Biomarkers associated with checkpoint inhibitors.

Checkpoint inhibitors (CPI), namely anti-CTLA4 and anti-PD1/PD-L1 antibodies, demonstrated efficacy across multiple types of cancer. However, only subgroups of patients respond to these therapies. Additionally, CPI can induce severe immune-related adverse events (irAE). Biomarkers that predict efficacy and toxicity may help define the patients who may benefit the most from these costly and potentially toxic therapies. In this study, we review the main biomarkers that have been associated with the efficacy (pharmacodynamics and clinical benefit) and the toxicity (irAE) of CPIs in patients.

Why is high-tech healthcare at home purchasing underdeveloped and what could be done to improve it?

Executive Letter (95)5 initiated a change of health policy preventing general practitioners (GPs) from prescribing packages of "high-tech healthcare at home" (HTHC). From 1 April 1995, district health authorities were required to establish contracts to purchase such care. Several reasons were behind this policy change including the belief that contracting would improve service quality by encouraging competition between potential suppliers, securing better value for money, and establishing service specifications and monitoring mechanisms. Our survey of 98 health authorities, however, highlighted that contracting for home total parenteral nutrition, intravenous antibiotics for patients with cystic fibrosis, intravenous chemotherapy and continuous ambulatory peritoneal dialysis is largely undeveloped. The majority of districts contracted with historic providers and authorities freely admitted that they did not know whether they were obtaining value for money or a service of adequate quality. Only three districts had developed a strategy for purchasing HTHC as required by the Executive Letter, and only 17 had plans to re-examine their approach. Contracting for HTHC presents practical problems, including the complexity of the process and the significant time demands for efficient and effective contracting. Phase two of this research sought to produce a "guide to good practice" for health authorities wishing to re-examine and improve their purchasing. We conducted case study analyses in districts that had made effective progress and those that had encountered difficulties, drawing upon lessons learned. We reported our findings to the NHS Executive and supplemented this with a "toolbox" that included sample documents covering areas such as tendering, monitoring mechanisms, service specifications and different purchasing approaches.

Rhodococcus equi pulmonary infection in a pancreas-alone transplant recipient: consequence of intense immunosuppression.

We report the case of a pancreas-alone transplant recipient who developed Rhodococcus equi pneumonia after receiving multiple courses of antilymphocyte therapy for the treatment of recurrent acute pancreas allograft rejection. We also review and discuss the diagnosis, clinical course, and treatment of 18 cases of R. equi infection reported in solid organ transplant recipients. The lung is the most common primary site of infection, but R. equi infection is difficult to diagnose because of the pleomorphic, gram-positive, and partially acid-fast nature of the organism. Treatment usually involves a combination of antibiotics including rifampin, macrolides, vancomycin, and ciprofloxacin. The optimal duration of therapy is unknown, but relapse is common if the duration of treatment is less than 14 days. The duration of therapy should be guided by clinical recovery, culture results, and radiographic findings. Monitoring levels of immunosuppressive agents-such as tacrolimus and cyclosporine-is needed in order to avoid clinically significant drug interactions with rifampin or the macrolides when these agents are used in order to treat R. equi infection in the transplant population.

Oxidative interactions of synthetic lung epithelial lining fluid with metal-containing particulate matter.

