L-serine treatment in patients with GRIN-related encephalopathy: a phase 2A, non-randomized study.

GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2-18 years with GRIN loss-of-function pathogenic variants received L-serine for 52 weeks. Primary end points included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3 months and 1 day before starting treatment and 1, 3, 6 and 12 months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity. L-serine normalized the EEG pattern in five children and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes.

Orbital manifestations of granulomatosis with polyangiitis: 12-year experience in Mexico City.

PURPOSE: To present the clinical picture and radiological characteristics of orbital manifestations of granulomatosis with polyangiitis in a Mexican hospital and compare them with worldwide literature. METHODS: Retrospective, observational study from January 2007 to January 2019. An electronic file review was performed. All patients with the diagnosis of granulomatosis with polyangiitis (GPA) in the Oculoplastics department were included. Ophthalmological examination, biopsy, antibodies and tomographical results were included in the data collected. Descriptive statistics were obtained. RESULTS: One hundred and one patients in our institute had a diagnosis of GPA. Only 15 (14.8%) had orbital manifestations and were included in our study. 73.3% were female with a median age of 46.20 years (17-81). Diagnostic delay was on average 6 months. Only 6.7% had bilateral manifestations. No past medical history was found in 40%, 20% had a previous diagnosis of systemic GPA. Pain was reported in 73.3%. Increase of volume (proptosis or diffuse orbital mass) was present in 86.7%. C-ANCA antibodies were positive in seven patients (46.7%). In tomography, lacrimal gland involvement was present in 33.3% and diffuse orbital mass was present in 66.6%. Definite diagnosis was done with biopsy in 93.3%. One patient died from complications of GPA. CONCLUSIONS: Ophthalmologists should consider this rare disease as a differential diagnosis of orbital tumors, as it may have different clinical manifestations, even in non-Caucasian population. When in doubt, biopsy is always valuable. The statistics at our reference center correspond with statistics reported worldwide.

Clinical Description, Molecular Analysis of TWIST2 Gene, and Surgical Treatment in a Patient With Barber-Say Syndrome.

Barber-Say syndrome is a rare autosomal dominant disease characterized by dysmorphic features, mainly of the eyelids and skin. It is caused by heterozygous mutations in gene TWIST2, localized in chromosome 2q37.3. The authors present the case of a pediatric patient with a clinical diagnosis of Barber-Say syndrome with ocular symptoms related to exposure keratitis. Molecular analysis of her DNA revealed a mutation on TWIST2 gene confirming the diagnosis of Barber-Say syndrome. Surgical treatment of the patient's eyelids resolved her signs and symptoms.

Orbital Emphysema as a Rare Complication of Retina Surgery.

Three patients with a history of previous pars-plana vitrectomy, 2 of them with perfluoropropane, and 1 with sulfur hexafluoride used, experienced eyelid swelling and pain after travelling to a higher altitude city. Gas was found in the orbit and periocular tissues, causing orbital compartment syndrome in 2 of the patients. The gas persisted on these patients despite surgical intervention, so hyperbaric oxygen therapy was advised. One patient refused, the other patient responded well to this therapy and the gas disappeared. The patient without an orbital compartment syndrome made a full recovery without needing medical or surgical intervention.

An update on the management of acute esophageal variceal bleeding.

The mortality rate in acute variceal haemorrhage remains high (around 15%). Treatment is based on the combined use of vasoactive drugs, endoscopic band ligation, and prophylactic antibiotics. Effective resuscitation (haemostasis, volume management) is essential to prevent complications. Treatment failure is best managed by transjugular intrahepatic portosystemic shunt (TIPS). Balloon tamponade or specifically designed covered oesophageal stents can be used as a bridge to definitive therapy in unstable patients. Early, pre-emptive TIPS should be the first choice in patients at high risk of treatment failure (Child-Pugh B with active bleeding or Child-Pugh C<14). This article reviews the most recent advances in the management of variceal bleeding and discusses the recent recommendations of the Baveno VI consensus conference.

Mortality following durable left ventricular assist device implantation by timing and type of first infection.

