Transient fluid flow improves photoimmunoconjugate delivery and photoimmunotherapy efficacy.

Circulating drugs in the peritoneal cavity is an effective strategy for advanced ovarian cancer treatment. Photoimmunotherapy, an emerging modality with potential for the treatment of ovarian cancer, involves near-infrared light activation of antibody-photosensitizer conjugates (photoimmunoconjugates) to generate cytotoxic reactive oxygen species. Here, a microfluidic cell culture model is used to study how fluid flow-induced shear stress affects photoimmunoconjugate delivery to ovarian cancer cells. Photoimmunoconjugates are composed of the antibody, cetuximab, conjugated to the photosensitizer, and benzoporphyrin derivative. Longitudinal tracking of photoimmunoconjugate treatment under flow conditions reveals enhancements in subcellular photosensitizer accumulation. Compared to static conditions, fluid flow-induced shear stress at 0.5 and 1 dyn/cm2 doubled the cellular delivery of photoimmunoconjugates. Fluid flow-mediated treatment with three different photosensitizer formulations (benzoporphyrin derivative, photoimmunoconjugates, and photoimmunoconjugate-coated liposomes) led to enhanced phototoxicity compared to static conditions. This study confirms the fundamental role of fluid flow-induced shear stress in the anti-cancer effects of photoimmunotherapy.

Conjugated linoleic acid decreases prostaglandin synthesis in bovine luteal cells in vitro.

Feeding conjugated linoleic acids (CLA) improves reproductive performance in dairy cows; however, the molecular mechanisms by which CLA improves reproduction are not understood. The effect of the CLA isomers, trans-10, cis-12 CLA and cis-9, trans-11 CLA on synthesis of progesterone, PGE(2) , and PGF(2α) , in bovine luteal cells was determined in this study. Luteal cells from three cows were cultured in medium containing 0 or 0.1 µM of trans-10, cis-12 CLA and cis-9, trans-11 CLA in varying ratios in the presence and absence of 1 µM of forskolin. Prostaglandin and progesterone concentrations were not altered by CLA isomer and ratio. Luteal cells cultured in the presence of CLA had lower PGF(2α) concentrations (62.6 ± 13.4 pg/ml vs. 55.7 ± 12.2 pg/ml; P = 0.005) and, in the absence of forskolin, lower PGE(2) concentrations (65.3 ± 15.1 pg/ml vs. 32.4 ± 14.1 pg/ml; P = 0.002) in culture media, while progesterone concentrations were not altered (P = 0.63). Relative steady-state mRNA amounts of COX-2 (1.7-fold decrease; P = 0.002), PGE synthase (1.5-fold decrease; P = 0.03) and 3ß-hydroxysteroid dehydrogenase (1.6-fold decrease; P = 0.0003) were lower in CLA-treated cultures, but CLA did not significantly alter mRNA amounts of PGE(2) 9-keto-reductase, StAR, and cytochrome P450 side chain cleavage enzyme. In conclusion, a potential mechanism exists by which trans-10, cis-12 CLA and cis-9, trans-11 CLA may improve reproductive performance in dairy cows, by suppressing PGF(2α) synthesis in luteal cells via attenuation of COX-2 gene expression.

Postcode lotteries in public health--the NHS Health Checks Programme in North West London.

BACKGROUND: Postcode lotteries in health refer to differences in health care between different geographic areas. These have been previously associated with clinical services. However there has been little documentation of postcode lotteries relating to preventative health care services. This paper describes a postcode lottery effect in relation to the NHS Health Checks Programme (a national cardiovascular screening programme in England) in eight PCTs in the North West sector of London. METHODS: A descriptive cross-sectional analysis of the Health Checks Programme was carried out in eight PCTs in North West London using a structured data-collecting instrument. RESULTS: The analysis found variation in the implementation of the national Health Checks Programme in terms of: the screening approach taken; the allocated budget (which varied from £69,000 to £1.4 million per 100,000 eligible population); payment rates made to providers of Health Checks; tools used to identify and measure risk of cardiovascular disease and diabetes; monitoring and evaluation; and preventative services available following the health check. CONCLUSIONS: This study identifies a postcode lottery effect related to a national public health programme. Although it is important to allow enough flexibility in the design of the Health Checks Programme so that it fits in with local factors, aspects of the programme may benefit from greater standardisation or stronger national guidance.

