Bringing templates to life: overcoming obstacles to the organizational implementation of Agile methods

Agile software development methods have become accepted as a template for organizations to create new products. Though generally viewed as an aid to productivity, there are a number of barriers to experiencing their full benefit. One such barrier pertains to the implementation of agile methods across the range of organizational levels from the use of tools to culture, norms, and policies creating the context within which projects are performed. This essay examines in detail the experiences of one expert at integrating agile technique, approach, and philosophy into the broader organizational setting. Numerous particular lessons and prescriptions result from this discussion. Turning around the grounded theory approach where numerous individuals are interrogated mildly in regard to a particular phenomenon, the discussion surfaced in this paper results from repeated interviews with one domain expert. Lessons and comments are organized into four sections: individual team member, organization, transitioning, and tools and techniques

Adjunctive Nebulized Antibiotics: What Is Their Place in ICU Infections?

Inhaled antibiotics have been used as adjunctive therapy for patients with pneumonia, primarily caused by multidrug resistant (MDR) pathogens. Most studies have been in ventilated patients, although non-ventilated patients have also been included (but not discussed in this review), and most patients have had nosocomial pneumonia. Aerosolized antibiotics are generally added to systemic therapy, and have shown efficacy, primarily as salvage therapy for failing patients and as adjunctive therapy after an MDR gram-negative has been identified. An advantage to aerosolized antibiotics is that they can achieve high intra-pulmonary concentrations that are potentially effective, even for highly resistant pathogens, and because they are generally not well-absorbed systemically, it is possible to avoid some of the toxicities of systemic therapy. When using inhaled antibiotics, it is essential to choose the appropriate agent and the optimal delivery method. Animal and human studies have shown that aerosolized antibiotics reach higher concentrations in the lung than systemic antibiotics, but that areas of dense pneumonia may not receive as much antibiotic as less affected areas of lung. Optimal delivery in ventilated patients depends on device selection, generally with a preference for vibrating mesh nebulizers and with careful attention to where the device is placed in the ventilator circuit and how the delivery is coordinated with the ventilator cycle. Although some studies have shown a benefit for clinical cure, adjunctive therapy has not led to reduced mortality. In some studies, adjunctive aerosol therapy has reduced the duration of systemic antibiotic therapy, thus serving to promote antimicrobial stewardship. Two recent multicenter, randomized, double-blinded, placebo-controlled trials of adjunctive nebulized antibiotics for VAP patients with suspected MDR gram-negative pneumonia were negative for their primary endpoints. This may have been related to trial design and execution and the lessons learned from these studies need to be incorporated in any future trials. Currently, routine use of adjunctive aerosolized therapy cannot be supported by available data, and this therapy is only recommended to assist in the eradication of highly resistant pathogens and to be used as salvage therapy for patients failing systemic therapy

International Respiratory Infections Society COVID Research Conversations: Podcast 2 with Dr. Michael S. Niederman and Dr. Edward J. Schenck

Section(s) Topics 1–4 Introductions 5 COVID-19 in New York City 6–7 Telemedicine, long-term sequelae 8 Development of a multi-disciplinary ICU team 9–10 Treatment of ARDS, COVID-19 pathogenesis 11–12 Prioritizing treatment at research 13 Challenges in tracing the natural history of severe COVID-19 14–15 Experience with mechanically ventilated patients; non-pulmonary organ failure 16–17 Mapping COVID-19 trajectories by SOFA score 18–20 Findings: additive organ dysfunction, improving vs. worsening trajectory 21 ARDS therapeutic approaches 22 Clinical trials involving Cornell 23–25 Lessons learned: patient care, research, education, caring for critical care workers 26–30 2021 predictions: improved therapies and research, endemic COVID-19, vaccines 31–33 Prioritizing research projects at Cornell 34–38 Explanations for caseload reduction 39–43 Thanks and sign-of

Effect of Corticosteroids on C-Reactive Protein in Patients with Severe Community-Acquired Pneumonia and High Inflammatory Response: The Effect of Lymphopenia

