Complications after benign hysterectomy, according to procedure: a population-based prospective cohort study from the Danish hysterectomy database, 2004-2015.

OBJECTIVE: To compare the risk of complications associated with benign hysterectomy according to surgical procedure. DESIGN: Register-based prospective cohort study. SETTING: Danish Hysterectomy Database, 2004-2015. POPULATION: All Danish women with benign elective hysterectomy (n = 51 141). METHODS: Multivariate log-binomial regression to compute relative risks (RRs) stratified by calendar period, and adjusted for age, height, weight, smoking habits, use of alcohol, comorbidity, indications, uterine weight and adhesions. Multiple imputation and 'intention to treat' analyses were performed. MAIN OUTCOME MEASURES: Major (grades III-V) and minor (grades I-II) Clavien-Dindo modified complications within 30 days. RESULTS: Overall, major complications occurred in 3577 (7.0%) hysterectomies and minor complications occurred in 4788 (9.4%). The proportions of major and minor complications according to type of hysterectomy were: 10.3 and 9.6% for abdominal hysterectomy (AH); 4.1 and 12.1% for laparoscopic hysterectomy (LH); and 4.9 and 8.0% for vaginal hysterectomy (VH) for non-prolapse, and 2.3 and 6.4% for prolapse. In multivariate analyses, compared with VH for non-prolapse, the risk of major complications was higher for AH (RR 1.82, 95% CI 1.63-2.03) but lower for both LH (RR 0.78, 95% CI 0.68-0.90) and VH for prolapse (RR 0.55; 95% CI 0.41-0.75). For LH, the risk of major complications reduced from a RR of 0.96 (95% CI 0.75-1.22) in the time period 2004-2009 to an RR of 0.72 (95% CI 0.60-0.87) between 2010 and 2015. CONCLUSION: Laparoscopic hysterectomy and VH for uterine prolapse are associated with fewer major complications, and AH is associated with more major complications, compared with VH performed in the absence of uterine prolapse. TWEETABLE ABSTRACT: Laparoscopic hysterectomy has fewer major complications compared with vaginal hysterectomy, in the absence of uterine prolapse.

In vitro screening of inhibition of PPAR-γ activity as a first step in identification of potential breast carcinogens.

Alcohol consumption and increased estrogen levels are major risk factors for breast cancer, and peroxisome proliferator-activated receptor γ (PPAR-γ) plays an important role in alcohol-induced breast cancer. PPAR-γ activity is inhibited by ethanol, leading to increased aromatase activity and estrogen biosynthesis ultimately leading to breast cancer. If other organic solvents inhibit PPAR-γ activity, they should also lead to increased oestrogen biosynthesis and thus be potential breast carcinogens. Ten commonly used hydrophilic organic solvents were first tested in a cell-based screening assay for inhibitory effects on PPAR-γ transactivation. The chemicals shown to inhibit PPAR-γ were tested with vectors encoding PPAR-γ with deleted AB domains and only the ligand-binding domain to rule out unspecific toxicity. Next, the effects on biosynthesis of estradiol, testosterone and oestrone sulphate were measured in the H295R steroidogenesis assay after incubation with the chemicals. Ethylene glycol, ethyl acetate, and dimethyl sulphoxide inhibited PPAR-γ transactivation in a dose-dependent manner. The inhibitory effect on PPAR-γ was specific for PPAR-γ since the AB domain of PPAR-γ was required for the inhibitory effect. In the second step, ethylene glycol significantly increased production of oestradiol by 19% (p < 0.05) and ethyl acetate inhibited production of testosterone (p < 0.05). We here show that screening of 10 commonly used organic solvents for the ability to inhibit PPAR-γ transactivation followed by a well-established steroidogenesis assay for production of sex hormones in exposed H295 R cells may provide a screening tool for potential breast carcinogens. This initial screening thus identified ethylene glycol and possibly ethyl acetate as potential breast carcinogens.

[Evaluation of cancer therapy from the perspective of a statutory health insurance]. / Bewertung onkologischer Therapien aus Sicht einer Kasse.

Increasing life expectancy, the introduction of costly new drugs and contributions from the health fund which do not cover overall costs, all contribute to financial problems for statutory health insurances (SHI) in oncology. Only an evidence-based approach can help to address these problems. In a first step patient-relevant benefits have to be substantiated as a necessary prerequisite for coverage of any treatment by SHIs. For products with no additional benefit compared to established forms of therapy the price will be limited by the established cost-benefit ratio. For products with additional benefits pricing is more difficult. For this situation the Institute for Quality and Efficiency in Healthcare (IQWiG) has developed general methods for the assessment of the relation of benefits to costs. Pricing based on this health economic evaluation is developed using efficiency frontier plots. However, this method is prone to manipulation and needs to be refined. Therapies without comparators, so-called soloists, cannot be priced in this way. New approaches to increase cost efficiency need to be developed in order to ensure the availability of high quality care in the future.