OBJECTIVE: Although infections are common after left ventricular assist device implantation, the relationship between timing and type of first infection with regard to mortality is less well understood. METHODS: The Society of Thoracic Surgeons Interagency Registry for Mechanically Assisted Circulatory Support patients receiving a primary left ventricular assist device from April 2012 to May 2017 were included. The primary exposure was defined 3 ways: any infection, timing of first infection (early: ≤90 days; intermediate: 91-180 days; late: >180 days), and type (ventricular assist device specific, ventricular assist device related, non-ventricular assist device). The association between first infection and all-cause mortality was estimated using Cox regression. RESULTS: The cohort included 12,957 patients at 166 centers (destination therapy: 47.4%, bridge-to-transplant: 41.2%). First infections were most often non-ventricular assist device (54.2%). Rates of first infection were highest in the early interval (10.7/100 person-months). Patients with any infection had a significantly higher adjusted hazard of death (hazard ratio, 2.63; 2.46-2.86). First infection in the intermediate interval was associated with the largest increase in adjusted hazard of death (hazard ratio, 3.26; 2.82-3.78), followed by late (hazard ratio, 3.13; 2.77-3.53) and early intervals (hazard ratio, 2.37; 2.16-2.60). Ventricular assist device-related infections were associated with the largest increase in hazard of death (hazard ratio, 3.02; 2.69-3.40), followed by ventricular assist device specific (hazard ratio, 2.92; 2.57-3.32) and non-ventricular assist device (hazard ratio, 2.42; 2.20-2.65). CONCLUSIONS: Relative to those without infection, patients with any postimplantation infection had an increased risk of death. Ventricular assist device-related infections and infections occurring in the intermediate interval were associated with the largest increase in risk of death. After left ventricular assist device implantation, infection prevention strategies should target non-ventricular assist device infections in the first 90 days, then shift to surveillance/prevention of driveline infections after 90 days.

Association of Days Alive and Out of the Hospital After Ventricular Assist Device Implantation With Adverse Events and Quality of Life.

Importance: There is a need to better assess the cumulative effect on morbidity and mortality in patients undergoing durable left ventricular assist device (LVAD) implantation. This study evaluates a patient-centered performance metric (days alive and out of hospital [DAOH]) for durable LVAD therapy. Objective: To determine the incidence of percent of DAOH before and after LVAD implantation and (2) explore its association with established quality metrics (death, adverse events [AEs], quality of life). Design, Settings, and Participants: This was a retrospective national cohort study of Medicare beneficiaries implanted with a durable continuous-flow LVAD between April 2012 and December 2016. The data were analyzed from December 2021 to May 2022. Follow-up was 100% complete at 1 year. Data from The Society of Thoracic Surgeons Intermacs registry were linked to Medicare claims. Main Outcomes and Measures: The number of DAOH 180 days before and 365 days after LVAD implantation and daily patient location (home, index hospital, nonindex hospital, skilled nursing facility, rehabilitation center, hospice) were calculated. Percent of DAOH was indexed to each beneficiary's pre- (percent DAOH-BF) and postimplantation (percentage of DAOH-AF) follow-up time. The cohort was stratified by terciles of percentage of DAOH-AF. Results: Among the 3387 patients included (median [IQR] age: 66.3 [57.9-70.9] years), 80.9% were male, 33.6% and 37.1% were Interfaces Patient Profile 2 and 3, respectively, and 61.1% received implants as destination therapy. Median (IQR) percent of DAOH-BF was 88.8% (82.7%-93.8%) and 84.6% (62.1-91.5%) for percent of DAOH-AF. While DAOH-BF was not associated with post-LVAD outcomes, patients in the low tercile of percentage of DAOH-AF had a longer index hospitalization stay (mean, 44 days; 95% CI, 16-77), were less likely to be discharged home (mean. -46.4 days; 95% CI, 44.2-49.1), and spent more time in a skilled nursing facility (mean, 27 days; 95% CI, 24-29), rehabilitation center (mean, 10 days; 95% CI, 8-12), or hospice (mean, 6 days; 95% CI, 4-8). Increasing percentage of DAOH-AF was associated with patient risk, AEs, and indices of HRQoL. Patients experiencing non-LVAD-related AEs had the lowest percentage of DAOH-AF. Conclusions and Relevance: Significant variability existed in the percentage of DAOH within a 1-year time horizon and was associated with the cumulative AEs burden. This patient-centered measure may assist clinicians in informing patients about expectations after durable LVAD implantation. Validation of percentage DAOH as a quality metric for LVAD therapy across centers should be explored.

