Effect of dosing and dosing frequency on the efficacy of ceftizoxime and the emergence of ceftizoxime resistance during the early development of murine abscesses caused by Bacteroides fragilis and Enterobacter cloacae mixed infection

The efficacy of beta-lactams is thought to be dependent on the time that the unbound concentrations exceed the MIC (fT>MIC). However, the pharmacokinetic/pharmacodynamic index (PDI) that correlates best to the selection of resistance is not yet clear. The selection of ceftizoxime (CZX)-resistant Enterobacter cloacae mutant strains during the development of murine mixed-infection abscesses was studied to determine the PDI that is important for the emergence of resistance and the PDI value needed for the prevention of resistance. Studies were carried out 24 h after inoculation with Bacteroides fragilis ATCC 23745 and E. cloacae 22491. Six to 1,536 mg of CZX/kg of body weight/day given every 2 h (q2h), q4h, q6h, or q8h was started 30 min before inoculation and continued for 24 h. Resistant mutants were isolated to determine mutant frequencies (MF). The fT>MIC varied from 9 to 98% for E. cloacae, the peak concentration (unbound fraction) was 0.6 to 578 mg/liter, and the area under the concentration-time curve (unbound fraction) (fAUC) was 1.9 to 553 mg.h/liter. The fAUC-to-MIC ratio best explained the in vivo efficacy. CZX-resistant B. fragilis and E. cloacae mutants were isolated from untreated controls at an MF of 10(-5) to 10(-7). The MF of resistant B. fragilis did not increase during therapy. The selection of resistant E. cloacae strains at an MF of 10(-1) to 10(-2) was related to the fT>MIC and the ratio of fAUC to MIC following an inverse U shape. However, the ratio of fAUC to MIC was the stronger driver of resistance. The highest MFs were 0.7 to 0.9 at an fAUC-to-MIC ratio of approximately 250. We conclude that the ratio of fAUC to MIC is the PDI that correlated best to the in vivo efficacy of CZX and probably also to the emergence of resistant E. cloacae mutants. An fAUC-to-MIC ratio of 1,000 was needed to prevent the emergence of this resistance.     

Certification of creatinine in a human serum reference material by GC-MS and LC-MS

BACKGROUND: To meet recommendations given by the Laboratory Working Group of the National Kidney Disease Education Program for improving serum creatinine measurements, NIST developed standard reference material (SRM) 967 Creatinine in Frozen Human Serum. SRM 967 is intended for use by laboratories and in vitro diagnostic equipment manufacturers for the calibration and evaluation of routine clinical methods. METHODS: The SRM was produced from 2 serum pools with different creatinine concentrations. The concentrations were certified using a higher-order isotope-dilution GC-MS method and an isotope-dilution LC-MS method. The LC-MS method is a potential higher-order reference measurement procedure. RESULTS: The GC-MS mean (CV) concentrations were 67.0 (0.9%) mumol/L for serum pool 1 and 346.1 (0.45%) mumol/L for serum pool 2. The LC-MS results were 66.1 (0.2%) mumol/L and 346.3 (0.2%) mumol/L, respectively. For serum pool 1, there was a 1.4% difference between the mean GC-MS and LC-MS measurements, and a 0.10% difference for serum pool 2. The results from the 2 methods were combined to give the certified concentrations and expanded uncertainties. CONCLUSIONS: The certified concentration (expanded uncertainty) of SRM 967 was 66.5 (1.8) mumol/L for serum pool 1 (a value close to the diagnostically important concentration of 88.4 mumol/L) and 346.2 (7.4) mumol/L for serum pool 2 (a concentration corresponding to that expected in a patient with chronic kidney disease).     

COVID‐19 in solid organ transplant recipients: Initial report from the US epicenter

Solid organ transplant recipients may be at a high risk for SARS‐CoV‐2 infection and poor associated outcomes. We herein report our initial experience with solid organ transplant recipients with SARS‐CoV‐2 infection at two centers during the first 3 weeks of the outbreak in New York City. Baseline characteristics, clinical presentation, antiviral and immunosuppressive management were compared between patients with mild/moderate and severe disease (defined as ICU admission, intubation or death). Ninety patients were analyzed with a median age of 57 years. Forty‐six were kidney recipients, 17 lung, 13 liver, 9 heart, and 5 dual‐organ transplants. The most common presenting symptoms were fever (70%), cough (59%), and dyspnea (43%). Twenty‐two (24%) had mild, 41 (46%) moderate, and 27 (30%) severe disease. Among the 68 hospitalized patients, 12% required non‐rebreather and 35% required intubation. 91% received hydroxychloroquine, 66% azithromycin, 3% remdesivir, 21% tocilizumab, and 24% bolus steroids. Sixteen patients died (18% overall, 24% of hospitalized, 52% of ICU) and 37 (54%) were discharged. In this initial cohort, transplant recipients with COVID‐19 appear to have more severe outcomes, although testing limitations likely led to undercounting of mild/asymptomatic cases. As this outbreak unfolds, COVID‐19 has the potential to severely impact solid organ transplant recipients.     