Comparison of phenotypic and genotypic antimicrobial profiles in Escherichia coli and Salmonella enterica from the same dairy cattle farms.

Transmission of antimicrobial drug resistance from resistant bacteria to non-resistant strains is an important public health issue. In this study, we have examined the possibility of multiple resistance gene transfer between Escherichia coli and Salmonella in the natural setting. Bacteria isolated from calves concurrently shedding E. coli and Salmonella showed similar antimicrobial drug resistance patterns as measured by a broth dilution method. However, microarray analysis of the antibiotic resistance at the gene level revealed several differences in resistance gene profile. Resistance profiles of E. coli isolated from different farms were closer than the profile of E. coli and Salmonella isolated from the same farm. This shows that the chance of multiple resistance gene transfers between these species is unlikely.

An outbreak of multidrug-resistant Salmonella enterica serotype Oranienburg in Michigan dairy calves.

The objectives of this study were to report an outbreak of highly drug-resistant Salmonella enterica serotype Oranienburg in dairy calves, and conduct an epidemiological investigation of Oranienburg identified on a dairy herd during a study to determine whether discontinuing feeding medicated milk replacer to preweaned dairy calves resulted in increased antimicrobial susceptibility in enteric bacteria. Calf fecal samples and swabs of calf and maternity pens were collected monthly over 18 months. Samples were streaked onto XLT-4 agar and characteristic colonies were subjected to biochemical tests to confirm Salmonella. Strain relatedness was examined by Xbal and BlnI pulsed-field gel electrophoresis analysis on 62 randomly selected isolates. Antimicrobial susceptibility testing, using automated microbroth dilution, was conducted using a panel containing tetracycline, amikacin, amoxicillin-clavulanic acid, ampicillin, ceftiofur, ceftriaxone, cephalothin, chloramphenicol, ciprofloxacin, cefoxitin, gentamicin, kanamycin, nalidixic acid, streptomycin, sulfamethoxazole, and trimethoprim-sulfamethoxazole. A total of 190 Salmonella spp. were isolated from 604 calf and 36 pen samples, of which 86% were Oranienburg and 97% were resistant to at least 9 agents. Environmental isolates had lower levels of resistance than fecal isolates. Pulsed-field gel electrophoresis analysis identified three strains: the most common strain was consistently present before the outbreak and at its peak. One strain was exclusively an environmental isolate, with little antimicrobial resistance. Multiresistant isolates with resistance to ciprofloxacin appeared early in the outbreak, and were replaced by multiresistant isolates with resistance to cephalothin. The differences in strains and resistance patterns suggest that the strains of Oranienburg found in fecal isolates may have different origins from environmental isolates.

Imaging in clinical trials: a patient-led questionnaire study to assess impact of imaging regimes on patient participation.

BACKGROUND: Cancer trials often incorporate intensive imaging with Magnetic Resonance Imaging (MRI) and Positron Emission Tomography with Computerised Tomography (PET/CT), which can be physically and mentally exhausting for patients. This questionnaire study aimed to determine the aspects of imaging that affect a patient's decision to participate in clinical trials in order to inform the design of future trials that utilise imaging. This should achieve greater patient compliance and improve the patient experience. METHOD: A detailed questionnaire assessing patient expectation and acceptability of imaging within clinical trials was developed in collaboration with two patient representatives. The questionnaire addressed the influence of scan type, length, frequency, scheduling, invasiveness and staff support on acceptability of imaging. It was applied to three patient groups. Group 1 consisted of patients newly recruited to studies with imaging, Group 2 consisted of previous participants in studies with imaging and Group 3 consisted of patients having imaging for clinical care. RESULTS: One hundred ninety six patients completed the questionnaires (Group 1:47; Group 2: 50 and Group 3: 99). The use of ionising radiation and number of scans required were identified as negative influences on decision to participate by 25% of Group 3 but only by 6% of Groups 1 and 2. Scan duration >30mins was perceived as a negative factor for decision to participate by all Groups (12-22%). Good communication provided by researchers in terms of discussing the study before and after reading study materials was a key factor in influencing decision to participate (> 50% in Groups 1 and 2 and > 20% in Group 3). CONCLUSION: Factors relating to imaging procedures within clinical trials that affect participation have been identified with communication around study materials as the key determinant. These data will be used to influence the development of future research protocols. Modification of imaging requirements within clinical trials will improve patient tolerance and acceptability and is likely to raise recruitment.