Surgical management of congenital heart disease: correlation between hospital costs and the Aristotle complexity score.

BACKGROUND: Hospital costs are expected to correlate with clinical complexity. Do costs for congenital heart surgery correlate with Aristotle complexity scores? METHODS: 442 inpatient stays in 2008 were evaluated. Aristotle scores and levels were determined. Costs were estimated according to the German Institute for Hospital Reimbursement system. Pearson and Spearman R correlation coefficients and corresponding goodness-of-fit regression coefficients R2 were calculated. RESULTS: Mean basic and comprehensive Aristotle scores were 7.60 +/- 2.74 and 9.23 +/- 2.94 points, respectively. Mean expenses per hospital stay amounted to 29,369 +/- 30,823 Euros. Aristotle basic and comprehensive scores and levels were positively correlated with hospital costs. With a Spearman R of 1 and related R2 of 0.9436, scores of the 6 Aristotle comprehensive levels correlated best. Mean hospital reimbursement was 26,412 +/- 17,962 Euros. Compensation was higher than expenses for patients in comprehensive levels 1 to 3, but much lower for those in levels 4 to 6. CONCLUSIONS: Aristotle comprehensive complexity scores were highly correlated with hospital costs. The Aristotle score could be used as a scale to establish the correct reimbursement after congenital heart surgery.

Congenital heart surgery: applicability of hospital reimbursement according to German diagnosis-related groups system in conformity with the Aristotle complexity score.

BACKGROUND: Scores of Aristotle comprehensive complexity (ACC) levels have been demonstrated to correlate with the case-mix index (CMI) (cost-weights) generated by the German Diagnosis-Related Groups (DRG) 2009 version (G-DRG 2009). The equation used was "y = 0.5591 + 0.939 x" whereby y stands for cost-weight and x for ACC score. We hypothesised that each ACC level could be assigned a DRG (ACC DRG) and be used to determine hospital reimbursement. METHODS: 185 patients underwent cardiac surgery between January and June 2009. The ACC scores of these 185 patients were grouped in ACC levels, based on the basic cost-weight value of their DRG. One ACC DRG was assigned to each group and a corresponding cost-weight calculated based on the aforementioned equation. The resulting ACC CMI was compared with the CMI generated by the G-DRG 2009 (G-DRG 2009 CMI). Finally, the ACC surgical performance (complexity x hospital survival) was used to calculate the cost-weight; the obtained CMI was called "effective ACC CMI". RESULTS: Mean ACC score was 9.515 +/- 3.611 points. Derived ACC CMI and related G-DRG 2009 CMI were 9.494 and 8.438, respectively. Hospital survival was 97.8 % (181/184). Therefore ACC surgical performance and "effective ACC CMI" were 9.306 and 9.297, respectively. For each ACC level, the number of patients (n), mean ACC score, ACC CMI and related G-DRG 2009 CMI were as follows: Level 1: n = 25, 4.024 +/- 0.879, 4.338 and 5.911; Level 2: n = 30, 6.563 +/- 0.574, 6.722 and 6.602; Level 3: n = 43, 8.665 +/- 0.540, 8.695 and 8.088; Level 4: n = 73, 11.730 +/- 1.690, 11.574 and 9.612; Level 5: n = 14, 16.710 +/- 1.380, 16.249 and 11.843, respectively. CONCLUSIONS: The Aristotle score can be used to adjust hospital reimbursement by assigning a DRG and cost-weight value to each ACC level. Missing figures for level 6 can be obtained from a previous study which showed a mean score of 22.11 +/- 1.24: the ACC CMI would be 21.320. The 6 ACC DRGs indicate the correct compensation based on the complexity of the procedure. Reimbursement using the German DRG 2009 appears to favour less complex cases, while procedures with a higher complexity are penalised. Reimbursement according to "effective ACC CMIs" would have a strong impact by supporting units providing high-quality care.

Analysis of the prodynorphin promoter polymorphism in atopic dermatitis and disease-related pruritus.

