bluuebunny/crossref_metadata_2025 huggingface dataset:
The nonpathogenic commensal Neisseria: friends and foes in infectious disease
Authors: Dorey Robert B. , Theodosiou Anastasia A. , Read Robert C. , Jones Christine E.
Published: July 2019

Purpose of review

Nonpathogenic commensal Neisseria are rarely considered in the clinical setting despite evidence that they can cause invasive opportunistic infections. In contrast, they may offer protection against pathogenic Neisseria, and such relationships are being actively explored in experimental studies.

Recent findings

Recent case reports are presented of invasive infection caused by nonpathogenic Neisseria in patients on novel biologic therapies. On the other hand, Neisseria lactamica, a nonpathogenic commensal, has been shown in human challenge studies to inhibit colonization by Neisseria meningitidis. Experimental mouse models have also explored the inhibitory effects of nonpathogenic Neisseria on Neisseria gonnhoreae infection. Cutting-edge advances in metagenomics and microbiomics are being used to understand the mechanisms underpinning these effects.

Clinicians should have increased awareness of nonpathogenic Neisseria. First, as new immunomodulating therapies become licenced, the interactions that maintain balance between commensals and their human hosts may be altered. Second, these bacteria are showing promise in their capacity to exclude pathogenic Neisseria species from their anatomical niches.
Usefulness of the Intersocietal Accreditation Commission (IAC) Quality Improvement Self-assessment Tool After 1 Year
Authors: Farrell Mary Beth , Lally Mary , Vermeiren Frank
Published: July 2019

Background and objectives:

The Intersocietal Accreditation Commission (IAC) created a voluntary quality improvement (QI) tool that allows imaging facilities to self-assess and document the quality of imaging studies. This study aimed to evaluate users' perceptions of the effectiveness and usefulness of the new QI self-assessment tool.

Methods:

The IAC's QI tool evaluates 4 quality measures: test appropriateness; technical quality/safety; interpretive quality; and report timeliness/completeness. A survey was appended to the tool to assess the perceived value.

Results:

Between May 2016 and July 2017, a total of 829 facilities completed 5312 self-assessments. During that time, 936 respondents completed the survey. There was a high level of agreement that the tool is easy to use (91.8%), encouraged critical thinking (90.3%), and the activity was worthwhile (89.6%).

Conclusion:

The results show that most respondents find value in using the voluntary IAC QI Self-assessment Tool. Respondents believed tool use encouraged critical thinking, and they were satisfied with the QI self-assessment process.
Physician Use of Health Care Teams for Improving Quality in Primary Care
Authors: Hoff Timothy , Prout Kathryn
Published: July 2019

Objectives:

Health care teams may be used to improve quality in the primary care setting. Absent in the extant literature on health care teams is knowledge of how physicians seek to deploy this innovation on an everyday basis to improve care quality. This study's aim was to explore how physicians use teams in practice to deliver higher-quality care.

Methods:

A qualitative study using data collected through 39 interviews with primary care physicians and 9 interviews with medical assistants, employed across different primary care settings in the northeastern region of the United States.

Results:

Physicians used teams for 2 care quality functions: “getting basic care duties off their plate” to have more time for complex care delivery and “as relational extensions” of themselves to enhance the patient experience and provide care continuity. Physicians identified the following ingredients for using teams for these functions: (a) achieving long-term continuity working with the same team members; (b) having the correct mix of personalities and skills sets on the team; and (c) a “who is doing what” focus in the team for achieving role clarity.

Conclusions:

The findings illuminate how primary care physicians attempt to use teams to improve care quality and enhance their role as care providers.
The Effect of Pay-for-Performance Compensation Model Implementation on Vaccination Rate: A Systematic Review
Authors: Benabbas Roshanak , Shan Gururaj , Akindutire Olumide , Mehta Ninfa , Sinert Richard
Published: July 2019

Background and objectives:

Pay-for-performance (P4P) is broadly defined as financial incentives to providers for attaining prespecified quality outcomes. Providers, payers, and public officials have worked over the years to develop innovative solutions to rapidly and consistently bring new diagnostic tests and therapies to our patients. P4P has been instituted in various forms over the last 30 years. Vaccines are one of society's greatest public health innovations and vaccination programs provide a unique opportunity for P4P programs. We attempted to investigate the effect of P4P compensation model implementation on the vaccination rate.

Methods:

Utilizing a systematic review and meta-analysis approach, we searched PubMed, Embase, Scopus, and Web of Science from inception to December 2018.

Results:

Nine articles were included with poor to moderate quality. Improvements in vaccination rates after implementation of P4P were statistically significant in 8 of 9 of studies. However, due to the heterogeneity of the methods used, we could not pool the data.

