bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased Use of Noninvasive Ventilation Associated With Decreased Use of Invasive Devices in Children With Bronchiolitis
Authors: Soshnick Sara H. , Carroll Christopher L. , Cowl Allison S.
Published: August 2019

Objective:

To assess how a change in practice to more frequent use of high-flow nasal cannula for the treatment of bronchiolitis would affect the use of invasive devices in children.

Design:

Retrospective cohort study of children under 2 years old admitted to the ICU with respiratory failure secondary to bronchiolitis. Outcomes and invasive device use were compared between two time periods, before and after the practice change.

Setting:

Eighteen bed tertiary care PICU.

Patients:

A total of 325 children: 146 from 2010 to 2012 and 179 from 2015 to 2016.

Interventions:

None.

Measurements and Main Results:

There were no significant differences between the two time periods regarding gender, race/ethnicity, medical history, and viral profile, although children were younger in the earlier cohort (median age of 1.9 mo [interquartile range, 1.2–3.5] vs 3.3 mo [1.7–8.6]; p < 0.001). There was an increased use of noninvasive ventilation in the second time period (94% from 69%; p < 0.001), as well as a decreased frequency of intubation (13% from 42%; p < 0.001) and reduced central venous catheter placement (7% from 37%; p < 0.001). There was no significant difference in mortality between the two groups. A logistic regression analysis was conducted, which found that time period, intubation, and hospital length of stay were all independently associated with central venous catheter placement.

Conclusions:

A practice change toward managing patients with bronchiolitis in respiratory failure with less invasive means was associated with a reduction in the use of other invasive devices. In our cohort, minimizing the use of invasive ventilation and devices was not associated with an increase in mortality and could potentially have additional benefits.
Detecting Delirium Using a Physiologic Monitor
Authors: Mulkey Malissa A. , Everhart Daniel Erik , Kim Sunghan , Olson DaiWai M. , Hardin Sonya R.
Published: August 2019

For the past 2500 years, delirium has been described based on the presence of behavioral symptoms. Each year, as many as 1 in 5 acute care and 80% of critically ill patients develop delirium. The United States spends approximately $164 million annually to combat the associated consequences of delirium. There are no laboratory tools available to assist with diagnosis and ongoing monitoring of delirium; therefore, current national guidelines for psychiatry, geriatrics, and critical care strongly recommend routine bedside screening. Despite the significance, health care teams fail to accurately identify approximately 80% of delirium episodes.

The utility of conventional electroencephalogram (EEG) in the diagnosis and monitoring of delirium has been well established. Neurochemical and the associated neuroelectrical changes occur in response to overwhelming stress before behavioral symptoms; therefore, using EEG will improve early delirium identification. Adding EEG analysis to the current routine clinical assessment significantly increases the accuracy of detection. Using newer EEG technology with a limited number of leads that is capable of processing EEG may provide a viable option by reducing the cost and need for expert interpretation. Because EEG monitoring with automatic processing has become technically feasible, it could increase delirium recognition. Electroencephalogram monitoring may also provide identification before symptom onset when nursing interventions would be more effective, likely reducing the long-term ramifications. Having an objective method that nurses can easily use to detect delirium could change the standard of care and provide earlier identification.
Implementing a Weaning Protocol for Cardiac Surgery Patients Using Simulation
Authors: Tierney Catherine C. , Oermann Marilyn H. , Molloy Margory A. , Brien Lori , Neisler Cherith
Published: August 2019

Background

Mechanical ventilation is the standard of care after cardiac surgery, but it imposes physiologic and psychological stress on patients. The Society of Thoracic Surgery recommends 6 hours as the goal for extubation, but 60% of our patients were not meeting this metric.

Objectives

The objectives of this project were to decrease cardiac surgery patients' ventilation hours and intensive care unit length of stay using a ventilator weaning protocol.

Methods

An evidence-based ventilator weaning protocol was developed, and nurses were prepared for its implementation using a simulation education program.

Results

Ventilator hours were reduced from 7.74 to 6.27 (t = 2.5, P = .012). The percentage of patients extubated in 6 hours increased from 40% to 63.5% (χ2 = 7.757, P = .005). There was no statistically significant decrease in cardiovascular intensive care unit length of stay (17.15 to 15.99, t = 0.619, P = .537). Nurses' scores on a knowledge test increased significantly from pre (6.11) to post (7.79) (t = −5.04, P < .001). Their perception of confidence increased in weaning from pre (median, 4; IQR, 4,4) to post (median, 4; interquartile range [IQR], 4,5), z = −2.71, P = .007, and also in using the protocol from pre (median, 4; IQR, 3,4) to post (median, 4; IQR, 4,5) (z = −3.17, P = .002).