Pruritus is one of the key symptoms in atopic dermatitis (AD). The prodynorphin polypeptide is a precursor protein of pruritus-modulating opioid peptides. It is encoded by the prodynorphin gene (PDYN). To investigate a possible correlation of PDYN promoter polymorphisms with intensity of pruritus in patients with AD, we genotyped 211 Austrian patients with AD and 197 nonatopic controls. No significant association of the PDYN promoter polymorphism with AD in general was found when patients with AD were compared with controls. The analysis of possible associations with pruritus intensity also showed no relevant difference in the allelic distribution between patients with different pruritus-score values. These data argue against an important role of the PDYN promoter polymorphism in AD in general and in the development of disease-related pruritus, although owing to our small sample size, a weak effect cannot be excluded. Additional studies are needed to further evaluate the influence of PDYN polymorphism in pruritus.

The impact of aluminium in acid-suppressing drugs on the immune response of BALB/c mice.

BACKGROUND: Recently we have shown that anti-acid drugs lead to an enhanced risk of food allergy. This may be due to hindered peptic digestion, caused by an elevation of the gastric pH. Additionally, it is known that aluminium-linked antigens lead to an increased probability of sensitization. OBJECTIVE: Our aim in this study was to show whether sucralfate promotes sensitization not only by preventing peptic digestion but also by acting as a T-helper type 2 (Th2) adjuvant. METHODS: To avoid the effect of sucralfate on the gastric pH and to show only the adjuvant effect, BALB/c mice were immunized on the parenteral route with codfish extract plus sucralfate, and control groups with aluminium hydroxide (alum) (Th2 adjuvant) or monophosphoryl lipid A (MPL) (Th1 adjuvant). Antigen-specific antibodies and cytokine levels were determined. The in vivo effect was investigated by intradermal skin tests. RESULTS: Codfish-specific high IgG1 and IgE antibody levels as well as elevated IL-4 and IL-5 levels in alum- and MPL-treated mice, but more importantly also in sucralfate-treated mice, indicated a Th2 shift. Positive skin tests confirmed this Th2 response. CONCLUSIONS: Our data show that parenterally applied sucralfate is able to induce a Th2 response probably due to the aluminium content. This indicates that orally applied sucralfate may lead to an enhanced risk of food allergy not only by inhibiting peptic digestion but also by acting as a Th2 adjuvant.

Successful use of acitretin in conjunction with narrowband ultraviolet B phototherapy in a child with severe pustular psoriasis, von Zumbusch type.

Severe pustular psoriasis von Zumbusch type is a therapeutic challenge not only in adults, but even more in children. We report a 3(1/2)-year-old boy who developed a generalized flare of diffusely scattered pustules on erythematous skin which rapidly progressed to large exuding areas. The clinical presentation and investigations including histopathological examination of a biopsy and negative bacterial cultures were consistent with the diagnosis of pustular psoriasis von Zumbusch type. Upon initial treatment with methylprednisolone, acitretin and antibiotics the extent of the disease declined. However, several attempts to reduce the dose of the oral corticosteroid were followed by immediate severe flares. Additional treatment with narrowband ultraviolet B (NB-UVB, 311-313 nm UVB) resulted in a rapid arrest of disease activity and allowed the corticosteroid to be tapered off. After 10 irradiations the patient was both off steroid and disease free. NB-UVB therapy was subsequently reduced to twice-weekly exposures and acitretin gradually diminished to a maintenance dose of 0.3 mg kg(-1) daily. We conclude that NB-UVB in conjunction with acitretin is a potent therapeutic regimen for the treatment of severe pustular psoriasis von Zumbusch type in childhood.

Selective immunohistochemical staining shows significant prognostic influence of lymphatic and blood vessels in patients with malignant melanoma.

Few data on the influence of lymphatic microvessel density (LMVD) on survival in patients with melanoma are available. The aim of this study was to assess LMVD and blood microvessel density (MVD) in tissue samples from 120 patients with melanoma. LMVD was stained with an antibody staining for podoplanin, and blood MVD was assessed by CD31 (PECAM-1)-immunostaining. Survival was determined using univariate and multivariate analysis. A significant association between a high CD31 MVD (but not LMVD) and the presence of lymph node metastases (P=0.007) was observed. Patients with a high LMVD had a significant shorter overall (OS) (P=0.0436) and disease-free survival (DFS) (P=0.0249) in univariate analysis. The survival analysis showed CD31 MVD was a strong prognostic factor for OS and DFS in both uni-and multivariate analyses. Our results demonstrate LMVD as a prognostic factor in malignant melanoma, although its prognostic relevance is much smaller compared with blood MVD.

Successful treatment of an aciclovir-resistant herpes simplex type 2 infection with cidofovir in an AIDS patient.