Conclusion:

The results of this systematic review indicate that the implementation of P4P programs can increase the vaccination rate. In recent times when it has become increasingly more popular not to vaccinate, implementing P4P becomes even more important if it is shown to be an effective tool in increasing vaccination rates.
Sensitivity of the Mount Fuji Sign After Evacuation of Chronic Subdural Hematoma in Nonagenarians
Authors: Moscovici Samuel , Halevy Dan , Mizrahi Cezar José , Goldberg S. Nahum , Brown Derek W. , Ben-David Eliel
Published: July 2019

Background

The Mount Fuji sign (MFS) is a radiological sign on computed tomographic scans depicting air between the frontal lobes. Air in this location indicates tension pneumocephalus (TP), considered a neurosurgical emergency.

We evaluate the correlation between the MFS and perioperative mortality attributed to TP in nonagenarians who have undergone evacuation of chronic subdural hemorrhage (cSDH).

Materials and Methods

We retrospectively reviewed the records of nonagenarians who had cSDH evacuation between 2006 and 2015. Postoperative computed tomographic images were evaluated for findings consistent with the MFS.

Results

Of 45 patients, 15 patients (33%) had radiological MFS, and 3 patients (20%) with MFS required reoperation because of new blood collection. No patient required reoperation because of TP. Perioperative (30-day) mortality in patients demonstrating the MFS was 6.67% caused by cardiac arrhythmia versus 13.33% mortality in patients with no evidence of the MFS.

Conclusion

Mount Fuji sign in nonagenarians after cSDH evacuation is not a specific sign of TP.
Glomerular Expression of Some Profibrotic Factors in Progressive Childhood Lupus Nephritis
Authors: Badawy Ahlam , Gamal Yasser , Hussein Almontaser
Published: July 2019

Background

Lupus nephritis (LN) is a major cause of mortality and morbidity in both adult and pediatric patients. However, studies regarding pathogenesis and predictors of renal outcomes in childhood LN are limited. Transforming growth factor-β1 (TGF-β1) and Connective tissue growth factor (CTGF) have an important role in proliferative and fibrotic changes in many renal diseases. We aim to evaluate the role of such two profibrotic factors in the progression of childhood onset LN and to detect if their glomerular expression could represent an early predictor of future deterioration of renal function.

Methods

34 children with new onset of LN were included. Glomerular expressions of TGF-β1 and CTGF were evaluated by immunohistochemical analysis in the renal tissue of such patients and in control tissue. GFR was estimated at time of renal biopsy at the onset of LN and after 2 years of follow-up. Rate of GFR change (ΔGFR) was calculated and used as indicative of degree of renal disease progression.

Results

Glomerular TGF-β1 and CTGF expressions in children with LN were significantly higher than in control tissue (LN 15.41 ± 9.84 and 15.56 ± 10.51 vs. 2.15 ± 1.45 and 1.35 ± 1.07 in control respectively, with p < 0.001 in both). In addition, the glomerular expressions of TGF-β1 and CTGF were significantly higher in patients with further decline in GFR (20.68 ± 7.73 and 21.05 ± 8.75) versus (5.75 ± 4.37 and 5.50 ± 3.78) in those without change in GFR with (p = 0.000 for both of them).

Conclusions

Patients with LN have increased glomerular expressions of TGF-β1 and CTGF, which were higher in those with further decline in GFR. These profibrotic factors are suspected to be involved in pathogenesis of LN and could be evaluated as a target for therapeutic intervention to stop progression of LN. In addition, their glomerular expression could be used as an early predictor of progression of LN, to justify early aggressive therapy in those with suspected rapid progression.
Lung Perfusion Scintigraphy in Eisenmenger Syndrome Due to Patent Ductus Arteriosus
Authors: Mitsui Kohei , Woodhams Reiko , Ukisu Ryutarou , Inoue Yusuke
Published: July 2019

Eisenmenger syndrome refers to the elevation of pulmonary arterial pressure to the systemic level caused by an increased pulmonary vascular resistance with right-to-left shunt through an intracardiac or aortopulmonary communication. A 36-year-old woman with Eisenmenger syndrome due to patent ductus arteriosus underwent 99mTc-MAA lung perfusion scintigraphy to evaluate right-to-left shunt. Whole-body imaging visualized extrapulmonary activity in both kidneys, spleen, and intestinal tract, confirming the presence of right-to-left shunt. Accumulation in the brain was visible but much weaker compared with that in the body trunk and was limited to the left cerebral hemisphere, which reflected the location of the shunt pathway.
68Ga-PSMA Uptake in Escherichia coli Spondylodiscitis
Authors: Klingenberg Søren , Jochumsen Mads Ryø , Pedersen Bodil Ginnerup , Bouchelouche Kirsten
Published: July 2019