Discussion

Using a nurse-led ventilator weaning protocol resulted in decreased ventilator hours for patients and increased knowledge and confidence for nurses.
Cerebrospinal fluid biomarkers of inflammation in trigeminal neuralgia patients operated with microvascular decompression
Authors: Ericson Hans , Abu Hamdeh Sami , Freyhult Eva , Stiger Fredrik , Bäckryd Emmanuel , Svenningsson Anders , Gordh Torsten , Kultima Kim
Published: August 2019

Compression of the trigeminal root entry zone by a blood vessel can cause trigeminal neuralgia (TN). However, a neurovascular conflict does not explain all cases of TN, and TN can exist without a neurovascular contact. A common observation during microvascular decompression surgery to treat TN is arachnoiditis in the region of the trigeminal nerve. Thus, aberrant inflammatory mechanisms may be involved in the pathophysiology of TN but information about the role of inflammation in TN is scarce. We used Proximity Extension Assay technology to analyse the levels of 92 protein biomarkers related to inflammation in lumbar cerebrospinal fluid from patients with TN (n = 27) before and after microvascular decompression compared to individuals without TN. We aimed to analyse the pattern of inflammation-related proteins in order to improve our understanding of the pathophysiology of TN. The main finding was that immunological protein levels in the cerebrospinal fluid from patients with TN decreased after surgery towards levels observed in healthy controls. Two proteins seemed to be of specific interest for TN: TRAIL and TNF-β. Thus, inflammatory activity might be one important mechanism in TN.
Housing Instability, Depression, and HIV Viral Load Among Young Black Gay, Bisexual, and Other Men Who Have Sex With Men in Atlanta, Georgia
Authors: Solomon Hiwote , Linton Sabriya L. , del Rio Carlos , Hussen Sophia A.
Published: August 2019

Housing instability is common among sexual minority youth. Research suggests that psychological distress, such as depression, may mediate the association between housing instability and poor HIV-related outcomes, but this hypothesis remains underexplored. Housing instability was assessed using two variables (residential moves in 6 months, and self-reported homelessness at any time since age 15 years). We examined cross-sectional relationships between the housing instability variables and detectable HIV-1 viral load (VL) in a sample of young Black gay, bisexual, and other men who have sex with men (YB-GBMSM) living with HIV (N = 81) in Atlanta, GA, in 2015–2016. Additionally, we explored whether depressive symptoms mediated this relationship. Our exploratory study suggests that psychological distress may partially mediate the association between housing instability and detectable VL. In addition to structural interventions that ensure housing stability, increasing use of mental health services by unstably housed YB-GBMSM may improve VL suppression in this high-risk population.
International perspectives on the pediatric nurse practitioner role
Authors: Würtz Gitte M. F. , Jensen Claus Sixtus , Egerod Ingrid
Published: August 2019

Introduction:

Advanced pediatric nurse practitioners (APNPs) working in acute settings are represented in pediatric hospitals, clinics, and wards around the world. They work independently and autonomously. The aim of this study was to compare the role of APNPs in four different countries to gain knowledge on the qualifications and experience of the practitioners and their impact on pediatric patients and families.

Method:

A qualitative design with semistructured keyinformant interviews with four nurses from Sweden, Norway, England, and the United States was conducted. Analyses were performed using thematic analysis.

Results:

Three themes were identified: 1) Qualification and Competencies, illustrated parallels within the four educations and daily practice. 2) Responsibility and Autonomy, highlighted differences. The informants experienced a mutual understanding of the concepts of advanced practice. Interprofessional collaboration with aphysician was crucial to ensure best practice. 3) Holistic Nurse Perspective highlighted the importance of APNPs having competencies to make holistic and family-centered decisions at a higher level.

Conclusion:

From the perspective of four APNPs, advanced pediatric nursing practice is beneficial to the patient, family, and professionals. The formal education varies in the countries studied, but the basic tenets of practice are the same. Family-centered practice and holism are basic to the APNP role.
Improving patient access through office hysteroscopy clinic redesign
Authors: Wygant Jenna N. , Laughlin-Tommaso Shannon K. , Green Isabel C. , Price Kelly R. , Burnett Tatnai L. , Hopkins Matthew R. , Famuyide Amimbola O. , Breitkopf Daniel M.
Published: August 2019

Background and objective:

Patients with abnormal uterine bleeding (AUB) often require hysteroscopy as part of the diagnostic workup. The purpose of this study was to improve efficiency by shortening the time to patient appointment for office hysteroscopy.

Interventions:

Preintervention, nurse practitioners (NPs) and gynecologists saw patients with abnormal uterine bleeding (AUB) separately. This created inefficiency for the patients, frequently requiring second visits for hysteroscopy. A new hysteroscopy clinic was designed to increase practice efficiency. A collaborative team model was created including consecutive visits with NPs and gynecologists. Each patient with AUB was first evaluated by an NP, followed immediately by a shorter visit with a gynecologist for office hysteroscopy as indicated. NPs managed other diagnostic evaluation and bleeding treatment if hysteroscopy was not warranted. Collaborative clinic staffing consisted of two NPs seeing patients with AUB paired with one gynecologist for procedural support.

Measurements and results:

Electronic records of 393 patients scheduled for AUB visits from January to June 2015 were evaluated for preintervention data. Postintervention, 647 patient records were reviewed from January to June of 2016. During the preintervention period, 30% of patients had a hysteroscopy appointment scheduled within 0–13 days from the initial visit for AUB. Postintervention, the wait time for appointments decreased, with 63% of patients scheduled within 0–13 days. Clinic redesign also resulted in an increase of 57.5% in appointment slots. No-show rates and appointment fill rates were not adversely affected.