Tumor-Targeted Responsive Nanoparticle-Based Systems for Magnetic Resonance Imaging and Therapy

Purpose

Design and synthesis of a tumor responsive nanoparticle-based system for imaging and treatment of various cancers.

Methods

Manganese oxide nanoparticles (Mn₃O₄ NPs) were synthesized and modified with LHRH targeting peptide or anti-melanoma antibodies (cancer targeting moieties) and a MMP2 cleavable peptide (a possible chemotactic factor). Nanostructured lipid carriers (NLCs) were used to entrap the BRAF inhibitor, vemurafenib, and enhance cytotoxicity of the drug. Size distribution, stability, drug entrapment, cytotoxicity and genotoxicity of synthesized nanoparticles were studied in vitro. Enhancement of MRI signal by nanoparticles and their body distribution were examined in vivo on mouse models of melanoma, ovarian and lung cancers.

Results

Uniform, stable cancer-targeted nanoparticles (PEGylated water-soluble Mn₃O₄ NPs and NLCs) were synthesized. No signs of cyto-,genotoxicity and DNA damage were detected for nanoparticles that do not contain an anticancer drug. Entrapment of vemurafenib into nanoparticles significantly enhanced drug toxicity in cancer cells with targeted V600E mutation. The developed nanoparticles containing LHRH and MMP2 peptides showed preferential accumulation in primary and metastatic tumors increasing the MRI signal in mice with melanoma, lung and ovarian cancers.

Conclusions

The proposed nanoparticle-based systems provide the foundation for building an integrated MRI diagnostic and therapeutic approach for various types of cancer.     

Stigmatization Behavior of Pre-Registration Nurses: Do the Self-Determined Psychological Needs Influence This?

Background/problem: Stigma and stigmatization are important concepts in the area of mental health and illness. Nursing and nurse education are continuously examining ways to understand and address the stigma toward people with a lived experience of mental illness. While the negative influence of stigma is understood, the variables that influence these behaviors are emerging. An area may provide insight into aspects that influence stigmatization of pre-registration nurses is motivation. Previous research has illustrated that individual motivation can significantly predict and influence work-related behaviors and actions across a range of work settings. Therefore, the purpose of this study was to examine the predictive influence that the motivational needs, as espoused by Self-Determination Theory, play in the stigmatization of pre-registration nurse toward people with a lived experience of mental illness. Approach: A total of 168 pre-registration nurses completed two surveys that measured support for their psychological needs and their stigmatization of people with a lived experience of mental illness. Outcomes/conclusions: Using a regression analysis, some psychological needs significantly influenced the stigmatization of pre-registration nurses. Results illustrate the potential importance of psychological needs in the training of the future nursing workforce.     

AIDS-Related Knowledge and High-Risk Behaviors of Pregnant,Substance-Dependent Women

The authors investigated AIDS-related knowledge, high-risk behaviors, and relationships between AIDS-related knowledge, high-risk behaviors, and sociodemographic characteristics of 41 pregnant women entering treatment who were dependent on cocaine or opiates. At entry, patients completed self-report questionnaires on AIDS-related knowledge and sexual and drug use practices. There was a high rate of understanding of risk associated with drug use and perinatal transmission of HIV. Knowledge of high-risk sexual behavior varied, and knowledge of the medical consequences of HIV was modest. Engagement in several high-risk behaviors was identified: lack of condom use, intravenous drug use, sharing of needles, sex with an injecting drug user, and exchanging sex for money or drugs. AIDS-related knowledge and engagement in high-risk behaviors were not significantly correlated. Authors discussed implications of these findings for developing effective HIV prevention strategies in this population. (American Journal on Addictions 1996; 5:292–300)     

Economic evaluation of fluoride varnish application of daily supervision versus daily supervision and additional six-monthly intervals in Scotland (Protecting Teeth @ 3): a randomised controlled trial