Epidemiology studies show association of morbidity and mortality with exposure to ambient air particulate matter (PM). Metals present in PM may catalyze oxidation of important lipids and proteins present in the lining of the respiratory tract. The present study investigated the PM-induced oxidation of human bronchoalveolar lavage (BAL) fluid (BALF) and synthetic lung epithelial lining fluid (sELF) through the measurement of oxygen incorporation and antioxidant depletion assays. Residual oil fly ash (ROFA), an emission source PM that contains approximately 10% by weight of soluble transition metals, was added (0-200 microg/ml) to BALF or sELF and exposed to 20% (18)O(2) (24 degrees C, 4 h). Oxygen incorporation was quantified as excess (18)O in the dried samples after incubation. BALF and diluted sELF yielded similar results. Oxygen incorporation was increased by ROFA addition and was enhanced by ascorbic acid (AA) and mixtures of AA and glutathione (GSH). AA depletion, but not depletion of GSH or uric acid, occurred in parallel with oxygen incorporation. AA became inhibitory to oxygen incorporation when it was present in high enough concentrations that it was not depleted by ROFA. Physiological and higher concentrations of catalase, superoxide dismutase, and glutathione peroxidase had no effect on oxygen incorporation. Both protein and lipid were found to be targets for oxygen incorporation; however, lipid appeared to be necessary for protein oxygen incorporation to occur. Based on these findings, we predict that ROFA would initiate significant oxidation of lung lining fluids after in vivo exposure and that AA, GSH, and lipid concentrations of these fluids are important determinants of this oxidation.

Diagnosis and management of respiratory tract infections for the primary care physician.

Respiratory tract infections cause nearly half of deaths owing to infectious disease in the United States. This article has discussed the management of several common respiratory tract infections, with an emphasis on appropriate diagnosis and use of antimicrobial agents. Understanding the cause of various respiratory tract infections enables primary care physicians to avoid unnecessary antibiotic use, decreasing adverse effects owing to medications and preventing the rise in antimicrobial resistance.

Trends in antibiotic prescribing and associated indications in primary care from 1993 to 1997.

BACKGROUND: Recent concerns that evidence on the appropriate use of antibiotics is not having an impact on prescribing trends are based on UK prescribing data relating to 1980-1991. The aim of this paper is to determine trends in antibiotic prescribing from 1993 to 1997 and link antibiotic prescriptions to diagnostic categories. METHODS: A retrospective analysis of antibiotic prescriptions linked to diagnostic codes was carried out using the West Midlands General Practice Research Database. RESULTS: The prescribing rate for antibiotics fell from 963 prescriptions/1,000 patients in 1993 to 807 prescriptions/1,000 patients in 1997 (p < 0.001). The proportion of antibiotic prescribing for respiratory conditions fell from 65 per cent in 1993 to 59 per cent in 1997 (p < 0.001). The main decreases in antibiotic prescribing are accounted for by non-specific lower respiratory tract infections (-22 prescriptions/1,000 patients), non-specific upper respiratory tract infections (-21/1,000 patients) and throat infections (-20/1,000 patients). There was increased prescribing for non-respiratory miscellaneous conditions (+6 prescriptions/1,000 patients). CONCLUSIONS: Overall antibiotic prescribing declined by 16 per cent between 1993 and 1997, primarily for respiratory conditions. These results of the current study are in marked contrast to an earlier review, which found an increase of 46 per cent between 1980 and 1991 in England. The level of antibiotic prescribing for conditions which may not be bacterial in origin is still high and there is scope for further reductions in antibiotic prescribing. This study highlights the need for regular epidemiological data to inform the debate on antibiotic prescribing.

Residual oil fly ash inhalation in guinea pigs: influence of absorbate and glutathione depletion.

