Faculty Bibliography

BACKGROUND:Hyperthermia (heating to 43 °C) activates the innate immune system and improves bladder cancer chemosensitivity. OBJECTIVE:To evaluate the tissue penetration and safety of convective hyperthermia combined with intravesical mitomycin C (MMC) pharmacokinetics in live porcine bladder models using the Combat bladder recirculation system (BRS). METHODS:Forty 60 kg-female swine were anesthetized and catheterized with a 3-way, 16 F catheter. The Combat device was used to heat the bladders to a target temperature of 43 °C with recirculating intravesical MMC at doses of 40, 80, and 120 mg. Dwell-heat time varied from 30-180 min. Rapid necropsy with immediate flash freezing of tissues, blood and urine occurred. MMC concentrations were measured by liquid chromatography tandem-mass spectrometry. RESULTS:The Combat BRS system was able to achieve target range temperature (42-44 °C) in 12 mins, and this temperature was maintained as long as the device was running. Two factors increased tissue penetration of MMC in the bladder: drug concentration, and the presence of heat. In the hyperthermia arm, MMC penetration saturated at 80 mg, suggesting that with heating, drug absorption may saturate and not require higher doses to achieve the maximal biological effect. Convective hyperthermia did not increase the MMC concentration in the liver, heart, kidney, spleen, lung, and lymph node tissue even at the 120 mg dose. CONCLUSIONS:Convective bladder hyperthermia using the Combat BRS device is safe and the temperature can be maintained at 43 °C. Hyperthermia therapy may increase MMC penetration into the bladder wall but does not result in an increase of MMC levels in other organs.

BACKGROUND:Hypertension is the leading risk factor for mortality worldwide and is more common in sub-Saharan Africa than any other region. Work to date confirms that a lack of human and material resources for healthcare access contributes to this gap. The ways in which patients' knowledge and attitudes toward hypertension determine their engagement with and adherence to available care, however, remains unclear. METHODS:We conducted an exploratory, qualitative descriptive study to assess awareness, knowledge, and attitudes towards hypertension and its management at a large private hospital in Kampala. We interviewed 64 participants (29 with hypertension and 34 without, 1 excluded) in English. General thematic analysis using the Integrated Conceptual Health Literacy Model was used to iteratively generate themes and categories. RESULTS:We identified three main themes: Timing of Hypertension Diagnosis, Aiming for Health Literacy, and the Influence of Knowledge on Behavior. Most participants with hypertension learned of their condition incidentally, speaking to the lack of awareness of hypertension as an asymptomatic condition. Drove nearly all participants to desire more information. However, many struggled to translate knowledge into self-management behaviors due to incomplete information and conflicting desires of participants regarding lifestyle and treatment. CONCLUSIONS:Internal patient factors had a substantial impact on adherence, calling attention to the need for educational interventions. Systemic barriers such as cost still existed even for those with insurance and need to be recognized by treating providers.

