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Levels of iron and iron-related proteins including ferritin are higher in the lung tissue and lavage fluid of individuals with chronic obstructive pulmonary disease (COPD), when compared to healthy controls. Whether more iron in the extracellular milieu of the lung associates with distinct clinical phenotypes of COPD, including increased exacerbation susceptibility, is unknown. We measured iron and ferritin levels in the bronchoalveolar lavage fluid (BALF) of participants enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD (SPIROMICS) bronchoscopy sub-study (n = 195). BALF Iron parameters were compared to systemic markers of iron availability and tested for association with FEV1 % predicted and exacerbation frequency. Exacerbations were modelled using a zero-inflated negative binomial model using age, sex, smoking, and FEV1 % predicted as clinical covariates. BALF iron and ferritin were higher in participants with COPD and in smokers without COPD when compared to non-smoker control participants but did not correlate with systemic iron markers. BALF ferritin and iron were elevated in participants who had COPD exacerbations, with a 2-fold increase in BALF ferritin and iron conveying a 24% and 2-fold increase in exacerbation risk, respectively. Similar associations were not observed with plasma ferritin. Increased airway iron levels may be representative of a distinct pathobiological phenomenon that results in more frequent COPD exacerbation events, contributing to disease progression in these individuals. [ABSTRACT FROM AUTHOR]

Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may arise de novo or in patients previously treated with hormonal therapies for prostate adenocarcinoma as a mechanism of resistance. Despite being important to recognise, the clinical features of NEPC are poorly defined and could help guide when to perform a biopsy to look for NEPC histologic transformation. We reviewed baseline, treatment and outcome data of 87 patients with metastatic prostate cancer and tumour biopsy confirming NEPC histology. Forty-seven (54.0%) NEPC cases presented de novo , and 40 (46.0%) were therapy-related (t-NEPC). Thirty-six (41.4%) were classified as pure small-cell carcinoma, and 51 (58.6%) demonstrated mixed features with both small-cell carcinoma and adenocarcinoma present. Genomic data were available for 47 patients. The median age at time of NEPC was 68.1 years, median prostate-specific antigen (PSA) was 1.20 ng/ml (0.14 ng/mL small-cell carcinoma, 1.55 ng/mL mixed carcinoma) and sites of metastases included bone (72.6%), lymph node (47.0%), and viscera (65.5%). Median time from adenocarcinoma to t-NEPC diagnosis was 39.7 months (range, 24.5–93.8) with a median of two lines of prior systemic therapy. Platinum chemotherapy was used to treat 57.5% of patients, with a median progression-free survival of 3.9 months. Small-cell carcinoma was associated with worse overall survival (OS) than mixed histology (8.9 months from NEPC diagnosis versus 26.1 months, P < 0.001). Median OS of de novo NEPC was shorter than that of t-NEPC (16.8 months from prostate cancer diagnosis versus 53.5 months, P = 0.043). An average PSA rise per month of ≤0.7 ng/ml before t-NEPC; elevated lactate dehydrogenase levels, RB1 and TP53 loss and liver metastases were poor prognostic features. We describe the clinical features of a cohort of patients with NEPC. These characteristics may inform future diagnostic strategies. • Neuroendocrine prostate cancer (NEPC) may arise de novo or develop in the later stages of castration-resistant prostate cancer as a mechanism of resistance. • NEPC is associated with low PSA and frequent visceral metastases. • Small-cell carcinoma is associated with worse overall survival than mixed histology. • RB1 and TP53 loss in both de novo and treatment-related NEPC harbours poor outcome. [ABSTRACT FROM AUTHOR]

