Publications

RATIONALE

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology. The genes TOLLIP and MUC5B play important roles in lung host defense, which is an immune process influenced by oxidative signaling. Whether polymorphisms in TOLLIP and MUC5B modify the effect of immunosuppressive and antioxidant therapy in individuals with IPF is unknown.

OBJECTIVES

To determine whether single-nucleotide polymorphisms (SNPs) within TOLLIP and MUC5B modify the effect of interventions in subjects participating in the Evaluating the Effectiveness of Prednisone, Azathioprine, and N-Acetylcysteine in Patients with Idiopathic Pulmonary Fibrosis (PANTHER-IPF) clinical trial.

METHODS

SNPs within TOLLIP (rs5743890/rs5743894/rs5743854/rs3750920) and MUC5B (rs35705950) were genotyped. Interaction modeling was conducted with multivariable Cox regression followed by genotype-stratified survival analysis using a composite endpoint of death, transplantation, hospitalization, or a decline of ≥ 10% in FVC.

MEASUREMENTS AND MAIN RESULTS

Significant interaction was observed between N-acetylcysteine (NAC) therapy and rs3750920 within TOLLIP (P interaction = 0.001). After stratifying by rs3750920 genotype, NAC therapy was associated with a significant reduction in composite endpoint risk (hazard ratio, 0.14; 95% confidence interval, 0.02-0.83; P = 0.03) in those with a TT genotype, but a nonsignificant increase in composite endpoint risk (hazard ratio, 3.23; 95% confidence interval, 0.79-13.16; P = 0.10) was seen in those with a CC genotype. These findings were then replicated in an independent IPF cohort.

CONCLUSIONS

NAC may be an efficacious therapy for individuals with IPF with an rs3750920 (TOLLIP) TT genotype, but it was associated with a trend toward harm in those with a CC genotype. A genotype-stratified prospective clinical trial should be conducted before any recommendation regarding the use of off-label NAC to treat IPF.

Esteban Gonzalez Burchard and colleagues explore how making medical research more diverse would aid not only social justice but scientific quality and clinical effectiveness, too.

OBJECTIVE

Patient-centred care has become a priority in many countries. It is unknown whether current tools capture aspects of care patients and their surrogates consider important. We investigated whether online narrative reviews from patients and surrogates reflect domains in the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) and we described additional potential domains.

DESIGN

We used thematic analysis to assess online narrative reviews for reference to HCAHPS domains and salient non-HCAHPS domains and compared results by reviewer type (patient vs surrogate).

SETTING

We identified hospitals for review from the American Hospital Association database using a stratified random sampling approach. This approach ensured inclusion of reviews of a diverse set of hospitals. We searched online in February 2013 for narrative reviews from any source for each hospital.

PARTICIPANTS

We included up to two narrative reviews for each hospital.

EXCLUSIONS

Outpatient or emergency department reviews, reviews from self-identified hospital employees, or reviews of <10 words.

RESULTS

50.0% (n=122) of reviews (N=244) were from patients and 38.1% (n=93) from friends or family members. Only 57.0% (n=139) of reviews mentioned any HCAHPS domain. Additional salient domains were: Financing, including unexpected out-of-pocket costs and difficult interactions with billing departments; system-centred care; and perceptions of safety. These domains were mentioned in 51.2% (n=125) of reviews. Friends and family members commented on perceptions of safety more frequently than patients.

CONCLUSIONS

A substantial proportion of consumer reviews do not mention HCAHPS domains. Surrogates appear to observe care differently than patients, particularly around safety.

Polymorphonuclear neutrophils (PMNs) are largely considered to foster cancer development despite wielding an arsenal of cytotoxic agents. Using a mouse model of PTEN-deficient uterine cancer, we describe a surprising inhibitory role for PMNs in epithelial carcinogenesis. By inducing tumor cell detachment from the basement membrane, PMNs impeded early-stage tumor growth and retarded malignant progression. Unexpectedly, PMN recruitment and tumor growth control occurred independently of lymphocytes and cellular senescence and instead ensued as part of the tumor's intrinsic inflammatory response to hypoxia. In humans, a PMN gene signature correlated with improved survival in several cancer subtypes, including PTEN-deficient uterine cancer. These findings provide insight into tumor-associated PMNs and reveal a context-specific capacity for PMNs to directly combat tumorigenesis.