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Background Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating blistering genodermatosis caused by mutations in the COL7A1 gene, which encodes for type VII collagen and is necessary for dermal-epidermal adhesion and integrity. Disease manifestations include severe and debilitating wounds, aggressive squamous cell carcinomas, and premature death; however, there are currently no approved therapies. This Phase 1/2a, open-label study evaluated the long-term efficacy and safety of gene-corrected autologous keratinocyte grafts (EB-101) for chronic RDEB wounds. Methods Autologous keratinocytes were harvested from participants with severe RDEB, transduced with a retrovirus containing the full-length COL7A1 gene, and grown into 5 × 7 cm (35 cm 2 ) sheets. Gene-corrected keratinocyte sheets were then transplanted onto chronic RDEB wounds present for ≥ 12 weeks. Results Seven adult participants with severe RDEB were grafted with six sheets each (42 total sheets) onto wounds and followed for a mean of 5.9 years (range 4–8 years). Long-term improvements in wound healing and symptoms were observed. At year five, 70% (21/30) of treated sites demonstrated ≥ 50% wound healing compared to baseline by investigator global assessment. No sites with ≥ 50% wound healing were painful or pruritic, compared to 67% (6/9) of sites with < 50% wound healing ( p  < 0.001) at year five. Grafts were well-tolerated throughout long-term follow-up. No serious adverse events related to treatment were reported over a mean of 5.9 years of follow-up. No persistent systemic autoimmunity against type VII collagen or replication-competent retrovirus infections were identified, and no participants developed squamous cell carcinomas related to treatment during long-term follow-up. Conclusions Treatment with EB-101 appears safe and efficacious, and produces long-term improvements in wound healing, pain, and itch for RDEB patients. Results from the Phase 3 randomized controlled trial are forthcoming. Trial registration ClinicalTrials.gov, NCT01263379. Registered December 15, 2010. https://clinicaltrials.gov/ct2/show/NCT01263379

Background Epidermolysis bullosa (EB) is a rare genetic skin fragility disease. The Recessive Dystrophic subtype (RDEB) causes severe manifestations and leads to early mortality. Two topical therapies have recently been approved, but they are not curative. We have developed a cell therapy utilizing genetically corrected patient‐derived stem cells to treat RDEB wounds. Preclinical animal studies showed effective delivery of these cells incorporating Spincare, a temporary skin substitute mimicking the extracellular matrix. While Spincare is approved in Europe for burns, it has not yet been evaluated in EB clinical trials. Objectives This study is a pilot trial assessing the safety and tolerability of Spincare matrix dressing on RDEB patients with chronic and recurrent wounds. Methods This is a randomized, split‐body, intra‐patient controlled trial conducted at a single site. Eligible patients had RDEB, were aged 6 years or older, with at least 6 wounds. Wounds within a matched pair were randomized to standard of care (control) or Spincare matrix (1:1). Caregivers applied the matrix to wounds weekly at home, and uploaded wound photos for healing assessment by blinded investigators. The primary endpoint was 90% wound closure from baseline to Week 16. Secondary endpoints included 50% and 70% wound closure, adverse events (AEs), wound pain and itch. Results Six RDEB patients with 42 wounds were enroled; 21 wounds were treated with Spincare matrix and 21 wounds with standard of care. There was no significant difference in wound closure between matrix‐treated and control wounds at all time points. Spincare matrix did not increase wound pain or itch compared with control wounds. No AEs were related to Spincare. Conclusions This pilot trial demonstrated that the Spincare matrix is a safe and feasible on RDEB wounds. Because the Spincare matrix does not heal wounds, it would be an effective vehicle for cell therapy in future RDEB trials.

The goal of this faculty practice model is to provide a clinical practice site for faculty and provide clinical instruction for baccalaureate nursing students and primary health care services to an underserved, uninsured population in a nonprofit outpatient clinic setting. Community partnerships include a regional university, the city housing authority, local hospitals, the tri-county dental association, the United Way, and other community organizations. The facility is provided by the city housing authority, and the laboratory and diagnostic services are provided by the local hospital. The clinic nurse practitioners are university faculty, and clinical time is part of the faculty workload. Many barriers have been overcome, including lack of funding, increased faculty workloads, and proration of the state’s allocation for higher education. Because the organization was initially set up as a nonprofit organization, federal, state, and local grants are available. [The goal of this faculty practice model is to provide a clinical practice site for faculty and provide clinical instruction for baccalaureate nursing students and primary health care services to an underserved, uninsured population in a nonprofit outpatient clinic setting. Community partnerships include a regional university, the city housing authority, local hospitals, the tri-county dental association, the United Way, and other community organizations. The facility is provided by the city housing authority, and the laboratory and diagnostic services are provided by the local hospital. The clinic nurse practitioners are university faculty, and clinical time is part of the faculty workload. Many barriers have been overcome, including lack of funding, increased faculty workloads, and proration of the state’s allocation for higher education. Because the organization was initially set up as a nonprofit organization, federal, state, and local grants are available. [ J Nurs Educ. 2014;53(11):654–658.]