Radiation exposure awareness from patients undergoing nuclear medicine diagnostic 99mTc-MDP bone scans and 2-deoxy-2-(18F) fluoro-D-glucose PET/computed tomography scans.

INTRODUCTION: Medical imaging is on average the largest source of artificial radiation exposure worldwide. This study seeks to understand patient's awareness of radiation exposure derived from nuclear medicine diagnostic scans and assess if current information provided by leaflets is adequate. METHODS: Single-centre cross-sectional questionnaire study applied to bone scan and FDG PET/computed tomography patients, at a nuclear medicine and PET/computed tomography department over a 15-week period in 2018. Questionnaires on dose comparators were designed in collaboration with patients, public, and experts in radiation exposure. Qualitative data were analysed using thematic analysis and quantitative data using SPSS (V. 24). RESULTS: A total of 102 questionnaires were completed (bone scan = 50; FDG PET/computed tomography = 52). Across both groups, 33/102 (32.4%) patients reported having a reasonable understanding of nuclear medicine and 21/102 (20.6%) reported a reasonable knowledge of ionising radiations. When asked to compare the exposure dose of respective scans with common comparators 8/50 (16%) of bone scan patients and 11/52 (21.2%) FDG PET/computed tomography answered correctly. On leaflet information, 15/85 (17.6%) patients reported the leaflets do not provide enough information on radiation exposure and of these 10/15 (66.7%) commented the leaflets should incorporate more information on radiation exposure dose. CONCLUSION: More observational and qualitative studies in collaboration with patients are warranted to evaluate patients' understanding and preferences in communication of radiation exposure from nuclear medicine imaging. This will ensure communication tools and guidelines developed to comply with ionising radiation (medical exposure) regulation 2017 are according to patients needs and preferences.

Changes in multidrug resistance of enteric bacteria following an intervention to reduce antimicrobial resistance in dairy calves.

An intervention study was conducted to determine whether discontinuing the feeding of milk replacer medicated with oxytetracycline and neomycin to preweaned calves reduced antimicrobial resistance in Salmonella, Campylobacter, and Escherichia coli bacteria. Results demonstrated that the intervention did reduce multidrug resistance in these bacteria but that other factors also influenced multidrug resistance.

Changes in tetracycline susceptibility of enteric bacteria following switching to nonmedicated milk replacer for dairy calves.

A randomized intervention study was conducted to determine if discontinuing use of calf milk replacer medicated with oxytetracycline results in increased tetracycline susceptibility in Salmonella and Campylobacter spp. and Escherichia coli in dairy calves over a 12-month period. Dairy herds with enteric bacteria with known low tetracycline susceptibility were enrolled for the study. Fecal samples from preweaned calves and environmental samples were collected from eight dairy herds in Michigan and New York State. Samples were collected monthly for 3 months prior to and 12 months after four of the eight herds discontinued medicated milk replacer feeding. Salmonella and Campylobacter spp. and E. coli were isolated, and antimicrobial susceptibility testing was conducted using automated broth microdilution. A total of 804 intervention and 1,026 control calf fecal samples and 122 intervention and 136 control environmental samples were collected for testing. No differences in owner-reported morbidity and mortality between treatment groups were seen. The intervention was significantly associated with increasing tetracycline susceptibility in E. coli and Salmonella. Tetracycline susceptibility increased in intervention herds for the first 3 months after switching to nonmedicated milk replacer but declined in subsequent months. Discontinuing the practice of feeding medicated milk replacers to calves increased tetracycline susceptibility in E. coli and Salmonella on dairy farms, without increasing cattle disease, but declines in effectiveness after 3 months suggest that other factors contribute to decreasing susceptibility on the farm.

