Costs and resource utilization patterns in surgical site infections: a pre-COVID-19 perspective from France, Germany, Spain, and the UK.

BACKGROUND: Surgical site infections (SSIs), mainly caused by Staphylococcus aureus, pose a significant economic burden in Europe, leading to increased hospitalization duration, mortality, and treatment costs, particularly with drug-resistant strains such as meticillin-resistant S. aureus. AIM: To conduct a case-control study on the economic impact of S. aureus SSI in adult surgical patients across high-volume centres in France, Germany, Spain, and the UK, aiming to assess the overall and procedure-specific burden across Europe. METHODS: The SALT study is a multinational, retrospective cohort study with a nested case-control analysis focused on S. aureus SSI in Europe. The study included participants from France, Germany, Italy, Spain, and the UK who underwent invasive surgery in 2016 and employed a micro-costing approach to evaluate health economic factors, matching S. aureus SSI cases with controls. FINDINGS: In 2016, among 178,904 surgical patients in five European countries, 764 developed S. aureus SSI. Matching 744 cases to controls, the study revealed that S. aureus SSI cases incurred higher immediate hospitalization costs (€8,810), compared to controls (€6,032). Additionally, S. aureus SSI cases exhibited increased costs for readmissions within the first year post surgery (€7,961.6 versus €5,298.6), with significant differences observed. Factors associated with increased surgery-related costs included the cost of hospitalization immediately after surgery, first intensive care unit (ICU) admission within 12 months, and hospital readmission within 12 months, as identified through multivariable analysis. CONCLUSION: The higher rates of hospitalization, ICU admissions, and readmissions among S. aureus SSI cases highlight the severity of these infections and their impact on healthcare costs, emphasizing the potential benefits of evidence-based infection control measures and improved patient care to mitigate the economic burden.

Modular air-liquid interface aerosol exposure system (MALIES) to study toxicity of nanoparticle aerosols in 3D-cultured A549 cells in vitro.

We present a novel lung aerosol exposure system named MALIES (modular air-liquid interface exposure system), which allows three-dimensional cultivation of lung epithelial cells in alveolar-like scaffolds (MatriGrids®) and exposure to nanoparticle aerosols. MALIES consists of multiple modular units for aerosol generation, and can be rapidly assembled and commissioned. The MALIES system was proven for its ability to reliably produce a dose-dependent toxicity in A549 cells using CuSO4 aerosol. Cytotoxic effects of BaSO4- and TiO2-nanoparticles were investigated using MALIES with the human lung tumor cell line A549 cultured at the air-liquid interface. Experiments with concentrations of up to 5.93 × 105 (BaSO4) and 1.49 × 106 (TiO2) particles/cm3, resulting in deposited masses of up to 26.6 and 74.0 µg/cm2 were performed using two identical aerosol exposure systems in two different laboratories. LDH, resazurin reduction and total glutathione were measured. A549 cells grown on MatriGrids® form a ZO-1- and E-Cadherin-positive epithelial barrier and produce mucin and surfactant protein. BaSO4-NP in a deposited mass of up to 26.6 µg/cm2 resulted in mild, reversible damage (~ 10% decrease in viability) to lung epithelium 24 h after exposure. TiO2-NP in a deposited mass of up to 74.0 µg/cm2 did not induce any cytotoxicity in A549 cells 24 h and 72 h after exposure, with the exception of a 1.7 fold increase in the low exposure group in laboratory 1. These results are consistent with previous studies showing no significant damage to lung epithelium by short-term treatment with low concentrations of nanoscale BaSO4 and TiO2 in in vitro experiments.

Biomimetic reconstruction of the hematopoietic stem cell niche for in vitro amplification of human hematopoietic stem cells.