Inhaled urban particulate matter (PM) often contains metals that appear to contribute to its toxicity. These particles first make contact with a thin layer of epithelial lining fluid in the respiratory tract. Antioxidants present in this fluid and in cells might be important susceptibility factors in PM toxicity. We investigated the role of ascorbic acid (C) and glutathione (GSH) as determinants of susceptibility to inhaled residual oil fly ash (ROFA) in guinea pigs (male, Hartley). Guinea pigs were divided into four groups, +C+GSH, +C-GSH, -C+GSH, and -C-GSH, and exposed to clean air or ROFA (< 2.5 micron diameter, 19--25 mg/m(3) nose-only for 2.0 h). C and/or GSH were lowered by either feeding C-depleted diet (1 microg C/kg diet, 2 weeks) and/or by ip injection of a mixture of buthionine-S,R-sulfoximine (2.7 mmol/kg body weight) and diethylmaleate (1.2 mmol/kg, 2 h prior). Nasal lavage (NL) and bronchoalveolar lavage (BAL) fluid and cells were examined at 0 h and 24 h postexposure to ROFA. The C-deficient diet lowered C concentrations in BAL fluid and cells and in NL fluid by 90%, and the GSH-depletion regimen lowered both GSH and C in the BAL fluid and cells by 50%. ROFA deposition was calculated at time 0 from lung Ni levels to be 46 microg/g wet lung. In unexposed animals, the combined deficiency of C and GSH modified the cellular composition of cells recovered in lavage fluid, i.e., the increased number of eosinophils and macrophages in BAL fluid. ROFA inhalation increased lung injury in the -C-GSH group only (evidenced by increased BAL protein, LDH and neutrophils, and decreased BAL macrophages). ROFA exposure decreased C in BAL and NL at 0 h, and increased BAL C and GSH (2- to 4-fold above normal) at 24 h in nondepleted guinea pigs, but had no effect on C and GSH in depleted guinea pigs. Combined deficiency of C and GSH resulted in the highest macrophage and eosinophil counts of any group. GSH depletion was associated with increased BAL protein and LDH, increased numbers of BAL macrophages and eosinophils, and decreased rectal body temperatures. We conclude that combined deficiency of C and GSH increased susceptibility to inhaled ROFA; caused unusual BAL cellular changes; resulted in lower antioxidant concentrations in BAL than were observed with single deficiencies. Antioxidant deficiency may explain increased susceptibility to PM in elderly or diseased populations and may have important implications for extrapolating animal toxicity data to humans.

A comparison of trends in problematic drug misuse from two reporting systems.

BACKGROUND: Regional Drug Misuse Databases (RDMDs) are considered the main source of intelligence on problem drug takers in England. Originally intended to provide trend data on visible drug use, a recent strategic review concluded that their purpose should be to monitor treatment targets for the Government's latest 10 year strategy to tackle drug misuse. The aim of this analysis was to explore whether the General Practice Research Database (GPRD) could supplement RDMDs. METHODS: A retrospective analysis was carried out using the GPRD and the RDMD in the West Midlands from 1993 to 1997. RESULTS: Extrapolation of GPRD data indicates 6,574 drug misusing or dependent diagnosed patients in primary care in 1997 compared with 3,643 clients reported by all agencies including general practitioners (GPs) to the RDMD. From 1993 to 1997, the RDMD notification rate fluctuated whereas the GPRD rate has increased steadily since 1995. Half of all drug misusing or dependent patients recorded on the GPRD had psychiatric co-morbidity and 10 per cent had been referred to hospital for a drug overdose. CONCLUSIONS: As the GPRD has been unaffected by the demise of statutory notification of drug dependence in 1997, interpretation of trends may be more reliable than on the RDMD. There is also considerable potential for analysis of prescribing patterns, co-morbidity and drug-related hospitalization. As the Department of Health's Strategic Review of RDMDs recommends GPs as 'core reporters' for providing data to the national system, there is a need for a strategy to ensure valid and comprehensive reporting from GPs.

Ratio of inhaled corticosteroid to bronchodilator treatment and asthma hospitalisation.

BACKGROUND: Previous research based on aggregated data has led to conflicting interpretations of the relationship between the corticosteroid:bronchodilator (C:B) ratio and outcome measures. OBJECTIVES: To assess whether the C:B ratio is associated with hospital contact for asthma at individual patient level. METHODS: The study was a retrospective multivariate analysis, using data from the U.K. General Practice Research Database from 1993 to 1996. The subjects were 3465 asthma-diagnosed patients receiving bronchodilator and corticosteroid medication. The main outcome measures were asthma-related hospital contacts. RESULTS: There was an inverse association between the C:B ratio and hospital contact after controlling for age. The odds ratio for the C:B ratio was 0.87 (95 % CI 0.73-0.98) and 1.04 (95% CI 1.01-1.07) for five-year agebands among patients aged five years and over. There was no systematic relationship between the C:B ratio and hospital contacts for patients aged under five years. CONCLUSION: The results of this study show that higher C:B ratios are associated with lower levels of hospital contacts at patient level, although there are exceptions possibly linked to disease severity. For patients under five years, the ratio may not be a good outcome measure, perhaps owing to the difficulty in diagnosing asthma or poor compliance.