Background: Observational studies suggest that some patients meeting criteria for ARDS no longer fulfill the oxygenation criterion early in the course of their illness. This subphenotype of rapidly improving ARDS has not been well characterized. We attempted to assess the prevalence, characteristics, and outcomes of rapidly improving ARDS and to identify which variables are useful to predict it.Methods: A secondary analysis was performed of patient level data from six ARDS Network randomized controlled trials. We defined rapidly improving ARDS, contrasted with ARDS > 1 day, as extubation or a Pao2 to Fio2 ratio (Pao2:Fio2) > 300 on the first study day following enrollment.Results: The prevalence of rapidly improving ARDS was 10.5% (458 of 4,361 patients) and increased over time. Of the 1,909 patients enrolled in the three most recently published trials, 197 (10.3%) were extubated on the first study day, and 265 (13.9%) in total had rapidly improving ARDS. Patients with rapidly improving ARDS had lower baseline severity of illness and lower 60-day mortality (10.2% vs 26.3%; P < .0001) than ARDS > 1 day. Pao2:Fio2 at screening, change in Pao2:Fio2 from screening to enrollment, use of vasopressor agents, Fio2 at enrollment, and serum bilirubin levels were useful predictive variables.Conclusions: Rapidly improving ARDS, mostly defined by early extubation, is an increasingly prevalent and distinct subphenotype, associated with better outcomes than ARDS > 1 day. Enrollment of patients with rapidly improving ARDS may negatively affect the prognostic enrichment and contribute to the failure of therapeutic trials. [ABSTRACT FROM AUTHOR]

Bronchoscopy is an essential therapeutic modality in the treatment of pulmonary bleeding. Although numerous endoscopic treatments exist, topical ε-aminocaproic acid has not been described in the literature. This study documents the use of this novel treatment for pulmonary bleeding and compares it to available evidence for tranexamic acid, a similar anti-fibrinolytic agent. Case-series study. ICU and general inpatient floors of a tertiary medical center. Forty-six patients receiving endobronchial ε-aminocaproic acid for the treatment or prevention of pulmonary bleeding. Of the 46 patients included in the study, 41.6% and 13% presented with non-massive and massive hemoptysis, respectively. In patients with active pulmonary bleeding, endobronchial application of ε-aminocaproic acid and accompanying therapies resulted in cessation of bleeding in 94.7% of cases. A total of six patients received ε-aminocaproic acid monotherapy; in three patients with active bleeding, 100% achieved hemostasis after treatment. Of the 36 patients successfully treated for active pulmonary bleeding, 27.8% had recurrent bleeding within 30 days. Thirty-day adverse events were as follows: death (10 patients), deep vein thrombosis (2 patients), renal failure (2 patients), and stroke (2 patients). Endobronchial administration of ε-aminocaproic acid during bronchoscopy may be a safe and efficacious option in the treatment and prevention of pulmonary bleeding. Further studies are necessary to better define ε-aminocaproic acid's safety profile, optimal routes of administration, and comparative effectiveness to tranexamic acid. [ABSTRACT FROM AUTHOR]

Background: Code status discussions (CSDs) can be challenging for many clinicians. Barriers associated with them include lack of education, comfort level, and experience. Objective: To conduct an educational intervention to improve knowledge and communication approaches related to CSDs. Design: A cross-sectional multidisciplinary educational intervention was conducted over one year consisting of an interactive presentation, live role-play, and pre- and post-intervention tests to measure impact of the formal training. Evaluations and comments were also collected. Setting/Subjects: Attending physicians, nurses, residents, fellows, and physician assistants (PAs) at an urban community teaching hospital of 500 beds serving an ethnically diverse population. Measurements: Data from pre- and post-intervention tests evaluating knowledge and communication approach regarding CSDs were collected. Participants completed a qualitative evaluation of the program. Results: There were 165 participants: 29 attending physicians, 26 residents, 17 fellows, 18 PAs, and 75 nurses. All (100%) completed the pre-intervention test and 154 (93.3%) completed the post-intervention test. There was an overall improvement in scores, 43.8% pre-intervention to 75.6% post-intervention (p-values <0.005). Attending physicians and fellows had the highest pre-intervention scores, while nurses and PAs had the lowest. Most participants (97%) reported they learned new information and 91% stated they would change patient management. Conclusions: Our study found that a brief educational intervention with multipronged teaching tools improved knowledge concerning CSDs. Participants felt it provided new insights and would change their practice. This study contributes to the literature by examining CSD training across different disciplines, allowing for cross-group comparisons. Future studies should try to correlate educational interventions and clinician knowledge with clinical practice outcomes. [ABSTRACT FROM AUTHOR]