Conclusions:

A collaborative team-based care model using NPs and gynecologists improved efficiency and access to office hysteroscopy services.
Optimizing therapy of bloodstream infection due to extended-spectrum β-lactamase-producing Enterobacteriaceae
Authors: Gudiol Carlota , Cuervo Guillermo , Carratalà Jordi
Published: August 2019

Purpose of review

Infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) are increasing worldwide. Carbapenems are usually regarded as the antibiotics of choice for the treatment of serious ESBL infections. However, because of the alarming emergence or carbapenem resistance, interest in effective alternatives has emerged. The present review summarizes the findings published on the antibiotics currently available for treatment of patients with an ESBL-E bloodstream infection (BSI).

Recent findings

Meropenem and imipenem are the drugs recommended for treatment of ESBL BSIs in critically ill patients, and in infections with high bacterial loads or elevated β-lactam minimum inhibitory concentrations. Ertapenem should be reserved for patients with less severe presentations, and should be used at high doses. In milder presentations or BSIs from low-risk sources, other carbapenem-sparing alternatives could be considered: cephamycins, fluoroquinolones, and particularly a β-lactam/β-lactam inhibitor combination (particularly piperacillin/tazobactam). Optimized dosing of piperacillin/tazobactam is recommended (high doses and extended infusion). There are few data on the use of the promising newly available drugs (e.g. ceftolozane/tazobactam, ceftazidime/avibactam, cefiderocol, and plazomicin), and it seems reasonable to reserve them as last-resort drugs.

Carbapenems should be used in patients with serious infections; alternatives could be used individually, particularly for definitive treatment of patients with milder presentations.
Implementation of an Emergency Department Screening and Care Management Referral Process for Patients With Sickle Cell Disease
Authors: Rushton Sharron , Murray Debbie , Talley Charles , Boyd Sandra , Eason Kern , Earls Marian , Tanabe Paula
Published: August 2019

Purpose of Study:

The purpose of the project was to describe the implementation and evaluation of a care management referral program from emergency departments (EDs) to care management services for patients with sickle cell disease (SCD).

Primary Practice Setting:

Patients were referred to Community Care of North Carolina (CCNC), which is a private–public collaboration providing care management services and served as a referral hub for the program. Patients received follow-up from either CCNC or the North Carolina Sickle Cell Syndrome Program.

Methodology and Sample:

A multidisciplinary, multiorganizational group streamlined the referral process for patients with SCD who have ongoing care needs by linking patients from the ED to care management services. The article presents a review of program implementation and evaluation over a 3½-year period. The target population were patients who had a diagnosis of SCD and presented to the ED for treatment. Emergency department staff used a modified version of the Emergency Department Sickle Cell Needs Assessment of Needs and Strengths tool to screen for social behavioral health needs in areas such as emotional, financial, pain management, and resources. All forms were faxed to a central number at CCNC for follow-up care management services. Community Care of North Carolina then linked the patient with the appropriate agency and staff for follow-up.

Results:

More than 900 referrals were received in 3½ years. Pain was the most common reason for referral. An increase in care management intensity was observed over time. All levels of care management intensity saw an increase in the number of patients.

Implications for Case Management:

Care management occurred across organizations after careful planning among stakeholders. The interagency cooperation permitted the development of a streamlined process. In particular, the creation of a single point for referral was an important component to allow for population-level monitoring and ease of making referrals. Patients with ongoing care needs were identified and there was an increase in the intensity of outpatient care management services delivered.
Clinical Findings and Electrodiagnostic Testing in Ulnar Neuropathy at the Elbow and Differences According to Site and Type of Nerve Damage
Authors: Vinciguerra Claudia , Curti Stefania , Aretini Alessandro , Sicurelli Francesco , Greco Giuseppe , Mattioli Stefano , Mondelli Mauro
Published: August 2019

Objective

The aim of the study was to evaluate the clinical and electrodiagnostic testing in ulnar neuropathy at the elbow and differences according to site (humeroulnar arcade vs. retroepicondylar groove) and injury physiopathology (axonal vs. demyelinating), through prospective multicenter case-control study.

Design

Cases and controls were matched by age and sex. Ulnar neuropathy at the elbow diagnosis was made on symptoms. Statistical analysis was performed using Mann-Whitney, χ2, and analysis of variance tests.

Results

One hundred forty-four cases and 144 controls were enrolled. Sensory loss in the fifth finger had the highest sensitivity (70.8%) compared with clinical findings. Motor conduction velocity across elbow reached the highest sensitivity (84.7%) in localizing ulnar neuropathy at the elbow recording from at least one of the two hand muscles (first dorsal interosseous and abductor digiti minimi). Abnormal sensory action potential amplitude from the fifth finger occurred more frequently in axonal than in demyelinating forms. Differences between retroepicondylar groove and humeroulnar arcade regarded conduction block and job type.

Conclusions

Clinical findings have less usefulness than electrodiagnostic testing in ulnar neuropathy at the elbow diagnosis. Motor conduction velocity across elbow recorded from both abductor digiti minimi and first dorsal interosseous increases diagnostic accuracy. Axonal forms have greater clinical and electrodiagnostic testing severity than demyelinating forms, which are more frequent in retroepicondylar groove. Manual workers prevailed in humeroulnar arcade. These findings may be helpful in prognostic and therapeutic approaches.
Severe malaria: update on pathophysiology and treatment
Authors: Brejt Josef A. , Golightly Linnie M.
Published: August 2019

Purpose of review

Malaria threatens the lives of over 200 million individuals with the disease each year. Plasmodium falciparum is the predominant cause of severe malaria which may be lethal and result in neurocognitive sequelae despite appropriate treatment. We review recent advances regarding the pathophysiology of severe malaria and treatment recommendations for severe disease in the United States.

