Incidence, associated disease burden and healthcare utilization due to Staphylococcus aureus prosthetic joint infection in European hospitals: the COMBACTE-NET ARTHR-IS multi-centre study.

BACKGROUND: The aim of this study was to estimate the incidence, associated disease burden and healthcare utilization due to Staphylococcus aureus prosthetic joint infections (SA-PJI) after primary hip and knee arthroplasty in European centres. METHODS: This study was conducted in patients who underwent primary hip and knee arthroplasty in 19 European hospitals between 2014 and 2016. The global incidence of PJI and SA-PJI was calculated. The associated disease burden was measured indirectly as infection-related mortality plus loss of function. For healthcare utilization, number and duration of hospitalizations, number and type of surgical procedures, duration of antibiotic treatments, and number of outpatient visits were collected. Subgroup and regression analyses were used to evaluate the impact of SA-PJI on healthcare utilization, controlling for confounding variables. RESULTS: The incidence of PJI caused by any micro-organism was 1.41%, and 0.40% for SA-PJI. Among SA-PJI, 20.7% were due to MRSA with substantial regional differences, and were more frequent in partial hip arthroplasty (PHA). Related deaths and loss of function occurred in 7.0% and 10.2% of SA-PJI cases, respectively, and were higher in patients with PHA. Compared with patients without PJI, patients with SA-PJI had a mean of 1.4 more readmissions, 25.1 more days of hospitalization, underwent 1.8 more surgical procedures, and had 5.4 more outpatient visits, controlling for confounding variables. Healthcare utilization was higher in patients who failed surgical treatment of SA-PJI. CONCLUSIONS: This study confirmed that the SA-PJI burden is high, especially in PHA, and provided a solid basis for planning interventions to prevent SA-PJI.

RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer.

The receptor for advanced glycation end products (RAGE) is implicated in diabetes and obesity complications, as well as in breast cancer (BC). Herein, we evaluated whether RAGE contributes to the oncogenic actions of Insulin, which plays a key role in BC progression particularly in obese and diabetic patients. Analysis of the publicly available METABRIC study, which collects gene expression and clinical data from a large cohort (n = 1904) of BC patients, revealed that RAGE and the Insulin Receptor (IR) are co-expressed and associated with negative prognostic parameters. In MCF-7, ZR75 and 4T1 BC cells, as well as in patient-derived Cancer-Associated Fibroblasts, the pharmacological inhibition of RAGE as well as its genetic depletion interfered with Insulin-induced activation of the oncogenic pathway IR/IRS1/AKT/CD1. Mechanistically, IR and RAGE directly interacted upon Insulin stimulation, as shown by in situ proximity ligation assays and coimmunoprecipitation studies. Of note, RAGE inhibition halted the activation of both IR and insulin like growth factor 1 receptor (IGF-1R), as demonstrated in MCF-7 cells KO for the IR and the IGF-1R gene via CRISPR-cas9 technology. An unbiased label-free proteomic analysis uncovered proteins and predicted pathways affected by RAGE inhibition in Insulin-stimulated BC cells. Biologically, RAGE inhibition reduced cell proliferation, migration, and patient-derived mammosphere formation triggered by Insulin. In vivo, the pharmacological inhibition of RAGE halted Insulin-induced tumor growth, without affecting blood glucose homeostasis. Together, our findings suggest that targeting RAGE may represent an appealing opportunity to blunt Insulin-induced oncogenic signaling in BC.

Redesign Of Breastfeeding Chair For Nursery Room

@#Breastfeeding chair is one of the essential facilities in the airport. This study designs the breastfeeding chair for the nursery room in Minangkabau International Airport. Quality Function Deployment (QFD) was used to investigate the customer requirements by distributing questionnaires to 100 mothers in Padang West Sumatra. Anthropometry data was also measured form those respondents. The study resulted in a design of ergonomic breastfeeding chair which was used features obtained from the voice of the customers. The design has considered the condition of the mother giving birth by normal as well as a cesarean. The design has an adjustable back seat with an angle of 95o,105o, and 110o; it has an adjustable footrest with 120o, 140o, and 180o angles. The chair has a headrest, baby support pad, a portable baby cushion, an adjustable baby bearings. The chair has also equipped with an assemble torn neck, a small drawer on the side of the chair, and a palm rest that can be used or not by adjusting the height.