Background: Lymphopenic patients with community-acquired pneumonia (CAP) have shown high mortality rates. Corticosteroids have immunomodulatory properties and regulate cytokine storm in CAP. However, it is not known whether their modulatory effect on cytokine secretion differs in lymphopenic and non-lymphopenic patients with CAP. Therefore, we aimed to test whether the presence of lymphopenia may modify the response to corticosteroids (mainly in C reactive protein (CRP)) in patients with severe CAP and high inflammatory status). Methods: A post hoc analysis of a randomized controlled trial (NCT00908713) which evaluated the effect of corticosteroids in patients with severe CAP and high inflammatory response (CRP > 15 mg/dL). Patients were clustered according to the presence of lymphopenia (lymphocyte count below 1000 cell/mm3 ). Results: At day 1, 35 patients (59%) in the placebo group presented with lymphopenia, compared to 44 patients (73%) in the corticosteroid group. The adjusted mean changes from day 1 showed an increase of 1.19 natural logarithm (ln) cell/mm3 in the corticosteroid group and an increase of 0.67 ln cell/mm3 in the placebo group (LS mean difference of the changes in ln (methylprednisolone minus placebo) 0.51, 95% CI (0.02 to 1.01), p = 0.043). A significant effect was also found for the interaction (p = 0.043) between corticosteroids and lymphopenia in CRP values at day 3, with lower values in patients without lymphopenia receiving corticosteroids after adjustments for potential confounders. Conclusion: In this exploratory post hoc analysis from ramdomized controlled trial (RCT) data, the response to corticosteroids, measured by CRP, may differ according to lymphocyte count. Further larger studies are needed to confirm this data

Community-Acquired Pneumonia Due to Multidrug- and Non–Multidrug-Resistant Pseudomonas aeruginosa

Background: Pseudomonas aeruginosa is not a frequent pathogen in community-acquired pneumonia (CAP). However, in patients with severe CAP, P aeruginosa can be the etiology in 1.8% to 8.3% of patients, with a case-fatality rate of 50% to 100%. We describe the prevalence, clinical characteristics, outcomes, and risk factors associated with CAP resulting from multidrug-resistant (MDR) and non-MDR P aeruginosa. Methods: Prospective observational study of 2,023 consecutive adult patients with CAP with definitive etiology. Results: P aeruginosa was found in 77 (4%) of the 2,023 cases with microbial etiology. In 22 (32%) of the 68 cases of P aeruginosa with antibiogram data, the isolates were MDR. Inappropriate therapy was present in 49 (64%) cases of P aeruginosa CAP, including 17/22 (77%) cases of MDR P aeruginosa CAP. Male sex, chronic respiratory disease, C-reactive protein <12.35 mg/dL, and pneumonia severity index risk class IV to V were independently associated with P aeruginosa CAP. Prior antibiotic treatment was more frequent in MDR P aeruginosa CAP compared with non-MDR P aeruginosa (58% vs 29%, P = .029), and was the only risk factor associated with CAP resulting from MDR P aeruginosa. In the multivariate analysis, age ≥65 years, CAP resulting from P aeruginosa, chronic liver disease, neurologic disease, nursing home, criteria of ARDS, acute renal failure, ICU admission, and inappropriate empiric treatment were the factors associated with 30-day mortality. Conclusions: P aeruginosa is an individual risk factor associated with mortality in CAP. The risk factors described can help clinicians to suspect P aeruginosa and MDR P aeruginosa

Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in nursing home residents: double blind, randomised and placebo controlled trial

Objective To determine the efficacy of a 23-valent pneumococcal polysaccharide vaccine in people at high risk of pneumococcal pneumonia

Treatment with macrolides and glucocorticosteroids in severe community-acquired pneumonia: A post-hoc exploratory analysis of a randomized controlled trial

