Comprehensive multi-cohort transcriptional meta-analysis of muscle diseases identifies a signature of disease severity.

Muscle diseases share common pathological features suggesting common underlying mechanisms. We hypothesized there is a common set of genes dysregulated across muscle diseases compared to healthy muscle and that these genes correlate with severity of muscle disease. We performed meta-analysis of transcriptional profiles of muscle biopsies from human muscle diseases and healthy controls. Studies obtained from public microarray repositories fulfilling quality criteria were divided into six categories: (i) immobility, (ii) inflammatory myopathies, (iii) intensive care unit (ICU) acquired weakness (ICUAW), (iv) congenital muscle diseases, (v) chronic systemic diseases, (vi) motor neuron disease. Patient cohorts were separated in discovery and validation cohorts retaining roughly equal proportions of samples for the disease categories. To remove bias towards a specific muscle disease category we repeated the meta-analysis five times by removing data sets corresponding to one muscle disease class at a time in a "leave-one-disease-out" analysis. We used 636 muscle tissue samples from 30 independent cohorts to identify a 52 gene signature (36 up-regulated and 16 down-regulated genes). We validated the discriminatory power of this signature in 657 muscle biopsies from 12 additional patient cohorts encompassing five categories of muscle diseases with an area under the receiver operating characteristic curve of 0.91, 83% sensitivity, and 85.3% specificity. The expression score of the gene signature inversely correlated with quadriceps muscle mass (r = -0.50, p-value = 0.011) in ICUAW and shoulder abduction strength (r = -0.77, p-value = 0.014) in amyotrophic lateral sclerosis (ALS). The signature also positively correlated with histologic assessment of muscle atrophy in ALS (r = 0.88, p-value = 1.62 × 10-3) and fibrosis in muscular dystrophy (Jonckheere trend test p-value = 4.45 × 10-9). Our results identify a conserved transcriptional signature associated with clinical and histologic muscle disease severity. Several genes in this conserved signature have not been previously associated with muscle disease severity.

Long-term outcomes and healthcare utilization following critical illness--a population-based study.

BACKGROUND: The purpose of this study was to examine hospital mortality, long-term mortality, and health service utilization among critically ill patients. We also determined whether these outcomes differed according to demographic and clinical characteristics. METHODS: We conducted a retrospective cohort study of adults (age ≥ 18 years) who survived admission to an intensive care unit (ICU) in Ontario, Canada, between 1 April 2002 and 31 March 2012, excluding isolated admissions to step-down or intermediate ICUs, coronary care ICUs, or cardiac surgery ICUs. Adults (age ≥ 18 years) who survived an acute hospitalization that did not include an ICU stay formed the comparator group. The primary outcome was mortality following hospital discharge. Secondary outcomes were healthcare utilization, including emergency room admissions and hospital readmissions during follow-up. RESULTS: Over the study interval, 500,124 patients were admitted to ICUs and 420,187 (84%) survived to hospital discharge. Median follow-up for survivors was 5.3 (interquartile range 2.5, 8.2) years. Patients admitted to an ICU were more likely to subsequently visit the emergency department, be readmitted to the hospital and ICU, receive home care support, require rehabilitation, and be admitted for long-term care. Those requiring more resources within the ICU required more resources after discharge. One-third of patients admitted to the ICU died during long-term follow-up, with overall probabilities of death of 11% and 29% at 1 year and 5 years, respectively. In the adjusted analysis, there was an increasing hazard of death with increasing age, reaching a hazard ratio of 18.08 (95 % confidence interval 16.60-19.68) for those ≥ 85 years of age compared with those aged 18-24 years. CONCLUSIONS: Healthcare utilization after hospital discharge was higher among ICU patients, and also among those requiring more healthcare resources during their ICU admission, than among all hospitalized patients as a group. One-third of ICU patients died within the 5 years following discharge, and age was the most influential determinant of outcome. These findings should help target post-ICU discharge services for high-risk groups and better inform goals-of-care discussions for elderly critically ill patients.

Outcomes after ARDS: a distinct group in the spectrum of disability after complex and protracted critical illness.