Recent findings

Infected red blood cell (iRBC) sequestration in microvascular beds is a critical factor in the development of severe malaria syndromes. Interactions between iRBC variant adhesive peptides and the endothelial protein C receptor (EPCR) result in perturbations of coagulation and cytopreservation pathways. Alterations in the protein C/EPCR axis are implicated in cerebral malaria, respiratory distress, and anemia. Brain MRIs reveal the posterior reversible encephalopathy syndrome in cerebral malaria patients. Transcriptomic analysis reveals commonalities in disease pathogenesis in children and adults despite differences in clinical presentation. US guidelines for severe malaria treatment currently recommend intravenous artesunate including in pregnant women and children.

Despite advances in our understanding of malarial pathogenesis much remains unknown. Antimalarial agents eradicate parasites but no treatments are available to prevent or ameliorate severe malaria or prevent disease sequelae. Further study is needed to develop effective adjunctive therapies.
Work-Related Musculoskeletal Discomfort and Injury in Craniofacial and Maxillofacial Surgeons
Authors: Howarth Ashley L. , Hallbeck M. Susan , Lemaine Valerie , Singh Davinder J. , Noland Shelley S.
Published: August 2019

Introduction:

Long, complex surgical procedures with non-ergonomic postures, headlights, loupe magnification, and microscope use may put craniofacial and maxillofacial surgeons at an increased risk of work-related musculoskeletal discomfort (WRMD). Identifying the prevalence and impact of WRMD may guide preventive strategies to prolong well-being, job satisfaction, and career duration.

Methods:

A 31-question survey was designed to evaluate WRMD. The survey was sent to American Society of Craniofacial Surgeons and American Society of Maxillofacial Surgeons members. The survey was created and distributed electronically through a private survey research center (Qualtrics Survey Software).

Results:

There were 95 respondents (23.75% response rate): 75% male, 56% aged 31 to 50 years old, and 73% in academic practice. On a scale of 0 to 10 (0 no pain, 10 worst pain), WRMD for surgery without loupes/microscope had a median of 3, with loupes 4, and with microscope 5. Pain was most common in the neck. Pain within 4 hours of surgery was present in 55% and 38% feared pain would influence future surgical performance. Surgeon discomfort affects posture (72%), stamina (32%), sleep (28%), surgical speed (24%), relationships (18%), and concentration (17%). Medical treatment for discomfort was sought by 22%. Time off work for treatment occurred in 9%.

Conclusion:

The WRMD can affect many aspects of a craniofacial or maxillofacial surgeon's life and has the potential to shorten or end a career. Occupational health and surgical ergonomics should be emphasized during surgical training and in surgical practice.
Predictors of Speech Outcome in Posterior Pharyngeal Fat Graft Surgery for Velopharyngeal Insufficiency Management
Authors: Denadai Rafael , Sabbag Anelise , Vieira Pedro Ribeiro , Raposo-Amaral Cesar Augusto , Buzzo Celso Luiz , Raposo-Amaral Cassio Eduardo
Published: August 2019

Background:

The identification of variables potentially correlated with speech outcome, following posterior pharyngeal fat grafting for treatment of velopharyngeal insufficiency (VPI), can provide useful information to guide decision-making and preoperative counseling. This study assessed the predictors of speech outcome after posterior pharyngeal fat grafting for VPI management.

Methods:

One hundred and sixty-seven consecutive patients with repaired cleft palate and VPI who underwent posterior pharyngeal fat grafting were retrospectively enrolled. Perceptual speech and nasendoscopic parameters were randomly rated by 3 blinded evaluators. Speech outcome was stratified based on previously published criteria. Bivariate and multivariate analyses were performed to identify independent predictors of 15-month postoperative speech outcomes.

Results:

Large velopharyngeal gap, higher number of previous palatal surgical procedures, and referral pattern (ie, patients who underwent primary palatoplasty elsewhere) were independently negative (for all, P < 0.05) predictors of speech outcome, whereas small velopharyngeal gap size was positively (P < 0.05) correlated with this outcome. Age, sex, race, Veau hierarchy, syndromic diagnosis, Angle classification of malocclusion, type of primary palatoplasty, body mass index, obstructive sleep apnea-related scores, surgical period, donor site, grafted volume, recipient site-related complications, and preoperative status (velopharyngeal closure pattern, hypernasality, audible nasal emissions, and intraoral pressure) were not associated (for all, P > 0.05) with speech outcomes.

Conclusion:

Posterior pharyngeal fat grafting improves speech function in patients with VPI, whereas gap size, number of previous palatal surgeries, and referral pattern affect the speech outcome.
Soft Tissue Damage in Patients With Hemifacial Microsomia
Authors: Wang Jiaxia , Liu Enwei , Du Linna , Hu Mingyan
Published: August 2019

Objective:

The aim of this study was to evaluate the extent of the damage to soft tissues on the affected side in patients with hemifacial microsomia (HFM).