Infections following left ventricular assist device implantation and 1-year health-related quality of life.

BACKGROUND: Left ventricular assist device (LVAD) implantation leads to substantial and sustained improvement in health-related quality of life (HRQOL) among patients. Infection following device implantation remains an important and frequent complication and adversely affects patient-reported HRQOL. METHODS: Patients in The Society of Thoracic Surgeons' Interagency Registry for Mechanically Assisted Circulatory Support receiving a primary LVAD between April 2012 to October 2016 were included. The primary exposure was one-year post-implant infection, characterized by: (1) any infection; (2) total number of infections and (3) type (LVAD-specific, LVAD-related, non-LVAD). The association between infection and the primary composite adverse outcome (defined as EuroQoL Visual Analog Scale< 65, too sick to complete the survey, or death at 1-year) was estimated using inverse probability weighting and Cox regression. RESULTS: The study cohort included 11,618 patients from 161 medical centers with 4,768 (41.0%) patients developing an infection, and 2,282 (19.6%) patients having> 1 infection during the follow up period. The adjusted odds ratio for the primary composite adverse outcome was 1.22 (95% CI, 1.19-1.24, p < 0.001) for each additional infection. Each additional infection was associated with a 3.49% greater probability of the primary composite outcome and was associated with worse performance across multiple dimensions of HRQOL as assessed by the EQ-5D for patients who survived to 1 year. CONCLUSIONS: For patients undergoing LVAD implantation, each additional infection within the first post-implantation year was associated with an incremental negative effect on survival free of impaired HRQOL.

In vivo expression of Helicobacter pylori virulence genes in patients with gastritis, ulcer, and gastric cancer.

The best-studied Helicobacter pylori virulence factor associated with development of peptic ulcer disease or gastric cancer (GC) rather than asymptomatic nonatrophic gastritis (NAG) is the cag pathogenicity island (cagPAI), which encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into host epithelial cells. Here we used real-time reverse transcription-PCR (RT-PCR) to measure the in vivo expression of genes on the cagPAI and of other virulence genes in patients with NAG, duodenal ulcer (DU), or GC. In vivo expression of H. pylori virulence genes was greater overall in gastric biopsy specimens of patients with GC than in those of patients with NAG or DU. However, since in vitro expression of cagA was not greater in H. pylori strains from patients with GC than in those from patients with NAG or DU, increased expression in GC in vivo is likely a result of environmental conditions in the gastric mucosa, though it may in turn cause more severe pathology. Increased expression of virulence genes in GC may represent a stress response to elevated pH or other environmental conditions in the stomach of patients with GC, which may be less hospitable to H. pylori colonization than the acidic environment in patients with NAG or DU.

Metformin targets ovarian cancer stem cells in vitro and in vivo.

PURPOSE: Studies in non-gynecologic tumors indicate that metformin inhibits growth of cancer stem cells (CSC). Diabetic patients with ovarian cancer who are taking metformin have better outcomes than those not taking metformin. The purpose of this study was to directly address the impact of metformin on ovarian CSC. METHODS: The impact of metformin on ovarian cancer cell line growth and viability was assessed with trypan blue staining. Aldehyde dehydrogenase (ALDH) expressing CSC were quantified using FACS®. Tumor sphere assays were performed to determine the impact of metformin on cell line and primary human ovarian tumor CSC growth in vitro. In vivo therapeutic efficacy and the anti-CSC effects of metformin were confirmed using both tumor cell lines and ALDH(+) CSC tumor xenografts. RESULTS: Metformin significantly restricted the growth of ovarian cancer cell lines in vitro. This effect was additive with cisplatin. FACS analysis confirmed that metformin reduced ALDH(+) ovarian CSC. Consistent with this, metformin also inhibited the formation of CSC tumor spheres from both cell lines and patient tumors. In vivo, metformin significantly increased the ability of cisplatin to restrict whole tumor cell line xenografts. In addition, metformin significantly restricted the growth of ALDH(+) CSC xenografts. This was associated with a decrease in ALDH(+) CSC, cellular proliferation, and angiogenesis. CONCLUSIONS: Metformin can restrict the growth and proliferation of ovarian cancer stem cells in vitro and in vivo. This was true in cell lines and in primary human CSC isolates. These results provide a rationale for using metformin to treat ovarian cancer patients.