Collaborating With the Fortress Around Early Childhood Trauma: A Depth Psychotherapy Process.

PURPOSE: A depth psychotherapy process is a deepening of experience facilitating access into a fortress of body and mind defenses that aims to protect although may imprison the adult survivor of early childhood trauma. CONCLUSIONS: When psychotherapy moves beyond managing manifest symptoms and behavior, individuals have an opportunity to connect with their authentic self and experience wholeness in their personality and relationships. PRACTICE IMPLICATIONS: A theoretical and practical approach including the therapeutic frame, therapeutic alliance, and body psychotherapy attempts to collaborate with a fortress to encourage its cooperation in the release of its captive.

Medicare covers the majority of FDA-approved devices and Part B drugs, but restrictions and discrepancies remain.

The Food and Drug Administration (FDA) and Medicare use different standards to determine, first, whether a new drug or medical device can be marketed to the public and, second, if the federal health insurance program will pay for use of the drug or device. This discrepancy creates hurdles and uncertainty for drug and device manufacturers. We analyzed discrepancies between FDA approval and Medicare national coverage determinations for sixty-nine devices and Part B drugs approved during 1999-2011. We found that Medicare covered FDA-approved drugs or devices 80 percent of the time. However, Medicare often added conditions beyond FDA approval, particularly for devices and most often restricting coverage to patients with the most severe disease. In some instances, Medicare was less restrictive than the FDA. Our findings highlight the importance for drug and device makers of anticipating Medicare's needs when conducting clinical studies to support their products. Our findings also provide important insights for the FDA's and Medicare's pilot parallel review program.

Prevalence and antimicrobial resistance of Enterococcus spp and Staphylococcus spp isolated from surfaces in a veterinary teaching hospital.

OBJECTIVE: To determine the prevalence and antimicrobial resistance of enterococci and staphylococci collected from environmental surfaces at a veterinary teaching hospital (VTH). DESIGN: Longitudinal study. SAMPLE: Samples collected from surfaces in 5 areas (emergency and critical care, soft tissue and internal medicine, and orthopedic wards; surgery preparation and recovery rooms; and surgery office and operating rooms) of a VTH. PROCEDURES: Selected surfaces were swabbed every 3 months during the 3-year study period (2007 to 2009). Isolates of enterococci and staphylococci were identified via biochemical tests, and antimicrobial susceptibility was evaluated with a microbroth dilution technique. A subset of isolates was analyzed to assess clonality by use of pulsed-field gel electrophoresis. RESULTS: 430 samples were collected, and isolates of enterococci (n = 75) and staphylococci (110) were identified. Surfaces significantly associated with isolation of Enterococcus spp and Staphylococcus spp included cages and a weight scale. Fourteen Enterococcus spp isolates and 17 Staphylococcus spp isolates were resistant to ≥ 5 antimicrobials. Samples collected from the scale throughout the study suggested an overall increase in antimicrobial resistance of Enterococcus faecium over time. Clonality was detected for E faecium isolates collected from 2 different surfaces on the same day. CONCLUSIONS AND CLINICAL RELEVANCE: Although not surprising, the apparent increase in antimicrobial resistance of E faecium was of concern because of the organism's ability to transmit antimicrobial resistance genes to other pathogens. Results reported here may aid in identification of critical control points to help prevent the spread of pathogens in VTHs.

Subclinical thyroid disease.

Subclinical thyroid disease, a term applied to patients with no or minimal thyroid-related symptoms with abnormal laboratory values, is diagnosed more frequently with the use of thyroid-stimulating hormone (TSH) screening and newer high-sensitivity assays. These are laboratory diagnoses, with subclinical hypothyroidism defined as an elevated TSH with a normal free thyroxine and triiodothyronine concentration, and subclinical hyperthyroidism as a subnormal TSH with normal free thyroxine and triiodothyronine levels. Although studies defining which patients require treatment are few, decisions should be individualized based upon laboratory values and symptoms. This article reviews the etiologies, diagnoses, treatments and indications, and monitoring of patients with subclinical thyroid disease.