Materials and methods:

Nine patients with HFM were included in this study and underwent computed tomography (CT) examination in the craniofacial area. The axial and coronal CT images were used for evaluating the damage to related soft tissues.

Results:

The results showed that the masseter muscle, temporal muscle, pterygoid muscles, and parotid gland were damaged on the affected side in all 9 patients with HFM. However, the extent of the damage to the pterygoid muscles was less than that to the masseter muscle, temporal muscle, and parotid gland.

Conclusions:

These findings indirectly support the crucial role of hemorrhage in the development of HFM, and the extent of damage to soft tissues may depend on the distance and barrier effect of the mandible between the hemorrhage and the affected tissues.
The Pathophysiology and Impact of Inflammation in Nonscarred Renal Interstitium: The Banff i Lesion
Authors: Nankivell Brian J. , P’Ng Chow H. , Shingde Meena , Viswanathan Seethalakshmi , Achan Anita , Renthawa Jasveen , Sharma Raghwa N. , Chapman Jeremy R.
Published: August 2019

Background.

Interstitial inflammation (i-INT) is the driver of T-cell–mediated rejection. Its causes, pathophysiology, kinetics, and outcomes are poorly documented.

Methods.

The role of i-INT was evaluated in 2055 biopsies from 775 renal transplant recipients.

Results.

i-INT was present in 374 (18.2% prevalence) from acute and subclinical rejection (67.4%); interstitial fibrosis and tubular atrophy (14.4%); BK virus nephropathy (BKVAN) 9.9%; and acute tubular necrosis (ATN with i-INT) in 5.9% of cases. i-INT was predicted by prior T-cell–mediated rejection and BKVAN, human leukocyte antigen mismatch, cyclosporine therapy, and indication biopsy for dysfunction. It correlated with tubulitis, arteritis, and antibody markers within concurrent histology (P < 0.001). After treatment, renal functional recovery was best with histological ATN, milder i-INT, and early posttransplant biopsy times. The initial histological improvement of inflammation depended on baseline i-INT severity. Complete resolution to Banff i0 was predicted by early biopsy time, antilymphocyte therapy, recipient age, and medication compliance (all P < 0.001). Clearance i-INT was followed by delayed resolution of tubulitis (P < 0.001). i-INT was associated with histological ATN, renal dysfunction, and increased incident fibrosis on sequential pathology. Progressive fibrosis following related-rejection i-INT was dependent on tubulitis using multivariable analysis. In contrast, fibrogenesis after BKVAN or ATN was unrelated to inflammation. i-INT cases were followed by recurrent rejection in 35.3%, increased graft loss, and greater patient mortality. Multiple complementary outcome analyses determined the optimal lower diagnostic threshold for inflammation was Banff i1 score.

Conclusions.

i-INT is a heterogeneous pathological phenotype that results in adverse functional and structural outcomes, for which active and robust therapy should be considered.
Allograft and Patient Outcomes Between Indigenous and Nonindigenous Kidney Transplant Recipients
Authors: Howson Prue , Irish Ashley B. , D’Orsogna Lloyd , Chakera Aron , Swaminathan Ramyasuda , Perry Gregory , De Santis Dianne , Tolentino Raelene , Wong Germaine , Lim Wai H.
Published: August 2019

Background.

Kidney transplant outcomes of indigenous Australians are poorer compared with nonindigenous Australians, but it is unknown whether the type of acute rejection differs between these patient groups or whether rejection mediates the effect between ethnicity, death-censored graft failure (DCGF), and death with a functioning graft (DWFG).

Methods.

Biopsy-proven acute rejection (BPAR) rates and types were compared between indigenous and nonindigenous recipients. The associations between ethnicity, BPAR, DCGF, and DWFG were examined using adjusted competing risk analyses, and mediation analysis was conducted to determine whether BPAR mediated the adverse effects between ethnicity and outcomes.

Results.

Fifty-seven (9.3%) of 616 patients who have received kidney-only transplants between 2000 and 2010 in Western Australia were indigenous. Compared with nonindigenous recipients, BPAR rates were higher in indigenous recipients (42 versus 74 episodes/100 recipients, P < 0.01), with an excess of antibody-mediated rejections. During a median follow-up of 8 years, indigenous recipients were more likely to experience BPAR, DCGF, and DWFG compared with nonindigenous recipients, with adjusted subdistribution hazard ratio of 1.94 (1.39-2.70), 1.53 (0.85-2.76; P = 0.159), and 2.14 (1.13-4.06; P = 0.020), respectively. Although 70% of the effect between ethnicity and DCGF was mediated by BPAR, no similar association was found for DWFG.

Conclusions.

Indigenous recipients experienced poorer allograft and patient outcomes compared with nonindigenous recipients, with BPAR an important determinant for DCGF. Future research identifying other risk factors and mediators associated with patient survival in indigenous recipients should be considered a priority.
Risk factors for heart failure with preserved or reduced ejection fraction among Medicare beneficiaries: Applications of competing risks analysis and gradient boosted model
Authors: Lee Moa P. , Glynn Robert J. , Schneeweiss Sebastian , Lin Kueiyu Joshua , Patorno Elisabetta , Barberio Julie , Levin Raisa , Evers Thomas , Wang Shirley V. , Desai Rishi J.
Published: August 2019

Background

The differential impact of various demographic characteristics and comorbid conditions on development of heart failure (HF) with preserved (pEF) and reduced ejection fraction (rEF) is not well studied among the elderly.