Patient factors associated with left ventricular assist device infections: A scoping review.

Infections are widely prevalent in left ventricular assist device (LVAD) recipients and associated with adverse events including mortality and rehospitalizations. Current evidence examining factors associated with infections in this setting predominantly comprises single-center observational data. We performed a scoping review to systematically summarize all existing studies examining patient-related factors associated with infections after LVAD implantation. Studies published between 01/06 and 02/19 were identified through searching 5 bibliographic databases: PubMed, Scopus, EMBASE, CINAHL, and Web of Science Core Collection. Inclusion criteria required examination of patient-related factors associated with infections among recipients of contemporary implantable, continuous flow LVADs. Key study characteristics were extracted by four independent reviewers and current literature described narratively. All analyses took place between February 2019 and May 2021. A total of 31 studies met inclusion criteria. All included studies were observational, and most commonly focused on driveline infections (n = 17). Factors studied most commonly included body composition (n = 8), diabetes and other comorbidities (n = 8), and psychosocial/socio-economic factors (n = 6). Studies were frequently single-center with heterogeneity in definition of infectious outcomes as well as exposure variables. Patient race and sex did not correlate with infection risk. There was no consistent association noted between obesity, diabetes, or psychosocial/socio-economic factors and infections in LVAD recipients. Two studies reported a significant association between malnutrition and hypoalbuminemia and post implant infections. This review summarizes 31 studies that described patient-related factors associated with infection after LVAD implantation. Patient related comorbidities, especially body composition and diabetes, were most commonly evaluated, but were not consistently associated with infections after LVAD implantation.

Care fragmentation predicts 90-day durable ventricular assist device outcomes.

OBJECTIVES: To examine whether fragmentation of care is associated with worse in-hospital and 90-day outcomes following durable ventricular assist device (VAD) implant. STUDY DESIGN: Cohort study. METHODS: This study was conducted using Medicare claims linked to the Society of Thoracic Surgeons (STS) Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs) among patients undergoing VAD implant between July 2009 and April 2017. Medicare data were used to measure fragmentation of the multidisciplinary care delivery network for the treating hospital, based on providers' history of shared patients within the previous year. STS Intermacs data were used for risk adjustment and outcomes ascertainment. Hospitals were sorted into terciles based on the degree of network fragmentation, measured as the mean number of links separating providers in the network. Multivariable regression was used to associate network fragmentation with 90-day death or infection risk. RESULTS: The cohort included 5159 patients who underwent VAD implant, with 11.2% dying and 27.6% experiencing an infection within 90 days after implant. After adjustment, a 1-unit increase in network fragmentation was associated with an increase of 0.179 in the probability of in-hospital infection and an increase of 0.183 in the probability of 90-day infection (both P < .05). Similar results were observed in models of the numbers of in-hospital and 90-day infections. Network fragmentation was predictive of the probability of 90-day mortality, although this relationship was not significant after adjustment. CONCLUSIONS: Care delivery network fragmentation is associated with higher in-hospital and 90-day infection rates following durable VAD implant. These networks may serve as novel targets for enhancing outcomes for patients undergoing VAD implant.

Non-patient factors associated with infections in LVAD recipients: A scoping review.