Background: Systemic corticosteroids have anti-inflammatory effects, whereas macrolides also have immunomodulatory activity in addition to their primary antimicrobial actions. We aimed to evaluate the potential interaction effect between corticosteroids and macrolides on the systemic inflammatory response in patients with severe community-acquired pneumonia to determine if combining these two immunomodulating agents was harmful, or possibly beneficial. Methods: We performed a post-hoc exploratory analysis of a randomized clinical trial conducted in three tertiary hospitals in Spain. This trial included patients with severe community-acquired pneumonia with high inflammatory response (C-reactive protein [CRP] >15 mg/dL) who were randomized to receive methylprednisolone 0.5 mg/kg/tpd or placebo. The choice of antibiotic treatment was at the physician's discretion. One hundred and six patients were classified into four groups according to antimicrobial therapy combination (β-lactam plus macrolide or β-lactam plus fluoroquinolone) and corticosteroid arm (placebo or corticosteroids). The primary outcome was treatment failure (composite outcome of early treatment failure, or of late treatment failure, or of both early and late treatment failure). Results: The methylprednisolone with β-lactam plus macrolide group had more elderly patients, with comorbidities, and higher pneumonia severity index (PSI) risk class V, but a lower proportion of intensive care unit admission, compared to the other groups. We found non differences in treatment failure between groups (overall p = 0.374); however, a significant difference in late treatment failure was observed (4 patients in the placebo with β-lactam plus macrolide group (31%) vs. 9 patients in the placebo with β-lactam plus fluoroquinolone group (24%) vs. 0 patients in the methylprednisolone with β-lactam plus macrolide group (0%) vs. 2 patients [5%] in the methylprednisolone with β-lactam plus fluoroquinolone group overall p = 0.009). We found a significant difference for In-hospital mortality in the per protocol population (overall p = 0.01). We did not find significant differences in treatment failure, early or late; or In-hospital mortality after adjusting for severity (PSI), year and centre of enrolment. Conclusions: In this exploratory analysis, we observed that the glucocorticosteroids and macrolides combination had no statistically significant association with main clinical outcomes compared with other combinations in patients with severe community acquired pneumonia and a high inflammatory response after taking account potential confounders

Effect of combined β-Lactam/Macrolide therapy on mortality according to the microbial etiology and inflammatory status of patients with community-acquired pneumonia

Antibiotic combinations that include macrolides have shown lower mortality rates than β-lactams in monotherapy or combined with fluoroquinolones in patients with community-acquired pneumonia (CAP). However, this effect has not been studied according to the levels of C-reactive protein in CAP with identified microbial cause. In patients with CAP and known microbial cause we aimed to evaluate 30-day mortality of a β-lactam plus macrolide (BL + M) compared with a fluoroquinolone alone or with a β-lactam (FQ ± BL). METHODS: We analyzed a prospective observational cohort of patients with CAP admitted to the Hospital Clinic of Barcelona between 1996 and 2016. We included only patients with known microbial cause. RESULTS: Of 1,715 patients (29%) with known etiology, a total of 932 patients (54%) received BL + M. Despite lower crude mortality in the BL + M group in the overall population (BL + M, 5% vs FQ ± BL, 8%; P = .015), after adjustment by a propensity score and baseline characteristics, the combination of BL + M had a protective effect on mortality only in patients with high inflammatory response (C-reactive protein, > 15 mg/dL) and pneumococcal CAP (adjusted OR, 0.28; 95% CI, 0.09-0.93). No benefits on mortality were observed for the population without high inflammatory response and pneumococcal CAP or with other etiologies. CONCLUSIONS: The combination of a β-lactam with a macrolide was associated with decreased mortality in patients with pneumococcal CAP and in patients with high systemic inflammatory response. When both factors occurred together, BL + M was protective for mortality in the multivariate analysis

The Dynamics of EBV Shedding Implicate a Central Role for Epithelial Cells in Amplifying Viral Output

To develop more detailed models of EBV persistence we have studied the dynamics of virus shedding in healthy carriers. We demonstrate that EBV shedding into saliva is continuous and rapid such that the virus level is replaced in ≤2 minutes, the average time that a normal individual swallows. Thus, the mouth is not a reservoir of virus but a conduit through which a continuous flow stream of virus passes in saliva. Consequently, virus is being shed at a much higher rate than previously thought, a level too high to be accounted for by replication in B cells in Waldeyer's ring alone. Virus shedding is relatively stable over short periods (hours-days) but varies through 3.5 to 5.5 logs over longer periods, a degree of variation that also cannot be accounted for solely by replication in B cells. This variation means, contrary to what is generally believed, that the definition of high and low shedder is not so much a function of variation between individuals but within individuals over time. The dynamics of shedding describe a process governing virus production that is occurring independently ≤3 times at any moment. This process grows exponentially and is then randomly terminated. We propose that these dynamics are best explained by a model where single B cells sporadically release virus that infects anywhere from 1 to 5 epithelial cells. This infection spreads at a constant exponential rate and is terminated randomly, resulting in infected plaques of epithelial cells ranging in size from 1 to 105 cells. At any one time there are a very small number (≤3) of plaques. We suggest that the final size of these plaques is a function of the rate of infectious spread within the lymphoepithelium which may be governed by the structural complexity of the tissue but is ultimately limited by the immune response