BackgroundEconomic evaluations of public health interventions aid decision makers in efficient resource allocation. Our aim was to do an economic evaluation of a subintake of the Protecting Teeth @ 3 Study ([email protected]), a Scottish, 2 year, parallel group, randomised controlled trial, which explored the additional preventive value of fluoride varnish application at six-monthly intervals in nursery settings over and above daily supervised toothbrushing in nursery settings (treatment as usual).MethodsFrom Nov 21, 2012 to Aug 31, 2017, eligible children were randomly assigned to receive either fluoride varnish plus treatment as usual (fluoride varnish group) or treatment as usual in a 1:1 ratio. The economic evaluation was a within-trial, cost-utility analysis comparing the fluoride varnish group with the treatment as usual group. Cost-utility analysis was done from a National Health Service perspective. Within-trial costs included intervention and health-care resource use costs. Health outcomes were expressed in quality-adjusted life-years (QALYs) accrued over the 2 year period. The Child Health Utility 9 Dimensions questionnaire was used to obtain utility scores. Staff travel and labour costs were collected using a staff costs form. Information on other costs was requested from the trial coordinators. National reference costs were used, a discount rate of 1·5% for public health investments was adopted, multiple imputation methods for missing data were employed, sensitivity analyses done, and incremental cost-effectiveness ratios calculated. Ethical approval was from the West of Scotland Research Ethics Service. This trial is registered with EudraCT, 2012-002287-26.FindingsThe data for 534 participants from the 2014–15 intake were used in the analyses. Of these, 265 were assigned to fluoride varnish and assigned to 269 treatment as usual. The mean difference in costs between the fluoride varnish and treatment as usual group was GBP£36·64 (95% CI –48·51 to 111·47; p=0·64). The mean difference in QALYs was –0·0044 (95% CI –0·0168 to 0·0065; p=0·64). The fluoride varnish intervention had higher costs and resulted in less QALYs than that of the treatment as usual. The probability that the fluoride varnish intervention was cost-effective at the £30 000 threshold was 18·5%.InterpretationOur results indicate that there was no substantial difference in costs and QALYs between the two groups. Applying fluoride varnish in nursery settings in addition to daily supervised nursery toothbrushing seems not to be good value for money. We recommended that the funds could be used better on other more cost-effective oral health interventions.Funding[email protected] was funded by the Scottish Government.     

Bedbug Complaints among Public Housing Residents—New York City, 2010–2011

Few studies have evaluated population-level risk factors for having a bedbug infestation. We describe characteristics associated with bedbug complaints among New York City Housing Authority (NYCHA) residents. Unique households receiving bedbug extermination services in response to a complaint during January 1, 2010 to December 31, 2011 were identified from NYCHA’s central facilities work order database. We examined associations between household characteristics and having a bedbug complaint using a generalized estimating equation Poisson regression model, accounting for clustering by housing development. Of the 176,327 NYCHA households, 11,660 (6.6 %) registered a bedbug complaint during 2010–2011. Bedbug complaints were independently associated with households having five or more children versus no children (prevalence ratio [PR] = 2.0), five or more adults versus one adult (PR = 1.6), a head of household (HOH) with impaired mobility (PR = 1.3), a household member receiving public assistance (PR = 1.2), a household income below poverty level (PR = 1.1), and a female HOH (PR = 1.1). Infestations were less likely to be reported by households with employed members (PR = 0.9), and an HOH aged 30–44 years (PR = 0.9) or 45–61 years (PR = 0.9), compared with an HOH aged 18–29 years. These results indicate that bedbug control efforts in public housing should be targeted toward households with low income and high occupancy.     

Breast Cancer Diagnosis from Screening in Trinidad and Tobago: Opportunities for Cancer Prevention

Trinidad and Tobago (TT) experiences the highest breast cancer mortality in the Caribbean; the distribution of traditional breast cancer risk factors in this population has not been analyzed. Data on women who underwent breast cancer screening at the TT Cancer Society between January 2009–December 2011(N = 2,689) were retrospectively collected. The screening detected 131 incident breast cancers; variables significantly associated with breast cancer diagnosis were, a positive family history of breast cancer (adjusted odds ratio [OR_adj]: 1.55; 95 % CI 1.00–2.41), presence of symptoms (OR_adj: 1.91; 95 % CI 1.25–2.92), and previous breast surgery (OR_adj: 1.67; 95 % CI 0.97–2.88). Breast cancer was significantly associated with increased breast density. Among healthy women, breast density was positively associated with nulliparity (OR_adj: 1.46, 1.37, 2.52 respectively for density level 2, 3 and 4 vs. 1) and previous breast surgeries (OR_adj: 2.27, 3.09 and 4.13 respectively for density level 2, 3 and 4 vs. 1). This analysis confirms that breast density is an important predictor of newly diagnosed breast cancer in this Caribbean population. Screening is still a diagnostic tool rather than a preventive measure in TT.