treatment followed by a temporary IFN maintenance therapy may enable a high rate of treatment discontinuation in CML patients in at least MMR when stopping imatinib.