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin disease caused by mutations in the COL7A1 gene encoding type VII collagen. Individuals with RDEB have fragile skin and most develop large, chronic wounds. The aim of the VIITAL study was to evaluate the efficacy and safety of a one-time surgical application of prademagene zamikeracel in wound healing. This randomised, open-label, intrapatient-controlled, phase 3 trial was conducted at two institutions in the USA. Eligible patients were aged 6 years or older, had a confirmed clinical and genetic diagnosis of RDEB, at least two chronic wounds (>20 cm2), had no evidence of an immune response to type VII collagen, and expressed the amino-terminal NC1 fragment of type VII collagen. Large, chronic wounds on the participants were matched in pairs by size, chronicity, and anatomical region and computer randomised (1:1) to treatment (prademagene zamikeracel) or control (standard of care). There was no masking. Prademagene zamikeracel is an autologous COL7A1 gene-modified cellular sheet that is sutured onto to a large, chronic RDEB wound. A maximum of six wounds could be treated with prademagene zamikeracel per patient. The coprimary endpoints were the proportion of wounds with at least 50% healing and pain reduction from baseline at week 24 in the intention-to-treat population of all patients and their randomised wounds. The safety analysis population included all patients and evaluated wounds, randomised and non-randomised. This completed trial was registered with ClinicalTrials.gov (NCT04227106). Between Jan 1, 2020, and March 31, 2022, 15 patients were screened and 11 were enrolled (43 randomised wound pairs). Four (36%) of 11 participants were male and seven (64%) of 11 participants were female, with a median age of 21 years (IQR 17–30). 86 wounds were matched and randomised: 43 (50%) to prademagene zamikeracel and 43 (50%) to control. At week 24, 35 (81%) of 43 treated wounds were at least 50% healed from baseline for prademagene zamikeracel compared with seven (16%) of 43 control wounds (mean difference 67% [95% CI 50 to 89]; p<0·0001). The mean change from baseline to week 24 in wound pain was –3·07 with prademagene zamikeracel and –0·90 in controls (mean pairwise difference –2·23 [–3·45 to –0·66]; p=0·0002). No serious treatment-related adverse events were observed. Prademagene zamikeracel improved wound healing and pain versus control and was well tolerated, supporting its potential to reduce wound burden in patients with large, chronic RDEB wounds. Abeona Therapeutics.

Background The aim of this study was to describe data on epidemiology, ventilatory management, and outcome of acute respiratory distress syndrome (ARDS) in immunocompromised patients. Methods We performed a post hoc analysis on the cohort of immunocompromised patients enrolled in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) study. The LUNG SAFE study was an international, prospective study including hypoxemic patients in 459 ICUs from 50 countries across 5 continents. Results Of 2813 patients with ARDS, 584 (20.8%) were immunocompromised, 38.9% of whom had an unspecified cause. Pneumonia, nonpulmonary sepsis, and noncardiogenic shock were their most common risk factors for ARDS. Hospital mortality was higher in immunocompromised than in immunocompetent patients (52.4% vs 36.2%; p  < 0.0001), despite similar severity of ARDS. Decisions regarding limiting life-sustaining measures were significantly more frequent in immunocompromised patients (27.1% vs 18.6%; p  < 0.0001). Use of noninvasive ventilation (NIV) as first-line treatment was higher in immunocompromised patients (20.9% vs 15.9%; p  = 0.0048), and immunodeficiency remained independently associated with the use of NIV after adjustment for confounders. Forty-eight percent of the patients treated with NIV were intubated, and their mortality was not different from that of the patients invasively ventilated ab initio . Conclusions Immunosuppression is frequent in patients with ARDS, and infections are the main risk factors for ARDS in these immunocompromised patients. Their management differs from that of immunocompetent patients, particularly the greater use of NIV as first-line ventilation strategy. Compared with immunocompetent subjects, they have higher mortality regardless of ARDS severity as well as a higher frequency of limitation of life-sustaining measures. Nonetheless, nearly half of these patients survive to hospital discharge. Trial registration ClinicalTrials.gov, NCT02010073 . Registered on 12 December 2013.