Methods and Results

Using Medicare claims data linked to electronic health records, we conducted an observational cohort study of individuals ≥ 65 years of age without HF. A Cox proportional hazards model accounting for competing risk of HFrEF and HFpEF incidence was constructed. A gradient boosted model (GBM) assessed the relative influence (RI) of each predictor in development of HFrEF and HFpEF. Among 138,388 included individuals, 9,701 developed HF (IR= 20.9 per 1,000 person-year). Males were more likely to develop HFrEF than HFpEF (HR = 2.07, 95% CI: 1.81-2.37 vs. 1.11, 95% CI: 1.02-1.20,Pfor heterogeneity < 0.01). Atrial fibrillation and pulmonary hypertension had stronger associations with the risk of HFpEF (HR = 2.02, 95% CI: 1.80-2.26 and 1.66, 95% CI: 1.23-2.22) while cardiomyopathy and myocardial infarction were more strongly associated with HFrEF (HR = 4.37, 95% CI: 3.21-5.97 and 1.94, 95% CI: 1.23-3.07). Age was the strongest predictor across all HF subtypes with RI from GBM >35%. Atrial fibrillation was the most influential comorbidity for development of HFpEF (RI = 8.4%) while cardiomyopathy was most influential for HFrEF (RI = 20.7%).

Conclusions

These findings of heterogeneous relationships between several important risk factors and heart failure types underline the potential differences in the etiology of HFpEF and HFrEF.

Key Questions

What is already known about this subject?

Previous epidemiologic studies describe the differences in risk factors involved in developing heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF), however, there has been no large study in an elderly population.

What does this study add?

This study provides further insights into the heterogeneous impact of various clinical characteristics on the risk of developing HFpEF and HFrEF in a population of elderly individuals.

Employing an advanced machine learning technique allows assessing the relative importance of each risk factor on development of HFpEF and HFrEF.

How might this impact on clinical practice?

Our findings provide further insights into the potential differences in the etiology of HFpEF and HFrEF, which are critical in prioritizing populations for close monitoring and targeting prevention efforts.
Exploring the role of the metabolite-sensing receptor GPR109a in diabetic nephropathy
Authors: Snelson Matthew , Tan Sih Min , Higgins Gavin C. , Lindblom Runa , Coughlan Melinda T.
Published: August 2019

Alterations in gut homeostasis may contribute to the progression of diabetic nephropathy. There has been recent attention on the renoprotective effects of metabolite-sensing receptors in chronic renal injury, including the G-protein-coupled-receptor (GPR)109a, which ligates the short chain fatty acid butyrate. However, the role of GPR109a in the development of diabetic nephropathy, a milieu of diminished microbiome-derived metabolites, has not yet been determined. This study aimed to assess the effects of insufficient GPR109a signalling via genetic deletion of GPR109a on the development of renal injury in diabetic nephropathy. Gpr109a−/− mice or their wildtype littermates (Gpr109a+/+) were rendered diabetic with streptozotocin (STZ). Mice received a control diet or an isocaloric high fiber diet (12.5% resistant starch) for 24 weeks and gastrointestinal permeability and renal injury were determined. Diabetes was associated with increased albuminuria, glomerulosclerosis and inflammation. In comparison, Gpr109a−/− mice with diabetes did not show an altered renal phenotype. Resistant starch supplementation did not afford protection from renal injury in diabetic nephropathy. Whilst diabetes was associated with alterations in intestinal morphology, intestinal permeability assessed in vivo using the FITC-dextran test was unaltered. GPR109a deletion did not worsen gastrointestinal permeability. Further, 12.5% resistant starch supplementation, at physiological concentrations, had no effect on intestinal permeability or morphology. These studies indicate that GPR109a does not play a critical role in intestinal homeostasis in a model of type 1 diabetes or in the development of diabetic nephropathy.
Effects of IgG and IgM autoantibodies on non-infected erythrocytes is related to ABO blood group in Plasmodium vivax malaria and is associated with anemia
Authors: Mourão Luiza Carvalho , Pantuzzo Medeiros Camila Maia , Cardoso-Oliveira Gustavo Pereira , Silva Roma Paula Magda da , Sultane Aboobacar Jamila da Silva , Medeiros Rodrigues Beatriz Carolina , Agero Ubirajara , Fernandes Fontes Cor Jesus , Braga Érika Martins
Published: August 2019

Autoantibodies play an important role in the destruction of non-infected red blood cells (nRBCs) during malaria. However, the relationship between this clearance and ABO blood groups is yet to be fully enlightened, especially for Plasmodium vivax infections. Here we show that anti-RBC IgG and IgM are increased in anemic patients with acute vivax malaria. Furthermore, both antibodies are able to decrease the deformability of nRBCs, but only IgG can induce in vitro erythrophagocytosis. Such effects are enhanced in type O erythrocytes, suggesting that individuals from this blood group infected with P. vivax malaria may be more susceptible to develop anemia.
Structure-based screening of binding affinities via small-angle X-ray scattering
Authors: Chen P. , Masiewicz P. , Perez K. , Hennig J.
Published: August 2019