Background: There is a lack of mechanism-driven, clinically relevant biomarkers in chronic obstructive pulmonary disease (COPD). Mitochondrial dysfunction, a proposed disease mechanism in COPD, is associated with the release of mitochondrial DNA (mtDNA), but plasma cell-free mtDNA has not been previously examined prospectively for associations with clinical COPD measures.Methods: P-mtDNA, defined as copy number of mitochondrially-encoded NADH dehydrogenase-1 (MT-ND1) gene, was measured by real-time quantitative PCR in 700 plasma samples from participants enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Associations between p-mtDNA and clinical disease parameters were examined, adjusting for age, sex, smoking status, and for informative loss to follow-up.Results: P-mtDNA levels were higher in participants with mild or moderate COPD, compared to smokers without airflow obstruction, and to participants with severe COPD. Baseline increased p-mtDNA levels were associated with better CAT scores in female smokers without airflow obstruction and female participants with mild or moderate COPD on 1-year follow-up, but worse 6MWD in females with severe COPD. Higher p-mtDNA levels were associated with better 6MWD in male participants with severe COPD. These associations were no longer significant after adjusting for informative loss to follow-up.Conclusion: In this study, p-mtDNA levels associated with baseline COPD status but not future changes in clinical COPD measures after accounting for informative loss to follow-up. To better characterize mitochondrial dysfunction as a potential COPD endotype, these results should be confirmed and validated in future studies.Trial Registration:  ClinicalTrials.gov NCT01969344 (SPIROMICS). [ABSTRACT FROM AUTHOR]

Background: Speckle-type POZ protein (SPOP) mutation defines one of the dominant prostate cancer genomic subtypes, yet the impact of this mutation on clinical prognosis is unknown.Methods: We defined SPOP mutation status either by DNA sequencing or by transcriptional signature in a pooled retrospective multi-institutional cohort, the Decipher retrospective cohort, the Decipher Genomics Resource Information Database prospective cohort, and The Cancer Genome Atlas. Kaplan-Meier survival analysis and multivariable Cox models were used to assess the independent impact of SPOP mutation on survival, biochemical recurrence and time to metastasis. The Decipher retrospective cohort was also used to assess the impact of the addition of SPOP mutation status to a model predicting adverse pathology at prostatectomy which was then validated in the Decipher prospective cohort.Results: A fixed-effect model incorporating results from multivariable Cox regression including 5,811 subjects demonstrated that SPOP mutation was associated with a lower rate of adverse pathology at radical prostatectomy (odds ratios 0.57, 95% confidence interval 0.34-0.93), independent of preoperative prostate-specific antigen, age, and pathologic Gleason score. SPOP was not associated with biochemical recurrence, metastasis-free survival, or cancer-specific survival independent of pathologic information. The addition of SPOP status to prognostic models reclassified a large proportion of patients with the mutation (55%) into a favorable risk group when used to predict adverse pathology.Conclusion: While the clinical utility of delineating any single molecular alteration in prostate cancer remains unclear, these results illustrates the importance of genomic subtypes in prostate cancer behavior and potential role in prognostic tools. [ABSTRACT FROM AUTHOR]