Hematopoietic stem cell transplantation is successfully applied since the late 1950s; however, its efficacy still needs to be increased. A promising strategy is to transplant high numbers of pluripotent hematopoietic stem cells (HSCs). Therefore, an improved ex vivo culture system that supports proliferation and maintains HSC pluripotency would override possible limitations in cell numbers gained from donors. To model the natural HSC niche in vitro, we optimized the HSC medium composition with a panel of cytokines and valproic acid and used an artificial 3D bone marrow-like scaffold made of polydimethylsiloxane (PDMS). This 3D scaffold offered a suitable platform to amplify human HSCs in vitro and, simultaneously, to support their viability, multipotency and ability for self-renewal. Silicon oxide-covering of PDMS structures further improved amplification of CD34+ cells, although the conservation of naïve HSCs was better on non-covered 3D PDMS. Finally, we found that HSC cultivated on non-covered 3D PDMS generated most pluripotent colonies within colony forming unit assays. In conclusion, by combining biological and biotechnological approaches, we optimized in vitro HSCs culture conditions, resulting in improved amplification, multipotency maintenance and vitality of HSCs.

Treatment strategies of space-occupying intradural metastases of the cauda equina of nonneurogenic origin.

BACKGROUND: Compressive intradural metastases of the cauda equina are a rare site of metastatic spread in systemic cancer. So far, only few reports have been published with conflicting statements concerning a surgical versus nonsurgical approach. METHOD: Five patients with symptomatic space-occupying intradural metastases of the cauda equina were analyzed retrospectively, focusing on the influence of surgical intervention on pain relief, neurological outcome and thus the patients' quality of life. FINDINGS: At the time of diagnosis, all patients were in an advanced metastatic state. Surgical resection was the primary treatment in four patients and radiotherapy in one. Despite infiltration of the cauda rootlets, gross total tumour resection could be achieved in two of the four patients treated surgically. Functional outcome was beneficial in these patients with marked and immediate relief of pain and improvement of motor function even following incomplete tumour resection. CONCLUSIONS: Surgical treatment of compressive intradural metastases of the cauda equina seems to be feasible with low operative risk and with the potential benefit of an immediate relief of pain and improvement in motor function and thus an increase in quality of life.

Variability in infectivity of primary cell cultures of human brain tumors with HSV-1 amplicon vectors.

We investigated the variability in infectivity of cells in primary brain tumor samples from different patients using an HSV-1 amplicon vector. We studied the infectivity of HSV-1 amplicon vectors in tumor samples derived from neurosurgical resections of 20 patients. Cells were infected with a definite amount of HSV-1 amplicon vector HSV-GFP. Transduction efficiency in primary tumor cell cultures was compared to an established human glioma line. Moreover, duration of transgene expression was monitored in different tumor cell types. All primary cell cultures were infectable with HSV-GFP with variable transduction efficiencies ranging between 3.0 and 42.4% from reference human Gli36 Delta EGFR glioma cells. Transduction efficiency was significantly greater in anaplastic gliomas and meningiomas (26.7+/-17.4%) compared to more malignant tumor types (glioblastomas, metastases; 11.2+/-8.5%; P=0.05). To further investigate the possible underlying mechanism of this variability, nectin-1/HevC expression was analyzed and was found to contribute, at least in part, to this variability in infectability. The tumor cells expressed the exogenous gene for 7 to 61 days with significant shorter expression in glioblastomas (18+/-13 d) compared to anaplastic gliomas (42+/-24 d; P<0.05). Interindividual variability of infectivity by HSV-1 virions might explain, at least in part, why some patients enrolled in gene therapy for glioblastoma in the past exhibited a sustained response to HSV-1-based gene- and virus therapy. Infectivity of primary tumor samples from respective patients should be tested to enable the development of efficient and safe herpes vector-based gene and virus therapy for clinical application.

Loss of BRCA2 correlates with reduced long-term survival of sporadic breast cancer patients.