Protein-protein and protein-ligand interactions can alter the scattering properties of participating molecules, and thus be quantified by solution small-angle X-ray scattering (SAXS). In such cases, scattering reveals structural details of the bound complex, number of species involved, and in principle strength of the interaction. However, determining binding affinities from SAXS-based titrations is not yet an established procedure with well-defined performance expectations. We thus used periplasmic binding proteins and in particular histidine-binding protein as a standard reference, then examined precision and accuracy of affinity prediction at multiple concentrations and exposure times. By analyzing several structural and comparative scattering metrics, we found that the volatility of ratio between titrated scattering curves and a common reference most reliably quantifies ligand-triggered changes. This ratio permits the determination of affinities at low signal-to-noise ratios and without pre-determining the complex scattering, demonstrating that SAXS-based ligand screening is a promising alternative biophysical method for drug discovery pipelines.

SIGNIFICANCE

Solution X-ray scattering can be used to screen a set of biomolecular interactions, which yields quantitative information on both structural changes and dissociation constants between binding partners. However, no common benchmarks yet exist for the application of SAXS within drug discovery workflows. Thus, investigations into its performance limitations are currently needed to make SAXS a reliable source for high-throughput screening. This study establishes a generalizable protocol based on protein-ligand interactions, and demonstrates its reproducibility across several beamline setups. In the simplest case, the micromolar binding affinities can be determined directly from measured intensities without knowledge of the molecular structure, with material consumption that is competitive with other biophysical screening techniques.
Low coverage whole genome sequencing enables accurate assessment of common variants and calculation of genome-wide polygenic scores
Authors: Homburger Julian R. , Neben Cynthia L. , Mishne Gilad , Zhou Alicia Y. , Kathiresan Sekar , Khera Amit V.
Published: August 2019

Background

The inherited susceptibility of common, complex diseases may be caused by rare, ‘monogenic’ pathogenic variants or by the cumulative effect of numerous common, ‘polygenic’ variants. As such, comprehensive genome interpretation could involve two distinct genetic testing technologies -- high coverage next generation sequencing for known genes to detect pathogenic variants and a genome-wide genotyping array followed by imputation to calculate genome-wide polygenic scores (GPSs). Here we assessed the feasibility and accuracy of using low coverage whole genome sequencing (lcWGS) as an alternative to genotyping arrays to calculate GPSs.

Methods

First, we performed downsampling and imputation of WGS data from ten individuals to assess concordance with known genotypes. Second, we assessed the correlation between GPSs for three common diseases -- coronary artery disease (CAD), breast cancer (BC), and atrial fibrillation (AF) -- calculated using lcWGS and genotyping array in 184 samples. Third, we assessed concordance of lcWGS-based genotype calls and GPS calculation in 120 individuals with known genotypes, selected to reflect diverse ancestral backgrounds. Fourth, we assessed the relationship between GPSs calculated using lcWGS and disease phenotypes in 11,502 European individuals seeking genetic testing.

Results

We found imputation accuracy r2values of greater than 0.90 for all ten samples -- including those of African and Ashkenazi Jewish ancestry -- with lcWGS data at 0.5X. GPSs calculated using both lcWGS and genotyping array followed by imputation in 184 individuals were highly correlated for each of the three common diseases (r2= 0.93 - 0.97) with similar score distributions. Using lcWGS data from 120 individuals of diverse ancestral backgrounds, including South Asian, East Asian, and Hispanic individuals, we found similar results with respect to imputation accuracy and GPS correlations. Finally, we calculated GPSs for CAD, BC, and AF using lcWGS in 11,502 European individuals, confirming odds ratios per standard deviation increment in GPSs ranging 1.28 to 1.59, consistent with previous studies.

Conclusions

Here we show that lcWGS is an alternative approach to genotyping arrays for common genetic variant assessment and GPS calculation. lcWGS provides comparable imputation accuracy while also overcoming the ascertainment bias inherent to variant selection in genotyping array design.
A flexible pipeline combining clustering and correction tools for prokaryotic and eukaryotic metabarcoding
Authors: Brandt Miriam I. , Trouche Blandine , Quintric Laure , Wincker Patrick , Poulain Julie , Arnaud-Haond Sophie
Published: August 2019

Environmental metabarcoding is an increasingly popular tool for studying biodiversity in marine and terrestrial biomes. With sequencing costs decreasing, multiple-marker metabarcoding, spanning several branches of the tree of life, is becoming more accessible. However, bioinformatic approaches need to adjust to the diversity of taxonomic compartments targeted as well as to each barcode gene specificities. We built and tested a pipeline based on Illumina read correction with DADA2 allowing analyzing metabarcoding data from prokaryotic (16S) and eukaryotic (18S, COI) life compartments. We implemented the option to cluster Amplicon Sequence Variants (ASVs) into Operational Taxonomic Units (OTUs) with swarm v2, a network-based clustering algorithm, and to further curate the ASVs/OTUs based on sequence similarity and co-occurrence rates using a recently developed algorithm, LULU. Finally, flexible taxonomic assignment was implemented via Ribosomal Database Project (RDP) Bayesian classifier and BLAST. We validate this pipeline with ribosomal and mitochondrial markers using eukaryotic mock communities and 42 deep-sea sediment samples. The results show that ASVs, reflecting genetic diversity, may not be appropriate for alpha diversity estimation of organisms fitting the biological species concept. The results underline the advantages of clustering and LULU-curation for producing more reliable metazoan biodiversity inventories, and show that LULU is an effective tool for filtering metazoan molecular clusters, although the minimum identity threshold applied to co-occurring OTUs has to be increased for 18S. The comparison of BLAST and the RDP Classifier underlined the potential of the latter to deliver very good assignments, but highlighted the need for a concerted effort to build comprehensive, ecosystem-specific, databases adapted to the studied communities.
Temperature, photoperiod and life history traits inDrosophila subobscura
Authors: MacLean Heidi J. , Gilchrist George W.
Published: August 2019