Long-acting insulin analogs and cancer.

AIMS: Hyperinsulinemia is a recognized risk factor for cancer and plays a major role for the increased cancer incidence in diabetic patients. Whether insulin analogs, and particularly long-acting analogs, worsen the pro-cancer effect of excess insulin is still controversial. DATA SYNTHESIS: In this paper we summarize the biological bases for the potential detrimental effect of long-acting analogs on cancer cells and review the in vitro and in vivo evidence on this issue. Because of their different molecular structure relative to native insulin, insulin analogs may activate the insulin receptor (IR) and the post receptor pathways differently. Most, but not all, in vitro evidence indicate that long-acting analogs may have a stronger mitogenic potency than insulin on cancer cells. Notably insulin glargine, the most studied long-acting analog, also has a higher affinity for the insulin-like growth factor (IGF)-1 receptor, a potent growth mediator. In vitro observations, however, may not reflect what occurs in vivo when analogs are metabolized to derivatives with a different mitogenic activity. Clinical studies, mostly retrospective and predominantly concerning glargine, provide contrasting results. The only perspective trial found no cancer increase in patients treated with glargine. All these studies, however, have severe weaknesses because of the insufficient evaluation of important factors such as dose administered, length of exposure, patient follow-up duration and site-specific cancer investigation. Moreover, whether cancer promotion is a long-acting analog class characteristic or a specific effect of a single agent is not clear. CONCLUSIONS: In conclusion the carcinogenic risk of long-acting analogs, and specifically glargine, can be neither confirmed nor excluded. A personalized and shared decision, considering all the individual risk factors (metabolic and non-metabolic), is the suggestion for the clinician.

Isolation demand from carbapenemase-producing Enterobacteriaceae screening strategies based on a West London hospital network.

OBJECTIVE: To estimate the isolation demands arising from high-risk specialty-based screening for carbapenemase-producing Enterobacteriaceae (CPE), and the potential fraction of CPE burden detected. METHODS: Clinical specialty groups from three London hospitals were ranked by incidence of carbapenem resistance among Escherichia coli and Klebsiella spp. Contact precaution bed-days were estimated for three screening strategies: Strategy 1, 'circulation science and renal medicine'; Strategy 2, Strategy 1 plus 'specialist services'; and Strategy 3, Strategy 2 plus 'private patients'. Isolation bed occupancy rates and potential CPE detection rates were estimated. RESULTS: Of 99,105 admissions to the three hospitals in Financial Year 2014/15, Strategies 1, 2 and 3 would have screened 4371 (4.4%), 7482 (7.6%), and 13,542 (13.7%) patients, respectively. The specialties' isolation bed occupancy rates varied between 3% and 696% depending on strategy, number of consecutive tests, and whether or not pre-emptive isolation had been applied. Expected detection rates of the potential CPE burden in the hospital network would have varied between 17.1% and 47.5%. CONCLUSIONS: High-risk specialty-based screening has the potential to detect nearly half of the potential CPE burden, and would be more pragmatic than patient-level risk-factor-based screening. Pre-emptive isolation increases isolation requirements substantially. CPE screening strategies need to balance risk and resources.

Measures to eradicate multidrug-resistant organism outbreaks: how much do they cost?