BACKGROUND: Infections are the most common complication in recipients of durable left ventricular assist devices (LVAD) and are associated with increased morbidity, mortality, and expenditures. The existing literature examining factors associated with infection in LVAD recipients is limited and principally comprises single-center studies. This scoping review synthesizes all available evidence related to identifying modifiable, non-patient factors associated with infections among LVAD recipients. METHODS: Published studies were identified through searching 5 bibliographic databases: PubMed, Scopus, EMBASE, CINAHL, and Web of Science Core Collection. Inclusion criteria required examination of factors associated with infections among recipients of contemporary, implantable, continuous flow LVADs. Key study characteristics were extracted by 4 independent reviewers and current literature described narratively. The Systems Engineering Initiative for Patient Safety (SEIPS) model was used to develop a taxonomy for non-patient related factors (e.g., tasks, tools, technologies, organization, and environment) associated with infections following LVAD implantation. All analyses took place between February 2019 and May 2021. FINDINGS: A total of 43 studies met inclusion criteria. The majority of included studies were observational (n = 37), single-center (n = 29), from the U.S. (n = 38), and focused on driveline infections (n = 40). Among the 22 evaluated sub-domains of non-patient related factors, only two: increasing center experience and establishing a silicone-skin interface at the driveline exit site, were identified as consistently being associated with a lower risk of infection. CONCLUSION: This review identified 43 studies that described non-patient related factors associated with infection in LVAD recipients. Only two factors were consistently associated with lower infection risk in LVAD recipients: increasing experience and establishing a silicone-skin interface at driveline exit site. The large variability in reporting across multiple studied interventions limited the ability to discern their effectiveness.

Association Between Care Fragmentation and Total Spending After Durable Left Ventricular Device Implant: A Mediation Analysis of Health Care-Associated Infections Within a National Medicare-Society of Thoracic Surgeons Intermacs Linked Dataset.

BACKGROUND: Care fragmentation is associated with higher rates of infection after durable left ventricular assist device (LVAD) implant. Less is known about the relationship between care fragmentation and total spending, and whether this relationship is mediated by infections. METHODS: Total payments were captured from admission to 180 days post-discharge. Drawing on network theory, a measure of care fragmentation was developed based on the number of shared patients among providers (ie, anesthesiologists, cardiac surgeons, cardiologists, critical care specialists, nurse practitioners, physician assistants) caring for 4,987 Medicare beneficiaries undergoing LVAD implantation between July 2009 - April 2017. Care fragmentation was measured using average path length, which describes how efficiently information flows among network members; longer path length indicates greater fragmentation. Terciles based on the level of care fragmentation and multivariable regression were used to analyze the relationship between care fragmentation and LVAD payments and mediation analysis was used to evaluate the role of post-implant infections. RESULTS: The patient cohort was 81% male, 73% white, 11% Intermacs Profile 1 with mean (SD) age of 63.1 years (11.1). The mean (SD) level of care fragmentation in provider networks was 1.7 (0.2) and mean (SD) payment from admission to 180 days post-discharge was $246,905 ($109,872). Mean (SD) total payments at the lower, middle, and upper terciles of care fragmentation were $250,135 ($111,924), $243,288 ($109,376), and $247,290 ($108,241), respectively. In mediation analysis, the indirect effect of care fragmentation on total payments, through infections, was positive and statistically significant (ß=16032.5, p=0.008). CONCLUSIONS: Greater care fragmentation in the delivery of care surrounding durable LVAD implantation is associated with a higher incidence of infections, and consequently, higher payments for Medicare beneficiaries. Interventions to reduce care fragmentation may reduce the incidence of infections and in turn enhance the value of care for patients undergoing durable LVAD implantation.

Correction: Understanding and Addressing Variation in Health Care-Associated Infections After Durable Ventricular Assist Device Therapy: Protocol for a Mixed Methods Study.

[This corrects the article DOI: 10.2196/14701.].

Incompleteness of health-related quality of life assessments before left ventricular assist device implant: A novel quality metric.