Temperature and photoperiod are generally reliable indicators of seasonality that have shaped the life histories of many temperate zone organisms. Anthropogenic climate change, however, may alter historical weather patterns and seasonal cues. Many studies have evaluated thermal effects on life history traits, but fewer have also examined photoperiodic effects. Because the degree of seasonal cue varies across latitude, we examine developmental plasticity inDrosophila subobscurapopulations sampled from latitudinal clines across Europe and North America. We examine the interaction between temperature and photoperiod on insect development time, adult survival, and fitness using a two by two factorial design with long (16L:8D) and short days (8L:16D) at high (23°C) and low temperatures (15°C).. We find that development time is dependent on both temperature and photoperiod but the low temperature/long day treatment revealed a dramatic and unexpected 4.5 day delay in eclosion. Fitness, estimated by the intrinsic rate of increase (r), showed a significant increase in response to temperature and a decrease in response to day length, and an interaction such that long-days reduced the effects of temperature. Additionally, cooler temperatures increased lifespan, and long-days reduced survivorship; temperature and day length interacted such that lifespan is relatively shorter in seasonally mismatched (long-cool, short-warm) conditions compared to matched conditions. These data highlight the importance of multiple abiotic factors in predicting species’ responses to climate change.
The role and robustness of the Gini coefficient as an unbiased tool for the selection of Gini genes for normalising expression profiling data
Authors: Muelas Marina Wright , Mughal Farah , O’Hagan Steve , Day Philip J. , Kell Douglas B.
Published: August 2019

We recently introduced the Gini coefficient (GC) for assessing the expression variation of a particular gene in a dataset, as a means of selecting improved reference genes over the cohort (‘housekeeping genes’) typically used for normalisation in expression profiling studies. Those genes (transcripts) that we determined to be useable as reference genes differed greatly from previous suggestions based on hypothesis-driven approaches. A limitation of this initial study is that a single (albeit large) dataset was employed for both tissues and cell lines.

We here extend this analysis to encompass seven other large datasets. Although their absolute values differ a little, the Gini values and median expression levels of the various genes are well correlated with each other between the various cell line datasets, implying that our original choice of the more ubiquitously expressed low-Gini-coefficient genes was indeed sound. In tissues, the Gini values and median expression levels of genes showed a greater variation, with the GC of genes changing with the number and types of tissues in the data sets. In all data sets, regardless of whether this was derived from tissues or cell lines, we also show that the GC is a robust measure of gene expression stability. Using the GC as a measure of expression stability we illustrate its utility to find tissue- and cell line-optimised housekeeping genes without any prior bias, that again include only a small number of previously reported housekeeping genes. We also independently confirmed this experimentally using RT-qPCR with 40 candidate GC genes in a panel of 10 cell lines. These were termed the Gini Genes.

In many cases, the variation in the expression levels of classical reference genes is really quite huge (e.g. 44 fold for GAPDH in one data set), suggesting that the cure (of using them as normalising genes) may in some cases be worse than the disease (of not doing so). We recommend the present data-driven approach for the selection of reference genes by using the easy-to-calculate and robust GC.
Mesolimbic dopamine D2 receptors and neural representations of subjective value
Authors: Castrellon Jaime J. , Young Jacob S. , Dang Linh C. , Cowan Ronald L. , Zald David H. , Samanez-Larkin Gregory R.
Published: August 2019

The process by which the value of delayed rewards is discounted varies from person to person. It has been suggested that these individual differences in subjective valuation of delayed rewards are supported by mesolimbic dopamine D2-like receptors (D2Rs) in the ventral striatum. However, no study to date has documented an association between direct measures of dopamine receptors and neural representations of subjective value in humans. Here, we examined whether individual differences in D2R availability were related to neural subjective value signals during decision making. Human participants completed a monetary delay discounting task during an fMRI scan and on a separate visit completed a PET scan with the high affinity D2R tracer [18F]fallypride. Region-of-interest analyses revealed that D2R availability in the ventral striatum was positively correlated with subjective value-related activity in the ventromedial prefrontal cortex and midbrain but not with choice behavior. Whole-brain analyses revealed a positive correlation between ventral striatum D2R availability and subjective value-related activity in the left inferior frontal gyrus. These findings are the first to identify a link between directly-measured mesolimbic dopamine function and subjective value representation in humans and suggest a mechanism by which individuals vary in neural representation of discounted subjective value.