BACKGROUND: The present study was undertaken to analyze the prognostic value of loss of heterozygosity (LOH) at 13q12-13, 17q21 and 17p13, harboring BRCA2, BRCA1 and p53 to predict the clinical course of sporadic breast cancer patients. MATERIALS AND METHODS: LOH analysis was performed by PCR amplification of genomic DNA using nine microsatellite markers. Fifty-three sporadic breast cancer patients were followed clinically for a median of 55 months. Disease-free and overall survival was documented as the endpoint for statistical evaluation. RESULTS: Patients presenting with LOH in their tumor samples at at least one of the loci examined were found to have a reduced overall survival time compared to those retaining heterozygosity (61% versus 48%). Focusing on the three target regions, patients with LOH at the BRCA2 locus died earlier compared to patients retaining heterozygosity (69% versus 50%) and, in addition, BRCA2 LOH-positive patients showed a shorter metastasis-free interval (30 versus 37 months). In a multivariate analysis, LOH at the 13q12-13 locus was found to be a significant predictor for reduced long-term survival (risk ratio 2.33, 95% C.I., 1.0-5.3; p<0.05) and earlier metastases manifestation (risk ratio 2.32, 95% C.I., 1.0-5.3, p<0.05). CONCLUSION: Allelic loss at the BRCA2 locus may be of use as a negative predictor for metastases-free and overall survival.

Differences in dietary patterns of nonsmoking adults married to smokers vs. nonsmokers.

PURPOSE: To compare dietary intakes of nonsmoking adults married to smokers or nonsmokers. DESIGN: Respondents to the U.S. Department of Agriculture's Continuing Survey of Food Intakes by Individuals (CSFII), 1994 to 1996 (response rate = 76.1% for 2 days of dietary intake). Nonsmoking adults aged 18 and older were grouped according to the smoking status of their spouse. SETTING: In-home interviews in all 50 states and Washington, D.C. SUBJECTS: The selected sample included 757 men and 754 women who were married to nonsmokers, and 197 men and 262 women who were married to smokers. MEASURES: Selected demographic variables, food group servings, food energy, and densities of selected nutrients were compared using chi 2 and analysis of covariance. RESULTS: Men and women married to smokers had greater (p < or = .025) energy-adjusted intakes of total and saturated fat but significantly lower (p < or = .05) energy-adjusted intakes of fiber and vitamin A. Men married to smokers consumed significantly more (p < .025) energy-adjusted cholesterol and ethanol but significantly less calcium (p = .026); women married to smokers consumed significantly less (p = .014) energy-adjusted folate. Men married to smokers consumed significantly more (p < or = .05) alcoholic beverages, coffee, and soft drinks; women married to smokers consumed significantly less water (p = .014) but more cheese and table sweeteners (p < or = .05). CONCLUSIONS: Nonsmoking men and women who were married to smokers had compromised dietary intakes. Nonsmoking men whose wives smoked, in particular, had unhealthy diets due to elevated intakes of fat and cholesterol and low intakes of vitamin A, calcium, and fiber. Health professionals should continue to provide tobacco cessation instruction and dietary guidance, but also be aware of at-risk patients' immediate family members who likely share an increased risk of disease because of poor diet quality and exposure to environmental tobacco smoke.

More Americans are eating "5 a day" but intakes of dark green and cruciferous vegetables remain low.

Epidemiological investigations repeatedly show that the regular consumption of dark green and cruciferous vegetables, tomatoes and citrus fruits in particular is related to reduced cancer risk. We used the 1994-1996 Continuing Survey of Food Intakes by Individuals to examine the types of fruits and vegetables consumed by Americans. The analytic sample population, which consisted of 4806 men and women (25-75 y old) who completed two nonconsecutive 24-h recalls, consumed 3.6 +/- 2.3 servings of vegetables and 1.6 +/- 2.0 servings of fruit daily. Iceberg lettuce, tomatoes, French fried potatoes, bananas and orange juice were the most commonly consumed fruits and vegetables, accounting for nearly 30% of all fruits and vegetables consumed. The most popular items, lettuce and tomatoes, were consumed by 39-42% of the sample population during the reporting period. Fewer respondents (16-24%) consumed French fried potatoes, bananas or orange juice. Only 3% of the sample consumed broccoli during the reporting period. White potato consumption averaged 1.1 servings daily, with French fried potatoes representing 0.4 serving. Tomato product consumption averaged 0.5 serving daily, dark green vegetable consumption averaged 0.2 serving daily and citrus, berries or melon consumption amounted to nearly 0.8 serving daily. These data indicate that Americans are consuming more fruits and vegetables but that dark green and cruciferous vegetable intake is low.

Antioxidant intakes and smoking status: data from the continuing survey of food intakes by individuals 1994-1996.