Klebsiella pneumoniae is a human gut communal organism and notorious opportunistic pathogen. The relative high burden of asymptomatic colonization by K. pneumoniae is often compounded by multidrug resistance-a potential problem for individuals with significant comorbidities or other risk factors for infection. A carbapenem-resistant K. pneumoniae strain classified as multilocus sequence type 258 (ST258) is widespread in the United States and is usually multidrug resistant. Thus, treatment of ST258 infections is often difficult. Inasmuch as new preventive and/or therapeutic measures are needed for treatment of such infections, we developed an ST258 pneumonia model in cynomolgus macaques and tested the ability of an ST258 capsule polysaccharide type 2 (CPS2) vaccine to moderate disease severity. Compared with sham-vaccinated animals, those vaccinated with ST258 CPS2 had significantly less disease as assessed by radiography 24 h after intrabronchial installation of 10⁸ CFU of ST258. All macaques vaccinated with CPS2 ultimately developed ST258-specific antibodies that significantly enhanced serum bactericidal activity and killing of ST258 by macaque neutrophils ex vivo Consistent with a protective immune response to CPS2, transcripts encoding inflammatory mediators were increased in infected lung tissues obtained from CPS-vaccinated animals compared with control, sham-vaccinated macaques. Taken together, our data provide support for the idea that vaccination with ST258 CPS can be used to prevent or moderate infections caused by ST258. As with studies performed decades earlier, we propose that this prime-boost vaccination approach can be extended to include multiple capsule types.IMPORTANCE Multidrug-resistant bacteria continue to be a major problem worldwide, especially among individuals with significant comorbidities and other risk factors for infection. K. pneumoniae is among the leading causes of health care-associated infections, and the organism is often resistant to multiple classes of antibiotics. A carbapenem-resistant K. pneumoniae strain known as multilocus sequence type 258 (ST258) is the predominant carbapenem-resistant Enterobacteriaceae in the health care setting in the United States. Infections caused by ST258 are often difficult to treat and new prophylactic measures and therapeutic approaches are needed. To that end, we developed a lower respiratory tract infection model in cynomolgus macaques in which to test the ability of ST258 CPS to protect against severe ST258 infection.

Objective: In occupational hearing conservation programmes, age adjustments may be used to subtract expected age effects. Adjustments used in the U.S. came from a small dataset and overlooked important demographic factors, ages, and stimulus frequencies. The present study derived a set of population-based age adjustment tables and validated them using a database of exposed workers.Design: Cross-sectional population-based study and retrospective longitudinal cohort study for validation.Study sample: Data from the U.S. National Health and Nutrition Examination Survey (unweighted n = 9937) were used to produce these tables. Male firefighters and emergency medical service workers (76,195 audiograms) were used for validation.Results: Cross-sectional trends implied less change with age than assumed in current U.S. regulations. Different trends were observed among people identifying with non-Hispanic Black race/ethnicity. Four age adjustment tables (age range: 18-85) were developed (women or men; non-Hispanic Black or other race/ethnicity). Validation outcomes showed that the population-based tables matched median longitudinal changes in hearing sensitivity well.Conclusions: These population-based tables provide a suitable replacement for those implemented in current U.S. regulations. These tables address a broader range of worker ages, account for differences in hearing sensitivity across race/ethnicity categories, and have been validated for men using longitudinal data.

CONTEXT/BACKGROUND:Persons with HIV are at increased risk for adipose dysfunction, which could mediate metabolic complications such as cardiovascular disease, fatty liver disease, and diabetes. We have previously reported reduced browning and beiging capacity of the subcutaneous adipose depot in HIV. OBJECTIVE:We sought to evaluate how HIV-related parameters are related to the expression of brown and beige fat genes in the abdominal subcutaneous adipose tissue. DESIGN/METHODS:Eighteen persons with HIV underwent punch biopsy of abdominal subcutaneous fat to determine mRNA expression of adipose-related genes using quantitative reverse transcriptase-polymerase chain reaction. RESULTS:Duration of antiretroviral therapy use, particularly related to protease inhibitor use, was significantly related to reduced expression of multiple brown and beige fat genes (including UCP1, PGC1α, PRDM16 and others, all P ≤ 0.04) in the abdominal subcutaneous fat. In addition, duration of HIV and CD4 T-cell count were significantly correlated with reduced expression of multiple brown and beige fat genes in the abdominal subcutaneous fat (PGC1α, P2XR5, TMEM26, CD137, all P ≤ 0.05 for duration of HIV; and PGC1α, ZIC1, PRDM16, PAT2, P2RX5, TMEM26, CD137, all P ≤ 0.04). In contrast, HIV viral load did not correlate with any brown or beige fat genes. CONCLUSIONS:Key HIV-related parameters reflective of nonacute infection (increased duration of HIV and duration of antiretroviral therapy use) or relatively reduced immunologic function (lower CD4 count) were linked to reduced expression of brown and beige fat gene in the abdominal subcutaneous adipose depot. CLINICAL TRIAL REGISTRATION/BACKGROUND:NCT01098045.