ARDS represents an important public health problem for patients, family caregivers and society. The last decade has seen a burgeoning literature focussed on the outcomes of this patient group and has informed important new knowledge about the devastating and often irreversible morbidity related to nerve, muscle and brain injury More recent studies have reinforced these robust themes of physical and neuropsychological morbidity in other patient groups and have shown that outcomes after ARDS are one segment of a spectrum of disability and may not be widely generalizable across older patients with multiple comorbidities and protracted length of stay in the critical care unit. Our literature has reached theme saturation in terms of morbidity and needs to identify and begin to address the research agenda for the next decade. Several of these themes will be addressed here and include the following: 1) to generate large diverse datasets to understand different outcome trajectories over time to facilitate risk stratification and inform development of rehabilitation programs; 2) to embrace mixed methodology as a new longitudinal study standard to facilitate detailed qualitative observations to augment insights from quantitative data; 3) to educate patients, families, colleagues and decision-makers about outcomes after critical illness to inform policy and decision-making; 4) to embrace family caregivers and provide intervention when needed and ongoing support across transitions of care; 5) prioritize functional outcome measures over those targeted at health-related quality of life for construction of more focussed rehabilitation interventions; 6) embrace translational research programs to elucidate the relationship between functional outcome and molecular mechanism to gain further insight into the pathophysiology of critical illness, muscle and brain injury and potential insights into novel therapeutic strategies.

An evidence-based approach to acute respiratory distress syndrome.

We provide an evidence-based approach to managing patients with acute lung injury and acute respiratory distress syndrome (ARDS). We searched MEDLINE and the Cumulative Index to Nursing and Allied Health for randomized trials evaluating lung-protective ventilation strategies, inhaled nitric oxide, prone positioning, and late-phase corticosteroids for managing these patients, and for additional literature related to long-term follow-up of ARDS survivors. The results of our review suggest that pressure- and volume-limited ventilation, according to the ARDS Network protocol, can reduce mortality for patients with acute lung injury, and so may an "open lung" approach to mechanical ventilation. Those 2 strategies are currently being compared in 2 multicenter randomized trials. Although both inhaled nitric oxide therapy and prone positioning can produce dramatic acute improvements in oxygenation for some patients, there is no evidence that these interventions can benefit patients with respect to patient-important outcomes. Therefore it is unreasonable to be dogmatic about the role of inhaled nitric oxide and prone positioning in ARDS. The role of corticosteroids in the late phase of ARDS is unclear and remains a very important unanswered question. With respect to long-term follow-up, we found that pulmonary dysfunction is probably not a major source of morbidity for ARDS survivors, whereas neuropsychological dysfunction is prominent. Ongoing research may suggest interventions to improve the outcome of ARDS and of critical illness in general.

Has high-frequency ventilation been inappropriately discarded in adult acute respiratory distress syndrome?

OBJECTIVES: To review the basic physiologic principles that support the role for high-frequency ventilation (HFV) in acutely lung-injured patients, to critically assess clinical trial data in this area, and discuss why a metasummary is not feasible and a large-scale clinical trial is needed. DATA SOURCES: We searched a computerized database (MEDLINE) from 1976 to January 1997 using the text words "high-frequency ventilation" and "acute respiratory distress syndrome" to retrieve all relevant candidate articles. STUDY SELECTION: We retrieved all English language clinical studies conducted in tertiary care centers that employed HFV in adult acute respiratory distress syndrome (ARDS) patients. DATA EXTRACTION: Only prospective, randomized trials, cohort/case-control studies, and case series evaluating HFV vs. conventional mechanical ventilation in adult ARDS patients were included. DATA SYNTHESIS: We independently screened 3,166 articles on ARDS and 494 papers on HFV in our computer search. We checked reference lists and contacted experts in the field of mechanical ventilation in ARDS to ensure that no relevant studies had been missed. Only four articles met our inclusion criteria and were evaluated in detail. CONCLUSIONS: Current clinical studies are statistically under-powered and a metasummary is not feasible because of study quality, as well as lack of similar clinical end points and measures of magnitude of benefit. A large, multicenter trial should be initiated to define the role of HFV in the treatment of adult ARDS.

Subglottic stenosis complicating Wegener's granulomatosis: surgical repair as a viable treatment option.