PurposeTo evaluate patients with resolved versus confirmed ARDS, identify subgroups with substantial mortality risk, and to determine the utility of day 2 ARDS reclassification.MethodsOur primary objective, in this secondary LUNG SAFE analysis, was to compare outcome in patients with resolved versus confirmed ARDS after 24 h. Secondary objectives included identifying factors associated with ARDS persistence and mortality, and the utility of day 2 ARDS reclassification.ResultsOf 2377 patients fulfilling the ARDS definition on the first day of ARDS (day 1) and receiving invasive mechanical ventilation, 503 (24%) no longer fulfilled the ARDS definition the next day, 52% of whom initially had moderate or severe ARDS. Higher tidal volume on day 1 of ARDS was associated with confirmed ARDS [OR 1.07 (CI 1.01–1.13), P = 0.035]. Hospital mortality was 38% overall, ranging from 31% in resolved ARDS to 41% in confirmed ARDS, and 57% in confirmed severe ARDS at day 2. In both resolved and confirmed ARDS, age, non-respiratory SOFA score, lower PEEP and P/F ratio, higher peak pressure and respiratory rate were each associated with mortality. In confirmed ARDS, pH and the presence of immunosuppression or neoplasm were also associated with mortality. The increase in area under the receiver operating curve for ARDS reclassification on day 2 was marginal.ConclusionsARDS, whether resolved or confirmed at day 2, has a high mortality rate. ARDS reclassification at day 2 has limited predictive value for mortality. The substantial mortality risk in severe confirmed ARDS suggests that complex interventions might best be tested in this population.Trial RegistrationClinicalTrials.gov NCT02010073.

Background To determine the frequency of, and factors associated with, death in hospital following ICU discharge to the ward. Methods The Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE study was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted across 459 ICUs from 50 countries globally. This study aimed to understand the frequency and factors associated with death in hospital in patients who survived their ICU stay. We examined outcomes in the subpopulation discharged with no limitations of life sustaining treatments (‘treatment limitations’), and the subpopulations with treatment limitations. Results 2186 (94%) patients with no treatment limitations discharged from ICU survived, while 142 (6%) died in hospital. 118 (61%) of patients with treatment limitations survived while 77 (39%) patients died in hospital. Patients without treatment limitations that died in hospital after ICU discharge were older, more likely to have COPD, immunocompromise or chronic renal failure, less likely to have trauma as a risk factor for ARDS. Patients that died post ICU discharge were less likely to receive neuromuscular blockade, or to receive any adjunctive measure, and had a higher pre- ICU discharge non-pulmonary SOFA score. A similar pattern was seen in patients with treatment limitations that died in hospital following ICU discharge. Conclusions A significant proportion of patients die in hospital following discharge from ICU, with higher mortality in patients with limitations of life-sustaining treatments in place. Non-survivors had higher systemic illness severity scores at ICU discharge than survivors. Trial Registration : ClinicalTrials.gov NCT02010073 .

Background Patients with acute respiratory failure caused by cardiogenic pulmonary edema (CPE) may require mechanical ventilation that can cause further lung damage. Our aim was to determine the impact of ventilatory settings on CPE mortality. Methods Patients from the LUNG SAFE cohort, a multicenter prospective cohort study of patients undergoing mechanical ventilation, were studied. Relationships between ventilatory parameters and outcomes (ICU discharge/hospital mortality) were assessed using latent mixture analysis and a marginal structural model. Results From 4499 patients, 391 meeting CPE criteria (median age 70 [interquartile range 59–78], 40% female) were included. ICU and hospital mortality were 34% and 40%, respectively. ICU survivors were younger (67 [57–77] vs 74 [64–80] years, p  < 0.001) and had lower driving (12 [8–16] vs 15 [11–17] cmH 2 O, p  < 0.001), plateau (20 [15–23] vs 22 [19–26] cmH 2 O, p  < 0.001) and peak (21 [17–27] vs 26 [20–32] cmH 2 O, p  < 0.001) pressures. Latent mixture analysis of patients receiving invasive mechanical ventilation on ICU day 1 revealed a subgroup ventilated with high pressures with lower probability of being discharged alive from the ICU (hazard ratio [HR] 0.79 [95% confidence interval 0.60–1.05], p  = 0.103) and increased hospital mortality (HR 1.65 [1.16–2.36], p  = 0.005). In a marginal structural model, driving pressures in the first week (HR 1.12 [1.06–1.18], p  < 0.001) and tidal volume after day 7 (HR 0.69 [0.52–0.93], p  = 0.015) were related to survival. Conclusions Higher airway pressures in invasively ventilated patients with CPE are related to mortality. These patients may be exposed to an increased risk of ventilator-induced lung injury. Trial registration Clinicaltrials.gov NCT02010073