Background: Acute respiratory distress syndrome (ARDS) is heterogeneous. As an indication of the heterogeneity of ARDS, there are patients whose syndrome improves rapidly (i.e., within 24 hours), others whose hypoxemia improves gradually and still others whose severe hypoxemia persists for several days. The latter group of patients with persistent severe ARDS poses challenges to clinicians. We attempted to assess the baseline characteristics and outcomes of persistent severe ARDS and to identify which variables are useful to predict it. Methods: A secondary analysis of patient-level data from the ALTA, EDEN and SAILS ARDSNet clinical trials was conducted. We defined persistent severe ARDS as a partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2:FiO2) of equal to or less than 100 mmHg on the second study day following enrollment. Regularized logistic regression with an L1 penalty [Least Absolute Shrinkage and Selection Operator (LASSO)] techniques were used to identify predictive variables of persistent severe ARDS. Results: Of the 1531 individuals with ARDS alive on the second study day after enrollment, 232 (15%) had persistent severe ARDS. Of the latter, 100 (43%) individuals had mild or moderate hypoxemia at baseline. Usage of vasopressors was greater [144/232 (62%) versus 623/1299 (48%); p<0.001] and baseline severity of illness was higher in patients with versus without persistent severe ARDS. Mortality at 60 days [95/232 (41%) versus 233/1299 (18%); p<0.001] was higher, and ventilator-free (p<0.001), intensive care unit-free [0 (0–14) versus 19 (7–23); p<0.001] and non-pulmonary organ failure-free [3 (0–21) versus 20 (1–26); p<0.001] days were fewer in patients with versus without persistent severe ARDS. PaO2:FiO2, FiO2, hepatic failure and positive end-expiratory pressure at enrollment were useful predictive variables. Conclusions: Patients with persistent severe ARDS have distinct baseline characteristics and poor prognosis. Identifying such patients at enrollment may be useful for the prognostic enrichment of trials. [ABSTRACT FROM AUTHOR]

Purpose: To validate prognostic factors and determine the impact of obesity, hypertension, smoking and diabetes mellitus (DM) on risk of recurrence after surgery in patients with localized renal cell carcinoma (RCC). Materials and methods: We performed a retrospective cohort study among patients that underwent partial or radical nephrectomy at Weill Cornell Medicine for RCC and collected preoperative information on RCC risk factors, as well as pathological data. Cases were reviewed for radiographic evidence of RCC recurrence. A Cox proportional-hazards model was developed to determine the contribution of RCC risk factors to recurrence risk. Disease-free survival and overall survival were analyzed using the Kaplan-Meier method and log-rank test. Results: We identified 873 patients who underwent surgery for RCC between the years 2000–2015. In total 115 patients (13.2%) experienced a disease recurrence after a median follow up of 4.9 years. In multivariate analysis, increasing pathological T-stage (HR 1.429, 95% CI 1.265–1.614) and Nuclear grade (HR 2.376, 95% CI 1.734–3.255) were independently associated with RCC recurrence. In patients with T1-2 tumors, DM was identified as an additional independent risk factor for RCC recurrence (HR 2.744, 95% CI 1.343–5.605). Patients with DM had a significantly shorter median disease-free survival (1.5 years versus 2.6 years, p = 0.004), as well as median overall survival (4.1 years, versus 5.8 years, p<0.001). Conclusions: We validated high pathological T-stage and nuclear grade as independent risk factors for RCC recurrence following nephrectomy. DM is associated with an increased risk of recurrence among patients with early stage disease. [ABSTRACT FROM AUTHOR]