This study aimed to assess the economic burden of infection control measures that succeeded in eradicating multidrug-resistant organisms (MDROs) in emerging epidemic contexts in hospital settings. The MEDLINE, EMBASE and Ovid databases were systematically interrogated for original English-language articles detailing costs associated with strict measures to eradicate MDROs published between 1 January 1974 and 2 November 2014. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Overall, 13 original articles were retrieved reporting data on several MDROs, including glycopeptide-resistant enterococci (n = 5), carbapenemase-producing Enterobacteriacae (n = 1), methicillin-resistant Staphylococcus aureus (n = 5), and carbapenem-resistant Acinetobacter baumannii (n = 2). Overall, the cost of strict measures to eradicate MDROs ranged from €285 to €57 532 per positive patient. The major component of these overall costs was related to interruption of new admissions, representing €2466 to €47 093 per positive patient (69% of the overall mean cost; range, 13-100%), followed by mean laboratory costs of €628 to €5849 (24%; range, 3.3-56.7%), staff reinforcement costs of €6204 to €148 381 (22%; range, 3.3-52%), and contact precautions costs of €166 to €10 438 per positive patient (18%; range, 0.7-43.3%). Published data on the economic burden of strict measures to eradicate MDROs are limited, heterogeneous, and weakened by several methodological flaws. Novel economic studies should be performed to assess the financial impact of current policies, and to identify the most cost-effective strategies to eradicate emerging MDROs in healthcare facilities.

Household contact investigation of multidrug-resistant and extensively drug-resistant tuberculosis in a high HIV prevalence setting.

SETTING: Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are now a nationwide epidemic in South Africa. Epidemiological data suggest nosocomial transmission as the primary route of spread; however, transmission among household contacts has not yet been investigated. OBJECTIVE: To determine the incidence rates of MDR- and XDR-TB among household contacts of MDR- and XDR-TB index cases diagnosed between January 2005 and September 2008 in a high human immunodeficiency virus prevalence setting. DESIGN: Prospective, observational study evaluating adult household contacts for active TB by culture and drug susceptibility testing at index case diagnosis and again 1 year later. Outcomes were incidence and time to diagnosis of MDR- and XDR-TB. RESULTS: A total of 1766 contacts of 221 MDR-TB and 287 XDR-TB index cases were screened. Of 793 contacts of MDR-TB index cases, 14 (1.8%) were diagnosed with MDR-TB (incidence 1765/100 000); 19 (2.0%) of 973 XDR-TB contacts had XDR-TB (incidence 1952/100 000). Median time to diagnosis of household cases was 70 days (interquartile range 57-89). CONCLUSION: Incidence rates of MDR- and XDR-TB among household contacts were extremely high, with most secondary cases occurring shortly after the diagnosis of the index case. Active case finding of drug-resistant TB is a high-yield public health activity and must be a priority, as early diagnosis may stem further disease spread and improve survival.

Resistance to antiretroviral drugs in newly diagnosed, young treatment-naïve HIV-positive pregnant women in the province of KwaZulu-Natal, South Africa.

In 2004, KwaZulu-Natal initiated one of the world's largest HIV/AIDS treatment programs. Studies in South Africa have shown that patients on antiretroviral therapy (ART) develop rapidly and transmit drug resistant mutations. Since resistance testing is not widely available in Kwazulu-Natal, the Department of Health conducted the first HIV drug resistance (HIVDR) threshold survey in 2005, which did not identify any mutations associated with HIVDR. The objective of this study was to conduct a follow-up threshold survey to update the information on HIVDR. This study was conducted in 2009 in five antenatal care sites in Kwazulu-Natal using the HIVDR threshold survey method developed by WHO. Two hundred and thirteen newly-diagnosed HIV positive, drug-naïve primigravidae, less than 22 years of age were included in the survey. Of the 82 HIV positive specimens, 17 had insufficient volume for genotyping and, of the remaining 65, 47 were genotyped sequentially. Drug resistance was identified by sequencing the HIV-1 pol gene, using the ViroSeq® HIV-1 genotyping system v2.0. Of the 47 samples that were genotyped, only one presented with a K103N mutation, which equates to a prevalence of transmitted HIVDR of <5%. The low prevalence of transmitted HIVDR is in keeping with statistical models of the early stages of ART rollout. As ART coverage is increasing continuously, there is a need to ensure that vigilance of HIVDR continues so that the emergence and spread of HIVDR is minimized.

BRAF(V600E) mutation and the biology of papillary thyroid cancer.