Management of the increasing frequency of aciclovir-resistant herpes simplex virus (HSV) infections among immunocompromised human immunodeficiency virus-infected people demands additional treatment options. We report the case of a 38-year-old patient with acquired immune deficiency syndrome who suffered from a perianal butterfly ulcer, which was HSV-2 positive by polymerase chain reaction (PCR) analysis. The ulcer appeared during treatment of a cytomegalovirus (CMV) pneumonitis with ganciclovir. Despite additional valaciclovir therapy the lesion gradually progressed in size. Investigations including histology, PCR analysis and in situ hybridization of a biopsy from the growing ulcer margin confirmed the presence of HSV-2 infection. Importantly, HSV isolates from this specimen were resistant to aciclovir. Based on a report about the successful treatment of aciclovir-resistant HSV infection with cidofovir, our patient received this drug intravenously at a dose of 5 mg kg-1 body weight once weekly for a total of 3 weeks. Concomitant oral probenecid and prehydration were administered to minimize nephrotoxicity. Within 30 days of treatment the ulcer had almost (> 95%) completely healed. We conclude that cidofovir is a potent antiviral drug with a potential usefulness in the treatment of aciclovir-resistant HSV-2 infection. It deserves further investigation in clinical trials.

Inflammatory skin disease in K14/p40 transgenic mice: evidence for interleukin-12-like activities of p40.

The proinflammatory cytokine interleukin-12, a p35/p40 heterodimer, is produced by resident cells in skin and has been implicated as a pathogenetic factor in T-cell-mediated skin diseases. Secretion of heterodimeric interleukin-12 is always accompanied by production of p40 monomer and p40/p40 homodimer. To investigate the possible in vivo role of p40 per se, we generated mice that constitutively express monomeric and homodimeric p40 in basal keratinocytes. These mice spontaneously developed an eczematous skin disease that was characterized by hyperkeratosis, focal epidermal spongiosis, and a mixed inflammatory infiltrate composed of T cells (CD4+), macrophages, eosinophils, mast cells, and few neutrophils. Fluorescence-activated cell sorter analysis of transgenic epidermal cell suspensions revealed induction of major histocompatibility complex class II molecules on keratinocytes and a 2-3-fold increase in the content of Langerhans cells. Cytokines produced by these activated epidermal cells include interleukin-1alpha and tumor necrosis factor alpha. The skin disease in K14/p40 mice was similar to that of littermate mice that received injections of interleukin-12, suggesting overlapping in vivo functional properties. As induction of interferon-gamma is a major function of interleukin-12, we tested the in vitro ability of transgenic p40 to induce interferon-gamma. In contrast to interleukin-12, transgenic p40 did not stimulate interferon-gamma secretion by cultured splenocytes. We conclude that transgenic p40 and interleukin-12 are equally capable of initiating cutaneous inflammation. Despite these in vivo similarities, there is a clear functional difference between interleukin-12 and transgenic p40 in vitro, suggesting that interferon-gamma is not a major factor contributing to interleukin-12-like activities of transgenic p40.

Generation and cyclic remodeling of the hair follicle immune system in mice.

In this immunohistomorphometric study, we have defined basic characteristics of the hair follicle (HF) immune system during follicle morphogenesis and cycling in C57BL/6 mice, in relation to the skin immune system. Langerhans cells and gammadelta T cell receptor immunoreactive lymphocytes were the predominant intraepithelial hematopoietic cells in neonatal mouse skin. After their numeric increase in the epidermis, these cells migrated into the HF, although only when follicle morphogenesis was almost completed. In contrast to Langerhans cells, gammadelta T cell receptor immunoreactive lymphocytes entered the HF only via the epidermis. Throughout HF morphogenesis and cycling, both cell types remained strikingly restricted to the distal outer root sheath. On extremely rare occasions, CD4+ or CD8+ alphabetaTC were detected within the HF epithelium or the sebaceous gland. Major histocompatibility complex class II+, MAC-1+ cells of macrophage phenotype and numerous mast cells appeared very early on during HF development in the perifollicular dermis, and the percentage of degranulated mast cells significantly increased during the initiation of synchronized HF cycling (first catagen). During both depilation- and cyclosporine A-induced HF cycling, the numbers of intrafollicular Langerhans cells, gammadelta T cell receptor immunoreactive lymphocytes, and perifollicular dermal macrophages fluctuated significantly. Yet, no numeric increase of perifollicular macrophages was detectable during HF regression, questioning their proposed role in catagen induction. In summary, the HF immune system is generated fairly late during follicle development, shows striking differences to the extrafollicular skin immune system, and undergoes substantial hair cycle-associated remodeling. In addition, synchronized HF cycling is accompanied by profound alterations of the skin immune system.