Background: Intensive robot-assisted arm training in the chronic phase of stroke recovery can lead to clinical improvement. Combinatorial therapeutic approaches are sought to further optimize stroke recovery. Transcranial direct current stimulation (tDCS) is one candidate to combine with robotic training, as transient increases in excitability and improvements in motor behavior have separately been reported. Objective: To determine whether tDCS, delivered prior to robotic training, could augment clinical improvement. Methods: We conducted a dual-site, randomized controlled trial in 82 chronic ischemic stroke patients (inclusion > 6 m post-injury, dominant hemisphere, first stroke; residual hemiparesis) who were split into two groups to receive tDCS (M1-SO montage, anode ipsilesional, 5×7 cm electrodes, 2 mA, 20 mins) or sham tDCS, prior to robotic upper-limb training (12 weeks; 36 sessions; shoulder-elbow robot or wrist robot on alternating sessions). The primary end-point was taken after 12 weeks of training, and assessed with the Upper Extremity Fugl-Meyer impairment scale (FM). Corticomotor conduction was assessed with transcranial magnetic stimulation (TMS). Results: For the combined group (n = 82; post-training) robotic training increased the FM by 7.36 points compared to baseline (p < 0.0001). There was no difference in the FM increase between the tDCS and sham groups (6.97 and 7.73 respectively, p = 0.46). In both groups, clinically meaningful improvement (≥5 points) from baseline was evident in the majority of patients (56/77), was sustained six months later (54/72), and could be attained in severe, moderate and mild baseline hemiparesis. Clinical improvement was associated with increased excitability in the affected hemisphere as assessed by resting motor threshold (pre-post p = 0.029; pre-post 6 months p = 0.029), but not with threshold-adjusted assessment of MEP amplitude (pre-post p = 0.09; pre-post 6 months p = 0.15). Participants with motor evoked potentials were more likely to improve clinically than those without (17/18, 94%, versus 39/59, 66%, p = 0.018). Conclusions: Our study confirms the benefit of intensive robot-assisted training in stroke recovery, and indicates that conventional tDCS does not confer further advantage to robotic training. We also showed that corticospinal integrity, as assessed by TMS, is a predictor of clinically meaningful response to intensive arm therapy in chronic stroke. [ABSTRACT FROM AUTHOR]

Background: Positive pressure ventilation can decrease venous return and cardiac output. It is not known if expiratory ventilation assistance (EVA) through a small endotracheal tube can improve venous return and cardiac output.Results: In a porcine model, switching from conventional positive pressure ventilation to (EVA) with − 8 cmH20 expiratory pressure increased the venous return and cardiac output. The stroke volume increased by 27% when the subjects were switched from conventional ventilation to EVA [53.8 ± 7.7 (SD) vs. 68.1 ± 7.7 ml, p = 0.003]. After hemorrhage, subjects treated with EVA had higher median cardiac output, higher mean systemic arterial pressure, and lower central venous pressure at 40 and 60 min when compared with subjects treated with conventional ventilation with PEEP 0 cmH20. The median cardiac output was 41% higher in the EVA group than the control group at 60 min [2.70 vs. 1.59 L/min, p = 0.029].Conclusion: EVA through a small endotracheal tube increased venous return, cardiac output, and mean arterial pressure compared with conventional positive pressure ventilation. The effects were most significant during hypovolemia from hemorrhage. EVA provided less effective ventilation than conventional positive pressure ventilation. [ABSTRACT FROM AUTHOR]

Background: Studies have shown that prophylactic biologic therapy can reduce post-surgical Crohn's disease recurrence.Aims: We aimed to identify the frequency of delay and risk factors associated with a delay in the initiation of prophylactic post-surgical biologic therapy in high-risk patients.Methods: We performed a cohort study of Crohn's disease patients who underwent a bowel resection. We identified those at risk of recurrence and explored multiple characteristics for those with and without a delay post-operatively.Results: A total of 84 patients were included in our analysis of which 69.0% had a greater than 4-week delay and 56.0% a greater than 8-week delay in post-surgical biologic prophylaxis. Publicly insured patients had a 100% delay in post-surgical prophylaxis initiation (p = 0.039, p = 0.003 at 4 and 8 weeks, respectively). Patients on a biologic pre-surgery were less likely to have a delay (p < 0.001) in post-operative prophylaxis. Care at an inflammatory bowel disease (IBD) center was associated with timely therapy when considering a post-operative immunomodulator or biologic strategy.Conclusions: There are a substantial number of delays in initiating post-operative prophylactic biologic therapy in high-risk patients. Identifying susceptible patients by insurance type or absence of pre-operative therapy can focus future improvement efforts. Additionally, consultation with IBD-specialized providers should be considered in peri-surgical IBD care. [ABSTRACT FROM AUTHOR]