BRAF((V600E)) mutation is the most frequent genetic alteration in papillary thyroid carcinomas (PTCs) that are 80-90% of all thyroid cancers. We evaluated the relationship between BRAF((V600E)) and tumor, host, and environmental factors in PTCs from all geographical areas of Sicily. By PCR, BRAF((V600E)) was investigated in a series of 323 PTCs diagnosed in 2002-2005. The correlation between clinicopathological tumor, host, and environmental characteristics and the presence of BRAF((V600E)) were evaluated by both univariate and multivariate analyses. BRAF((V600E)) was found in 38.6% PTCs, with a 52% frequency in the classical PTCs and 26.4% in the tall cell variant. Univariate analysis indicated that BRAF((V600E)) was associated with greater tumor size (P=0.0048), extra-thyroid invasion (P<0.0001), and cervical lymph nodal metastases (P=0.0001). Multivariate logistic regression analysis confirmed that BRAF((V600E)) was an independent predictor of extra-thyroid invasion (P=0.0001) and cervical lymph nodal metastasis (P=0.0005). The association between BRAF((V600E)) and extra-thyroid invasion was also found in micro-PTCs (P=0.006). In 60 classical PTCs, BRAF((V600E)) was positively correlated with matrix metalloproteinase-9 expression (P=0.0047), suggesting a possible mechanism for BRAF((V600E)) effect on PTC invasiveness. No association was found between BRAF((V600E)) and patient age, gender, or iodine intake. In contrast, a strong association was found with residency in Eastern Sicily (P<0.0001 compared with Western Sicily). These results indicate that BRAF((V600E)) mutation is a marker of aggressive disease in both micro- and macro-PTCs. Moreover, for the first time, a possible link between BRAF((V600E)) mutation and environmental carcinogens is suggested.

p53 family proteins in thyroid cancer.

At variance with other human malignancies, p53 mutations are not frequent in thyroid cancer and are believed to be responsible mainly for cancer progression to poorly differentiated and aggressive phenotype. p63 and p73, two proteins with a high degree of homology with p53, are overexpressed in thyroid cancer, but their role in cancer initiation or progression is controversial. Regulation of p53 family protein function depends on: (1) the balance between the expression of transcriptionally active (p53, TAp63, and TAp73) and inactive isoforms (DeltaNp63 and DeltaNp73); (2) their interaction and competition at DNA-responsive elements; (3) their interaction with regulatory proteins, either inhibitory or activating. In thyroid cancer, therefore, although mutations of the p53 oncosuppressor protein family are rare, other mechanisms are present, including aberrant expression of p53 family dominant negative isoforms, up-regulation of inhibitory proteins, and functional inhibition of activating proteins. The overall result is a defective oncosuppressor activity. These inactivating mechanisms may be present in the early stages of thyroid cancer and in different cancer histotypes. A better understanding of this complex network may not only ameliorate our comprehension of cancer biology, but also open the possibility of innovative diagnostic procedures and the development of targeted therapies.

Immunostaining for Met/HGF receptor may be useful to identify malignancies in thyroid lesions classified suspicious at fine-needle aspiration biopsy.

The receptor for hepatocyte growth factor (Met) is not expressed in the normal thyroid but it is overexpressed in most thyroid carcinomas. We evaluated whether Met immunostaining of cytological smears from fine-needle aspiration biopsy (FNAB) may be useful for the preoperative diagnosis of thyroid cancer. Notably, routine cytological examination often fails to distinguish well-differentiated follicular carcinomas and a proportion of papillary carcinomas (low-grade papillary carcinomas and papillary carcinomas follicular variant [FVPTC]) from benign lesions: all these lesions are usually classified as suspicious. We examined 80 thyroid lesions diagnosed as suspicious at cytology that had subsequently undergone surgery. The histologic diagnosis had been: papillary carcinomas (n = 14), FVPTC (n = 11), follicular carcinomas (n = 25), atypical follicular adenomas (n = 5), follicular adenomas (n = 20), and nodular goiters (n = 5). We also studied typical papillary carcinomas (n = 30) and nodular goiters (n = 10), all correctly diagnosed at cytology. In lesions classified suspicious at routine cytology, Met immunostaining was positive in 12 of 14 (85.7%) papillary carcinomas, 8 of 11 (72.7%) FVPTC, 7 of 25 (28%) follicular carcinomas, and 5 of 5 atypical adenomas. In contrast, none of the 25 lesions cytologically suspicious but benign at histology were positive. These data suggest that Met immunostaining of suspicious cytological smears are useful for identifying malignant lesions, especially those with a papillary histotype.