A case of tuberculosis in Memphis.

The resurgence of tuberculosis has been of increasing concern to public health. Laryngeal and cutaneous tuberculosis have long been regarded as two of the most infectious forms of the disease. In this article, we re-emphasize the public health consequences of a case of laryngeal TB, which must be considered in the differential diagnosis of a patient with persistent fever, cough, weight loss, and hoarseness.

Should the corticosteroid to bronchodilator ratio be promoted as a quality prescribing marker?

In recent years the ratio of inhaled corticosteroid:bronchodilator (C:B) prescribing has been promoted as a quality marker for asthma treatment and cross-sectional data indicate an association with hospital admissions. If prescribing advice has been followed then it can be hypothesised that the C:B ratio will have increased and hospitalisation decreased. The West Midlands General Practice Research Database was used to monitor changes in the C:B ratio and hospital referrals for asthma between 1993 and 1996. The C:B ratio increased from 0.5 to 0.6 (P<0.001) and hospital referrals decreased from 7% to 4% per annum (P<0.001). Overall, 38% of the variation in hospital referrals was explained by the C:B ratio. This is higher than previous studies, perhaps because the study was longitudinal and the ratio assessed accurately in terms of volume rather than prescription items. When measured in defined daily doses, the C:B ratio does appear to have validity as an indicator of good prescribing in primary care. The General Practice Research Database offers an opportunity for assessing the validity of prescribing indicators before they are considered for wider use by Primary Care Groups and Health Authorities.

Interaction between rifampin and levothyroxine.

Rifampin is a potent inducer of hepatic enzymes and is well documented to cause many clinically significant drug interactions. Studies in normal volunteers have shown its ability to decrease circulating levels of thyroid hormone, while having no effect on thyroid-stimulating hormone (TSH). Reports of rifampin's effects on patients on hormone replacement in the clinical setting are of interest since we believe only one such case has been described. We report the case of a man, stable on levothyroxine, who exhibited significantly elevated TSH levels during therapy with rifampin. Thyroid-stimulating hormone levels returned to baseline 9 days after discontinuance of rifampin.

Why are patients prescribed proton pump inhibitors? Retrospective analysis of link between morbidity and prescribing in the General Practice Research Database.

OBJECTIVES: To establish the relation between new prescriptions for proton pump inhibitors and recorded upper gastrointestinal morbidity within a large computerised general practitioner database. DESIGN: Retrospective survey of morbidity and prescribing data linked to new prescriptions for proton pump inhibitors and comparison with licensed indications between 1991 and 1995. SETTING: General Practice Research Database and prescribing analysis and cost (PACT) data for the former West Midlands region. SUBJECTS: Information for 612 700 patients in the General Practice Research Database. Anonymous PACT data for all general practitioners in West Midlands region. MAIN OUTCOME MEASURES: Diagnostic codes linked to the first prescriptions issued for proton pump inhibitors; relation between new prescriptions and licensed indications; yearly change in ratio of new to repeat prescriptions and prescribing volumes measured as defined daily doses. RESULTS: Oesophagitis was the commonest recorded indication in 1991, accounting for 31% of new prescriptions, but was third in 1995 (14%). During the study new prescriptions increased substantially, especially for duodenal disease (780%) and non-ulcer dyspepsia (690%). In 1995 non-specific morbidity accounted for 46% of new prescriptions. The total volume of prescribing rose 10-fold between 1991 and 1995, when repeat prescribing accounted for 77% of the total. CONCLUSIONS: Changes in recorded morbidity associated with new prescriptions of proton pump inhibitors did not necessarily reflect changes in licensed indications. Although general practitioners seemed to respond to changes in licensing, particularly for duodenal and gastric disease, prescribing for unlicensed indications non-ulcer dyspepsia and non-specific abdominal pain increased.