BACKGROUND: Cigarette smoking is a major risk factor for several chronic oxidative diseases that can be ameliorated by antioxidants. OBJECTIVES: This study identified the typical dietary intakes and the major food group contributors of the antioxidants beta-carotene, vitamin C, and vitamin E by smoking status. DESIGN: The 1994-1996 Continuing Survey of Food Intakes by Individuals (CSFII) provided the current sample (n = 6749), who were categorized as non- (n = 3231), former (n = 1684), and current (n = 1834) smokers. In the CSFII, individuals' food intakes were estimated with two 24-h dietary recalls. Data were analyzed by using a chi-square test with a simultaneous Fisher's z test, analysis of variance with Scheffe's test, multivariate analysis of covariance, and analysis of covariance with Bonferroni adjustment for multiple comparisons. RESULTS: The sample consisted of 3707 men and 3042 women. Current smokers tended to be younger with less education and lower incomes than nonsmokers and former smokers. The average body mass index (in kg/m(2)) of current smokers was 25.8, the lowest of the 3 groups. Current smokers had the lowest dietary antioxidant intake. Fatty foods such as luncheon meats, condiments and salad dressings, and ground beef contributed more to the antioxidant intakes of current smokers than to those of the other 2 groups, whereas fruit and vegetables contributed less. Current smokers consumed the fewest numbers of servings of all nutrient-bearing groups in the food guide pyramid, except the meat group. CONCLUSION: Future interventions should target the clustering of cigarette smoking and other unhealthy lifestyle habits, eg, an imprudent diet.

Clustering of lifestyle behaviors: the relationship between cigarette smoking, alcohol consumption, and dietary intake.

PURPOSE: To examine relationships between cigarette smoking, alcohol use, and dietary intake. DESIGN: Respondents to the U.S. Department of Agriculture's Continuing Survey of Food Intakes by Individuals, a nationwide probability sample conducted from January 1994 through January 1997 (n = 23,602; response rate = 80%), were selected. Adults ages 19 years and older were grouped according to their smoking and drinking habits. Selected demographic variables, food group servings, food energy, and densities of selected nutrients were compared. SETTING: In-home interviews were conducted in the 50 states and the District of Columbia. SUBJECTS: The selected sample (n = 6745) included 3229 nonsmokers, 1701 former smokers, and 1808 current smokers, and 2284 abstainers, 2713 occasional drinkers, 1000 moderate drinkers, and 748 liberal drinkers. MEASURES: Responses to standard questionnaires were examined by Student's t-test, chi 2, one-way analysis of variance, and univariate and multivariate analyses of covariance. RESULTS: Men were more likely than women to be current smokers and liberal drinkers (64% vs. 40% and 62% vs. 38%). For both, the use of cigarettes and alcohol was closely related. An additive relationship was observed between smoking/drinking classification and lower food group servings and nutrient intakes. Although cigarette and alcohol use may have been underreported, these findings support previous ones showing poor food choices along with lower nutrient intakes as smoking and drinking increase. CONCLUSIONS: Smoking and drinking habits may alter individuals' food selections and nutrient intakes. Future interventions for health promotion may achieve greater success by targeting multiple risk factors simultaneously or sequentially.

Cigarette use during adolescence: effects on nutritional status.

Despite numerous anti-tobacco campaigns, smoking among adolescents continues to be a predominant public health issue. This report details the interrelationships between adolescence, smoking, and nutrition and health. Current data indicate that most smokers become nicotine-dependent as adolescents, which places them at risk for chronic diseases associated with continuous oxidative damage. Additionally, nicotine has antidepressant and hypermetabolic effects, which may be of particular importance during adolescence because nicotine use leads to increased dependence on tobacco, contributes to difficulty in smoking cessation, and promotes weight gain following smoking cessation.

Loss of heterozygosity accumulation in primary breast carcinomas and additionally in corresponding distant metastases is associated with poor outcome.