Objective: To assess changes in the practice patterns of urologists performing male infertility procedures (vasal reconstruction, sperm retrieval, varicocelectomy) from 2004 to 2015 in the United States.Design: Examination of self-reported procedural volumes from urologists undergoing certification and recertification using case log data provided by the American Board of Urology. The study period was stratified into early (2004-2007) and recent (2012-2015) time periods.Setting: Not applicable.Patient(s): None.Intervention(s): None.Main Outcomes Measure(s): Temporal variations in male infertility practice patterns among different urologic subspecialties between the early and recent time periods.Result(s): The overall proportion of total male infertility procedures performed by andrologists significantly increased between the early and recent groups (23% to 26%). This growth was driven by a significant increase in the proportion of varicocele repairs being performed by andrologists between the early and recent periods (19% to 25%). Most notably, an assessment of total number of male infertility procedures performed by newly certifying urologists showed that there was a significant increase in the overall proportion of all male infertility procedures being performed by recently trained andrologists (24% to 35%). This significant increase was seen individually among all three types of male infertility procedures.Conclusion(s): With the increased trend in urologists obtaining fellowship training, male infertility surgical volume is beginning to shift from general urologists to subspecialized andrologists. [ABSTRACT FROM AUTHOR]

Purpose The aim of the study was to compare prostate cancer–specific mortality (PCSM) in young men with clinically localized prostate cancer treated by either external beam radiation (EBRT) alone or brachytherapy with or without external beam radiation. Methods and Materials Utilizing the Surveillance, Epidemiology and End Results database, 15,505 patients ≤60 years of age diagnosed with prostate cancer between 2004 and 2009 and treated with radiation therapy alone were identified. Incidence of PCSM was determined for both groups and compared using competing risk models. Results The overall 8-year PCSM for the study population was 1.9% (95% confidence interval [CI]: 1.6–2.2). For patients treated with EBRT or brachytherapy with or without external beam, the 8-year PCSM was found to be 2.8% (CI: 2.2–3.4) and 1.2% (CI: 0.9–1.6), respectively ( p < 0.001). Univariable analysis demonstrated that brachytherapy was associated with lower PCSM risk (hazard ratio = 0.40; CI: 0.30–0.54; p < 0.001). High Gleason risk category, black race, higher Tumor (T) stage, and higher grade were all associated with greater mortality risk ( p < 0.01). On multivariable analysis, brachytherapy continued to be associated with a significantly lower mortality risk (hazard ratio = 0.65; CI: 0.47–0.89; p = 0.008). Subgroup analyses found that among those with Gleason score ≥8, younger patients had increased risk of PCSM ( p = 0.001). Conclusions In men ≤60 years of age with prostate cancer, radiation therapy continues to offer excellent outcomes. After adjusting for relevant variables, the use of brachytherapy was associated with reduced PCSM compared to treatment with EBRT alone. [ABSTRACT FROM AUTHOR]

B METHODS: b This retrospective cohort study utilized the Weill Cornell-Critical Care Database for Advanced Research (WC-CEDAR) to obtain routinely collected patient-level data on all adult patients at a tertiary academic medical center with a diagnosis of a hematologic malignancy (leukemia, lymphoma, myeloma, or myelodysplastic syndrome) who were admitted to an intensive care unit (ICU). Medical and cardiac ICU patients comprised 71% of the hematologic malignancy cohort; of these, 89% had sepsis or septic shock. B CONCLUSIONS: b In an evaluation of 2,119 patients with hematologic malignancies admitted to medical and surgical ICUs, underweight status was associated with increased in-hospital mortality compared to normal weight. [Extracted from the article]