BACKGROUND: Improved health-related quality of life (HRQOL) is an important outcome following durable left ventricular assist device (LVAD) implant. However, half of pre-implant HRQOL data are incomplete in The Society of Thoracic Surgeons' Intermacs registry. Pre-implant HRQOL incompleteness may reflect patient status or hospital resources to capture HRQOL data. We hypothesized that pre-implant HRQOL incompleteness predicts 90 day outcomes and serves as a novel quality metric. METHODS: Risk factors for pre-implant HRQOL (EQ-5D-5L visual analog scale; 12-item Kansas City Cardiomyopathy Questionnaire "KCCQ") incompleteness were examined by stepwise logistic modeling. Direct standardization method was used to calculate adjusted incompleteness rates using a mixed effects logistic model. Hospitals were dichotomized as low or high based on median adjusted incompleteness rates. Andersen-Gill models were used to associate pre-implant HRQOL adjusted incompleteness rate with adverse events within 90 day post-implant. RESULTS: The study cohort included 14,063 patients receiving a primary LVAD (4/2012-8/2017). HRQOL incompleteness at high-rate hospitals was more often due to administrative reasons (risk difference, EQ-5D: 10.1%; KCCQ-12: 11.6%) and less likely due to patient reasons (risk difference, EQ-5D: -8.9%; KCCQ-12: -11.4%). A 10% increase in the adjusted pre-implant EQ-5D incompleteness rate was significantly associated with higher risk of infection-related mortality (HR: 1.09), infection (HR: 1.05), and renal dysfunction (HR: 1.03). A 10% increase in the adjusted pre-implant KCCQ-12 incompleteness rate was significantly associated with higher risk of infection (HR: 1.04). CONCLUSIONS: Hospital adjusted pre-implant HRQOL incompleteness was predictive of 90-day post-implant outcomes and may serve as a novel quality metric.

Evaluating the Impact of Pneumonia Prevention Recommendations After Cardiac Surgery.

BACKGROUND: Pneumonia is the most prevalent healthcare-associated infection after coronary artery bypass grafting (CABG), but the relative effectiveness of strategies to reduce its incidence remains unclear. We evaluated the relationship between healthcare-associated infection recommendations and risk of pneumonia after CABG. METHODS: Pneumonia prevention practice recommendations were developed based on literature review and analysis of semistructured interviews with key health care personnel across centers with low (<5.9%), medium (5.9%-6.1%), and high (>6.1%) rates of pneumonia. These practices were implemented among 2482 patients undergoing CABG from 2016 to 2017 across 18 centers. The independent effect of each practice in reducing pneumonia was assessed using multivariable logistic regression, adjusting for baseline risk and center. A composite (bundle) score was calculated as the number of practices (0 to 4) each patient received. RESULTS: Recommended pneumonia prevention practices included lung protective ventilation management, early extubation, progressive ambulation, and avoidance of postoperative bronchodilator therapy. Pneumonia occurred in 2.4% of patients. Lung protective ventilation (adjusted odds ratio [ORadj], 0.45; 95% confidence interval [CI], 0.22-0.92), ambulation (ORadj, 0.08; 95% CI, 0.04-0.17), and postoperative ventilation of less than 6 hours (ORadj, 0.47; 95% CI, 0.26-0.87) were significantly associated with lower odds of pneumonia. Postoperative bronchodilator therapy (ORadj, 4.83; 95% CI, 2.20-10.7) was significantly associated with higher odds. Risk-adjusted rates of pneumonia, operative mortality, and intensive care unit length of stay were lower in patients with higher bundle scores (all P-trend < .01). CONCLUSIONS: These pneumonia prevention recommendations may serve as effective targets for avoiding postoperative healthcare-associated infections.

Authorship Correction: Understanding and Addressing Variation in Health Care-Associated Infections After Durable Ventricular Assist Device Therapy: Protocol for a Mixed Methods Study.

[This corrects the article DOI: 10.2196/14701.].

Understanding and Addressing Variation in Health Care-Associated Infections After Durable Ventricular Assist Device Therapy: Protocol for a Mixed Methods Study.