The occurrence of distant metastases is the most feared manifestation of breast cancer, often occurring years after the primary surgery and associated with poor survival. The dominant metastatic clone is characterized by an accumulation of genetic alterations, but it is not actually known at what stage of the metastatic cascade these alterations have occurred. We investigated allelic losses during breast cancer progression in a series of 17 primary breast carcinomas and 22 corresponding brain, liver, lung, and bone metastases (mean metastasis-free interval, 31 months) by analyzing 19 microsatellite markers on seven breast cancer- or metastasis-related chromosomal regions and correlated the incidence of combined loss of heterozygosity (LOH) with metastasis-free and postmetastatic survival. We found that, in comparison with the corresponding primary tumor, additional LOH events are frequently found in metastases and that the incidence of combined LOH in the primary tumor, plus the occurrence of additional LOH events in the distant metastases, correlated significantly with decreased postmetastatic survival. Combined LOH of the three breast cancer-related chromosomal regions alone or in combination with allelic loss at the p53 gene region seems to have a specific influence on the aggressive behavior of metastases. We hypothesize that the occurrence of additional LOH events is either involved in termination of dormancy of micrometastatic tumor cells at distant organ sites or acquired during further progression of metastases.

The specificity of a weak gamma delta TCR interaction can be modulated by the glycosylation of the ligand.

The gamma delta T cell clone LBK5 recognizes the MHC molecule IEk. Here, we demonstrate that the affinity of this interaction is weaker than those typically reported for alpha beta TCRs that recognize peptide/MHC complexes. Consistent with our previous finding that peptide bound to the IE molecule does not confer specificity, we show that the entire epitope for LBK5 is contained within the polypeptide chains of the molecule, centered around the polymorphic residues 67 and 70 of the IE beta-chain. However, LBK5 recognition is profoundly influenced by the N-linked glycosylation at residue 82 of the IE alpha-chain. Since infected, stressed, or transformed cells often change the posttranslational modifications of their surface glycoproteins, this finding suggests a new way in which gamma delta T cell Ag recognition can be regulated.

Initiation of signal transduction through the T cell receptor requires the multivalent engagement of peptide/MHC ligands [corrected].

While much is known about intracellular signaling events in T cells when T cell receptors (TCRs) are engaged, the mechanism by which signaling is initiated is unclear. We have constructed defined oligomers of soluble antigen-major histocompatibility complex (MHC) molecules, the natural ligands for the TCR. Using these to stimulate specific T cells in vitro, we find that agonist peptide/MHC ligands are nonstimulatory as monomers and minimally stimulatory as dimers. Similarly, a partial-agonist ligand is very weakly active as a tetramer. In contrast, trimeric or tetrameric agonist ligands that engage multiple TCRs for a sustained duration are potent stimuli. Ligand-driven formation of TCR clusters seems required for effective activation and helps to explain the specificity and sensitivity of T cells.

Nutritional and socioeconomic factors in relation to prostate cancer mortality: a cross-national study.

BACKGROUND: Large international variations in rates of prostate cancer incidence and mortality suggest that environmental factors have a strong influence on the development of this disease. The purpose of this study was to identify predictive variables for prostate cancer mortality in data from 59 countries. METHODS: Data on prostate cancer mortality, food consumption, tobacco use, socioeconomic factors, reproductive factors, and health indicators were obtained from United Nations sources. Linear regression models were fit to these data. The influence of each variable fit in the regression models was assessed by multiplying the regression coefficient b by the 75th (X75) and 25th (X25) percentile values of the variable. The difference, bX75 - bX25, is the estimated effect of the variable across its interquartile range on mortality rates measured as deaths per 100000 males aged 45-74 years. Reported P values are two-sided. RESULTS: Prostate cancer mortality was inversely associated with estimated consumption of cereals (bX75 - bX25 = -7.31 deaths; P = .001), nuts and oilseeds (bX75 - bX25 = -1.72 deaths; P = .003), and fish (bX75 - bX25 = -1.47 deaths; P = .001). In the 42 countries for which we had appropriate data, soy products were found to be significantly protective (P = .0001), with an effect size per kilocalorie at least four times as large as that of any other dietary factor. Besides variables related to diet, we observed an association between prostate cancer mortality rates and a composite of other health-related, sanitation, and economic variables (P = .003). CONCLUSIONS: The specific food-related results from this study are consistent with previous information and support the current dietary guidelines and hypothesis that grains, cereals, and nuts are protective against prostate cancer. The findings also provide a rationale for future study of soy products in prostate cancer prevention trials.