Tyrosine kinase inhibitor STI571 enhances thyroid cancer cell motile response to Hepatocyte Growth Factor.

The Hepatocyte Growth Factor (HGF) and its receptor Met are physiological regulators of cell migration. HGF and Met have also been implicated in tumor progression and metastasis. We show here that the tyrosine kinase inhibitor STI571 has a stimulatory effect on HGF-induced migration and branching morphogenesis in thyroid cancer but not in primary or immortalized thyroid epithelial cells. These stimulatory effects of STI571 are observed at a concentration that is clinically relevant. The STI571-enhanced motile response can be correlated with an increase in the Met receptor tyrosine phosphorylation as well as ERK and Akt activation by HGF. Interestingly, one of the targets of STI571, namely the c-Abl tyrosine kinase, is activated by HGF and is recruited at the migrating edge of thyroid cancer cells. These data suggests that c-Abl and/or STI571-inhibited tyrosine kinases can negatively regulate the Met receptor to restrain the motile response in thyroid cancer cells.

The IGF system in thyroid cancer: new concepts.

In recent years, the activation of the insulin-like growth factor (IGF) system in cancer has emerged as a key factor for tumour progression and resistance to apoptosis. Therefore, a variety of strategies have been developed to block the type I IGF receptor (IGF-I-R), which is thought to mediate the biological effects of both IGF-I and IGF-II. However, recent data suggest that the IGF signalling system is complex and that other receptors are involved. To unravel the complexity of the IGF system in thyroid cancer, IGF-I and IGF-II production, and the expression and function of their cognate receptors were studied. Both IGFs were found to be locally produced in thyroid cancer: IGF-I by stromal cells and IGF-II by malignant thyrocytes. Values were significantly higher in malignant tissue than in normal tissue. IGF-I-Rs were overexpressed in differentiated papillary carcinomas but not in poorly differentiated or undifferentiated tumours, whereas insulin receptors (IRs) were greatly overexpressed in all tumour hystotypes, with a trend for higher values in dedifferentiated tumours. As a consequence of IR overexpression, high amounts of IR/IGF-I-R hybrids (which bind IGF-I with high affinity) were present in all thyroid cancer histotypes. Because of recent evidence that isoform A of IR (IR-A) is a physiological receptor for IGF-II in fetal life, the relative abundance of IR-A in thyroid cancer was measured. Preliminary data indicate that overexpressed IRs mainly occur as IR-A in thyroid cancer. These data indicate that both IR/IGF-I-R hybrids and IR-A play an important role in the overactivation of the IGF system in thyroid cancer and in IGF-I mitogenic signalling in these tumours. J Clin PATHOL: Mol Pathol

[Palliative treatment of esophageal and cardial carcinoma]. / La palliazione del carcinoma esofageo e cardiale.

Recent series reported increasing incidence of esophageal and cardial cancers with prognosis still severe in spite of surgical progress. The late diagnosis reduces the chance of radical surgery; on the other hand about 80-90% of patients develop local or distant recurrence. Therefore the treatment of esophageal and cardial cancer is often palliative: surgical resection is reserved only to selected cases. Endoscopic palliation was the treatment of choice in a total of 265 patients 174 of which received laser therapy and 91 prosthesis intubation. The results it good in about 80% of cases.

Insulin/IGF-I hybrid receptors play a major role in IGF-I signaling in thyroid cancer.