BACKGROUND: Durable ventricular assist device (VAD) therapy is reserved for patients with advanced heart failure who have a poor estimated 1-year survival. However, despite highly protocolized management processes, patients are at a unique risk for developing a health care-associated infection (HAI). Few studies have examined optimal strategies for HAI prevention after durable VAD implantation, despite variability in rates across centers and their impact on short- and long-term outcomes. OBJECTIVE: The objective of this study is to develop recommendations for preventing the most significant HAIs after durable VAD implantation. The study has 3 specific aims: (1) identify determinants of center-level variability in HAI rates, (2) develop comprehensive understanding of barriers and facilitators for achieving low center-level HAI rates, and (3) develop and disseminate a best practices toolkit for preventing HAIs that accommodates various center contexts. METHODS: This is a sequential mixed methods study starting with a cross-sectional assessment of current practices. To address aim 1, we will conduct (1) a systematic review of HAI prevention studies and (2) in-depth quantitative analyses using administrative claims, in-depth clinical data, and organizational surveys of VAD centers. For aim 2, we will apply a mixed methods patient tracer assessment framework to conduct semistructured interviews, field observations, and document analysis informed by findings from aim 1 at 5 high-performing (ie, low HAIs) and 5 low-performing (ie, high HAI) centers, which will be examined using a mixed methods case series analysis. For aim 3, we will build upon the findings from the previous aims to develop and field test an HAI preventive toolkit, acquire stakeholder input at an annual cardiac surgical conference, disseminate the final version to VAD centers nationwide, and conduct follow-up surveys to assess the toolkit's adoption. RESULTS: The project was funded by the Agency for Healthcare Research and Quality in 2018 and enrollment for the overall project is ongoing. Data analysis is currently under way and the first results are expected to be submitted for publication in 2019. CONCLUSIONS: This mixed methods study seeks to quantitatively assess the determinants of HAIs across clinical centers and qualitatively identify the context-specific facilitators and barriers for attaining low HAI rates. The mixed data findings will be used to develop and disseminate a stakeholder-acceptable toolkit of evidence-based HAI prevention recommendations that will accommodate the specific contexts and needs of VAD centers. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/14701.

Phase II clinical trial of metformin as a cancer stem cell-targeting agent in ovarian cancer.

BACKGROUNDEpidemiologic studies suggest that metformin has antitumor effects. Laboratory studies indicate metformin impacts cancer stem-like cells (CSCs). As part of a phase II trial, we evaluated the impact of metformin on CSC number and on carcinoma-associated mesenchymal stem cells (CA-MSCs) and clinical outcomes in nondiabetic patients with advanced-stage epithelial ovarian cancer (EOC).METHODSThirty-eight patients with stage IIC (n = 1)/III (n = 25)/IV (n = 12) EOC were treated with either (a) neoadjuvant metformin, debulking surgery, and adjuvant chemotherapy plus metformin or (b) neoadjuvant chemotherapy and metformin, interval debulking surgery, and adjuvant chemotherapy plus metformin. Metformin-treated tumors, compared with historical controls, were evaluated for CSC number and chemotherapy response. Primary endpoints were (a) a 2-fold or greater reduction in aldehyde dehydrogenase-positive (ALDH+) CD133+ CSCs and (b) a relapse-free survival at 18 months of more than 50%.RESULTSMetformin was well tolerated. Median progression-free survival was 18.0 months (95% CI 14.0-21.6) with relapse-free survival at 18 months of 59.3% (95% CI 38.6-70.5). Median overall survival was 57.9 months (95% CI 28.0-not estimable). Tumors treated with metformin had a 2.4-fold decrease in ALDH+CD133+ CSCs and increased sensitivity to cisplatin ex vivo. Furthermore, metformin altered the methylation signature in CA-MSCs, which prevented CA-MSC-driven chemoresistance in vitro.CONCLUSIONTranslational studies confirm an impact of metformin on EOC CSCs and suggest epigenetic change in the tumor stroma may drive the platinum sensitivity ex vivo. Consistent with this, metformin therapy was associated with better-than-expected overall survival, supporting the use of metformin in phase III studies.TRIAL REGISTRATIONClinicalTrials.gov NCT01579812.