Evidence that TSG101 aberrant transcripts are PCR artifacts.

Critical analysis of the data published so far concerning the TSG101 gene revealed some inconsistencies leading us to its re-evaluation in 80 breast, brain, colon, and neuroectodermal tumors and 37 normal tissue specimens. In this study, the occurrence of TSG101 cDNA aberrant transcripts was verified, but in addition we made observations that are in apparent conflict with the aberrant splicing theory supposed as the underlying mechanism for transcript formation: the location of most deletion breakpoints within exons and nonconformity of these putative splice sites with the highly conserved GT-AG rule, detection of insertions as well as nonreproducible and highly variable results in repeated RT-nested PCRs. Furthermore, we found that reamplification of full-length TSG101 cDNA products leads to the generation of deleted transcripts. In summary, for the first time we provide evidence that the acquired TSG101 transcripts are caused by PCR artifacts.

Accumulation of genetic alterations in brain metastases of sporadic breast carcinomas is associated with reduced survival after metastasis.

Tumor progression is characterized by stepwise accumulation of genetic alterations. To identify alterations associated with breast cancer metastasis, an analysis of comparative loss of heterozygosity (LOH) was performed on 38 primary sporadic breast carcinomas and 16 distant metastases. Two loci at 5q21 and 18q21 were chosen because of their reported increased deletion frequency in metastatic tumors. LOH at 17q21, 13q12-13, 17p13.1 and 11q22-23 was analyzed to determine whether there is a specific involvement of these breast cancer-associated gene loci in the metastatic process. Our data show that distant metastases are characterized by markedly increased LOH frequency at all loci examined. In both gene locus groups, significantly more distant metastases are affected by combined LOH. Furthermore, a significantly reduced postmetastatic survival time has been observed in patients with brain metastases affected by synchronous allelic loss at the four breast cancer-associated gene loci. Our results suggest that cumulative LOH of breast cancer-related gene loci is associated with a more aggressive phenotype of metastatic breast tumors.

The putative tumor suppressor gene FHIT at 3p14.2 is rarely affected by loss of heterozygosity in primary human brain tumors.

To elucidate the role of the recently identified FHIT gene, located at 3p14.2 in human brain tumor carcinogenesis, a total of 259 tumors were analyzed for loss of heterozygosity (LOH) at microsatellite loci D3S1313, D3S1234, D3S1300, and D3S1481. In primary brain tumors, LOH was detected at a frequency of 8.4% (n = 214). Low-grade gliomas exhibited insignificantly lower LOH rates in comparison to high-grade gliomas (5.3%, n = 19, versus 11.1%, n = 90). Notably, no allelic loss was observed in 12 recurrent glioblastomas analyzed in comparison to their corresponding primary tumor lesions and in two astrocytomas with progression to higher grades of malignancy. Our data indicate that allelic loss of the FHIT gene is neither a critical event in carcinogenesis of primary brain tumors nor tumor grade-associated in astrocytic tumors. In contrast, observed LOH rate for brain metastases was as high as 54.5% (n = 45), in accordance with data thus far accumulated from analyses of corresponding primary tumors.

A TCR binds to antagonist ligands with lower affinities and faster dissociation rates than to agonists.

T lymphocyte activation is mediated by the interaction of specific TCR with antigenic peptides bound to MHC molecules. Single amino acid substitutions are often capable of changing the effect of a peptide from stimulatory to antagonistic. Using surface plasmon resonance, we have analyzed the interaction between a complex consisting of variants of the MCC peptide bound to a mouse class II MHC (Ek) and a specific TCR. Using both an improved direct binding method as well as a novel inhibition assay, we show that the affinities of three different antagonist peptide-Ek complexes are approximately 10-50 times lower than that of the wildtype MCC-Ek complex for the TCR, largely due to an increased off-rate. These results suggest that the biological effects of peptide antagonists and partial agonists may be largely based on kinetic parameters.