Wegener's granulomatosis frequently involves the subglottis and trachea, often leading to compromise of the upper airway. Moreover, the stenotic segments may persist or progress despite control of the disease elsewhere in the body. In this report, we describe the cases of five patients with Wegener's granulomatosis who, in addition to nasal, sinus, pulmonary and renal involvement, had symptomatic subglottic or tracheal stenosis. Biopsy specimens from involved sites in the subglottis and trachea were often not diagnostic, and the diagnosis was later confirmed by a positive antineutrophil cytoplasm antibody titer. All patients had clinical remission on standard therapeutic regimens with prednisone and cyclophosphamide but continued to have symptoms of extrathoracic airway obstruction. Three of the five patients underwent primary thyrotracheal anastomosis while their disease was in clinical remission, without postoperative compromise of anastomotic integrity or wound healing despite concurrent use of prednisone and cyclophosphamide. There has been no evidence of local disease recurrence during follow-up periods ranging from 3 months to 14 years. We conclude that surgical intervention is a viable treatment option for patients who have symptomatic stenotic segments of the subglottis and trachea as a result of Wegener's granulomatosis in clinical remission.

Pleural complications in lung transplant recipients.

Pleural complications occurred in 30 (22%) of 138 patients after 53 single and 91 double lung transplants between September 1986 and February 1993. These were defined for the purpose of this study as pneumothorax persisting beyond the first 14 postoperative days, recurrent pneumothorax, or any other pleural process that necessitated diagnostic or therapeutic intervention. Overall, a higher pleural complication rate was seen in double lung transplantation (25 of 30) than in single lung transplantation (5 of 30) with no differences noted in the frequency among preoperative diagnostic groups (p > 0.05). Pneumothorax was the most frequent complication, affecting 14 of 30 patients, with 6 of 14 cases occurring after transbronchial biopsy. All pneumothoraces in single (n = 4) and double lung transplantation (n = 10) resolved spontaneously or with chest tube thoracostomy. One patient required placement of a Clagett window after open lung biopsy and another required thoracotomy and pleural abrasion after transbronchial biopsy. Parapneumonic effusion was observed in 4 of 30 double lung transplantations with spontaneous resolution in all cases. Empyema affected 7 of 30 patients and occurred exclusively in the double lung transplant group. Sepsis developed in three of the patients with this complication and they subsequently died. The risk of empyema was independent of preoperative diagnosis (p > 0.05). Of interest, all patients with cystic fibrosis (n = 3) with complicating empyema had Pseudomonas cepacia in the pleural fluid. Other miscellaneous complications included subpleural hematoma, chylothorax, and hemothorax. The latter two necessitated thoracic duct and bronchial artery ligation, respectively. In summary, a significant proportion of lung transplant recipients will have pleural space complications. The vast majority of these will resolve spontaneously or with conservative procedures. These complications were not related to preoperative diagnosis nor associated with a significant prolongation of hospital stay (p > 0.05). Empyema is the only pleural space complication associated with increased patient mortality and, as such, is an important clinical marker for those at risk for sepsis and death.

Hapten-induced model of chronic inflammation and ulceration in the rat colon.

We have developed a simple and reproducible rat model of chronic colonic inflammation by the intraluminal instillation of a solution containing a "barrier breaker" and a hapten. Administration of the hapten 2,4,6-trinitrobenzenesulfonic acid (5-30 mg) in 0.25 ml of 50% ethanol as the "barrier breaker" produced dose-dependent colonic ulceration and inflammation. At a dose of 30 mg, trinitrobenzenesulfonic acid/ethanol-induced ulceration and marked thickening of the bowel wall persisted for at least 8 wk. Histologically, the inflammatory response included mucosal and submucosal infiltration by polymorphonuclear leukocytes, macrophages, lymphocytes, connective tissue mast cells, and fibroblasts. Granulomas were observed in 57% of the rats killed 3 wk after induction of inflammation. Langhan's-type giant cells were also observed. Segmental ulceration and inflammation were common. The characteristics and relatively long duration of inflammation and ulceration induced in this model afford an opportunity to study the pathophysiology of colonic inflammatory disease in a specifically controlled fashion, and to evaluate new treatments potentially applicable to inflammatory bowel disease in humans.