The insulin-like growth factor-I (IGF-I) plays an important role in determining the biological behavior of a variety of malignancies. We measured IGF-I, its receptor and related receptors in thyroid cancer. IGF-I was present both in normal thyroid tissue and in thyroid cancer tissue and it was produced by stromal cells but not by thyrocytes. Values were significantly higher in malignant than in normal tissue. IGF-I receptors (IGF-I-Rs) and the homologous insulin receptors (IRs) were found overexpressed in both thyroid cancer cell lines (n = 4) and specimens (n = 17) as compared to normal values. In addition, high levels of hybrid IGF-I/insulin receptors (IR/IGF-I-Rs) were present in both thyroid cancer specimens and cell lines. IR/IGF-I-R hybrids were the most represented type of receptor in 14/17 specimens and exceeded the IGF-I-R content in all cases. Hybrid content correlated with the IR and IGF-I-R content, suggesting that in thyroid tissue hybrid formation occurs by random assembly of IR and IGF-I-R half receptors. Hybrid receptor autophosphorylation was stimulated by IGF-I with high affinity. In cells with a high IR/IGF-I-Rs content, blocking antibodies specific to these receptors substantially inhibited IGF-I induced cell growth. These data indicate that the IGF-I system is overactivated in thyroid cancer and that IR/IGF-I-R hybrid receptors play an important role in IGF-I mitogenic signaling in these tumors.

Endoscopic palliation of esophageal and cardial cancer: neodymium-yttrium aluminum garnet laser therapy.

The aim of this study was to evaluate the impact of laser palliation on symptoms such as dysphagia and bleeding in patients with esophageal and cardial carcinomas. From November 1992 to October 1997, 174 patients with unresectable esophageal and cardial carcinomas were treated with neodymium-yttrium aluminum garnet laser therapy. The indications for palliative treatment were advanced tumor in 96 patients and high surgical risk in 78. The tumor involved the esophagus and cardia in 107 and 67 patients respectively. The mean length of the tumors was 6 cm. Two laser sessions (range 1-4) were necessary for recanalization. During the follow-up, the average interval between the laser sessions was 2 months. Overall, no early and late complications or hospital mortality occurred. The quality of palliation was excellent or good in 82%, of the patients. The mean survival time was 6 months, and mortality was not related to the procedure. Endoscopic laser therapy in patients with vegetant or hemorrhagic carcinomas may represent the best therapy, with acceptable morbidity and mortality rates and satisfactory functional results.

Weight, height and arm circumference of children under 5 in the district of Mbarara, south-west Uganda.

This paper describes the growth of weight, height and arm circumference (MUAC) in children aged under 5 years and living in the south-west area of Uganda. The survey was carried out in 1988 and was based on a random sample of 31 villages of the Mbarara district. A total of 4320 children were measured by a team of 20 trained assessors. From these children a reference group was made up of the 3654 known to be still alive after 1 year. Growth charts were drawn by smoothing the non-parametric percentiles of the distribution of height, weight and MUAC for age and of weight for height. The anthropometric characteristics of children living in south-west Uganda differ considerably from those of children on which the FELS/NCHS/WHO references are based. Between 1 and 5 years of age, the median difference between Mbarara and American children increases from 1.5 to 3 kg for weight, from 4 to 7 cm for height, and from 1.5 to 2.5 cm for MUAC. These results imply that the use of the international reference may lead to low specificity and predictive values in screening malnourished children living in an underdeveloped country such as Uganda. The charts here proposed may apply to populations with a lifestyle similar to that of inhabitants of south-west Uganda, both from a nutritional and socioeconomic viewpoint.

Determinants of nutritional status in south-west Uganda.

In a cross-sectional survey carried out of 4320 children 0-59 months old in South-west Uganda various socio-economic and environmental factors were related to poor nutritional status. Diarrhoea was strongly associated with all the anthropometric parameters examined, suggesting a bidirectional influence of diarrhoea on malnutrition and of malnutrition on diarrhoea. The other most important variables independently associated with one or more anthropometric parameters were: distance from a health unit, living in a household not able to hire labour, and whose members worked on other people's land, religion, parental education, crowding conditions, sanitation, acreage, ownership of cow, father's occupation, birth order, ethnicity, and prolonged breastfeeding. This data indicates that a range of specific interventions are likely to be necessary for the improvement of nutrition in this community.