Closure of atrial septal defects in the cardiac catheterization laboratory: early results using the Amplatzer Septal Occlusion Device.

Transcatheter closure of the ostium secundum type of atrial septal defect (ASD) is a less invasive alternative to open heart surgery. This report constitutes the early results using the Amplatzer Septal Occluder for the closure of ASD at the Nemours Cardiac Center of the A. I. duPont Hospital for Children.

Evidence that exposure of particulate air pollutants to human and rat alveolar macrophages leads to differential oxidative response.

Macrophages and inflammatory cells generate active oxygen species in the process of killing and degrading microorganisms. Air pollutant particles may be ingested by macrophages and stimulate the same mechanisms to produce a long term oxidative burden to the lung if particles are not degraded. In the present study human and rat alveolar macrophages (AM) were compared in their response to inhaled particles using luminol dependent chemiluminescence (CL) and peroxide dependent CL assays. Cytotoxicity was measured by the release of lactate dehydrogenase (LDH) activity in the supernatant. Human AM produced more oxidants than rat AM whether, unstimulated, after addition of particles or addition of particles then peroxidase. Human AM also had a different spectrum of response to the same particles. Our results suggest that human macrophages produce more reactive oxygen species in respond to particles than rat AM.

Sensitivity of lungs of aging Fischer 344 rats to ozone: assessment by bronchoalveolar lavage.

Biological effects indicators in bronchoalveolar lavage fluid were studied in Fischer 344 rats of different ages after exposure to 0.4-0.8 ppm ozone for periods of 2-6 h on a single day or on 4 consecutive days. The magnitude of alveolar protein transudation induced by ozone was not different between age groups, but the interindividual variability of protein changes was higher in senescent (24-mo-old) rats. By comparison to juvenile (2-mo-old) and adult (9-mo-old) rats, senescent animals had higher increases of interleukin-6 (up to 10-fold higher) and N-acetyl-beta-D-glucosaminidase (NAGA; 2-fold higher) in lung lavage after ozone. Ascorbic acid was lower in lungs of senescent rats (one-half of juvenile values), and acute ozone exposure brought a further decrease in lung ascorbate. Whereas alveolar protein transudation was attenuated after ozone exposure on 4 days, persistent elevation of NAGA in senescent rats suggested only partial adaptation. Injection of endotoxin did not modify the patterns of effects. Incorporation of 18O-ozone into macrophages and surfactant was not different between age groups, indicating that the magnified biological responses in senescent rats were not dominated by differences in internal dose of ozone. The results indicate that senescent rats respond differently than juvenile and adult rats to lung injury.

Comparison of antioxidant substances in bronchoalveolar lavage cells and fluid from humans, guinea pigs, and rats.

Antioxidants located in the lining layer of the respiratory tract may be important in determining sensitivity of lung tissues to inhaled pollutants. This study addressed species differences in the amounts of ascorbic acid (AH2), glutathione (GSH), uric acid (UA), and alpha-tocopherol (AT) in bronchoalveolar lavage (BAL) fluid and cells of humans, guinea pigs, and rats. Protein and lipid phosphorus (lipid P) were used as normalizing factors. More than 90% of the lavageable AH2, UA, GSH, protein, and lipid P was present in the extracellular fraction of BAL in rats and guinea pigs, while over 95% of the lavageable AT was located in the BAL cells. BAL fluid AH2/protein in rats was 7- to 9-fold higher than in humans and guinea pigs. However, human BAL fluid had 2- to 8-fold higher UA/protein, GSH/protein, and AT/protein ratios than rats and guinea pigs. In BAL cells, rats had higher AH2/protein and AT/protein ratios than guinea pigs and humans, and both rats and guinea pigs had higher GSH and AT/protein ratios than humans. Individual variability among humans in the BAL fluid and cellular antioxidants was generally greater than in the laboratory animals. These data demonstrate that some large species differences exist in BAL fluid and cellular antioxidants which could affect susceptibility to oxidant pollutants.