In a patient with recently diagnosed intermediate-risk prostate cancer, 68Ga-prostate-specific-membrane-antigen (PSMA) PET/CT for primary staging discovered increased 68Ga-PSMA uptake in spondylodiscitis in the thoracic spine. The bacteria Escherichia coli was found both in blood cultures and bone biopsies from the thoracic lesion. This case presents spondylodiscitis as a potential benign pitfall to be aware of when interpreting PSMA PET/CT in prostate cancer patients.
Physiologic Uterine Uptake of Radioiodine During Menstruation Demonstrated by SPECT/CT
Authors: Liu Lina , Chen Yu , Tian Tian , Huang Rui , Liu Bin
Published: July 2019

A 35-year-old woman with papillary thyroid cancer underwent 131I therapy after thyroidectomy. Post-therapy whole body scan revealed increased activity in the pelvis, in addition to the activity in the neck. On SPECT/CT images, the radioactivity in the pelvis was localized in the rectum and cervix. Further inquiry discovered that the patient was menstruating. We concluded that abnormal radioiodine uptake in menstrual uterus might be an exceptional finding mimicking a metastasis.
Progressive Hydrocephalus Due to Ventriculoperitoneal Shunt Infection
Authors: Mathew Boon , Purandare Nilendu C. , Agrawal Archi , Shah Sneha , Puranik Ameya , Rangarajan Venkatesh
Published: July 2019

Ventriculoperitoneal shunt malfunction is common in patients after shunt surgery. Imaging is done to reveal the underlying cause and confirm the diagnosis. Shunt infection is one of the common causes of shunt malfunction. FDG PET CT is an accepted infection imaging tool and can be used to diagnose shunt infection accurately in a patient with high clinical suspicion.
A Surgical Endovascular Trauma Service Increases Case Volume and Decreases Time to Hemostasis
Authors: Morrison Jonathan J. , Madurska Marta J. , Romagnoli Anna , Ottochian Marcus , Adnan Sakib , Teeter William , Kuebler Tiffany , Hoehn Melanie R. , Brenner Megan L. , DuBose Joseph J. , Scalea Thomas M.
Published: July 2019

Objectives:

The aim of this study was to evaluate the effect of a recently active endovascular trauma service (ETS) on case volume and time to hemostasis, as a complement to an existing interventional radiology (IR) service.

Summary Background Data:

Endovascular techniques are vital for trauma care, but timely access can be a challenge. There is a paucity of data on the effect of a multispecialty team for delivery of endovascular hemorrhage control.

Methods:

The electronic medical record of trauma patients undergoing endovascular procedures between 2013 and 2018 was queried for provider type (IR or ETS). Case volume and rates were expressed per 100 monthly admissions, normalizing for seasonal variation. Interrupted time series analysis was used to model the case rate pre- and post-introduction of the ETS. Admission-to-procedure-time data were collected for pelvic angioembolization as a marker of patients requiring emergency hemostasis.

Results:

During 6 years, 1274 admission episodes required endovascular interventions. Overall case volume increased from 2.7 to 3.6 at a rate of 0.006 (P = 0.734) after introduction of the ETS. IR case volume decreased from 3.3 to 2.6 at a rate of 0.03 (P = 0.063). ETS case volume increased at a rate of 0.048 (P < 0.001), which was significantly different from the IR trend (P < 0.001). Median (interquartile range) time-to-procedure (hours) was significantly shorter for pelvic angioembolization [3.0 (4.4) vs 4.3 (3.6); P < 0.001] when ETS was compared to IR.

Conclusion:

A surgical ETS increases case volume and decreases time to hemostasis for trauma patients requiring time sensitive interventions. Further work is required to assess patient outcome following this change.
Pelvic Floor Organ Prolapse After Radical Cystectomy in Patients With Uroepithelial Carcinoma
Authors: Lipetskaia Lioudmila , Lee Toy Gee , Li Dongmei , Meyer Haley , Doyle Paula Jaye , Messing Edward
Published: July 2019

Objective

The aim of this study was to identify whether women who undergo a radical cystectomy for uroepithelial carcinoma are at increased risk of pelvic organ prolapse after surgical treatment.

Methods

A retrospective cohort study compared female subjects who had undergone a radical cystectomy for uroepithelial carcinoma, as identified through an institutional cancer survivor database, with subjects who presented to the Pelvic Health and Continence Clinic with symptoms of either uterovaginal prolapse or urinary incontinence. Demographic data were collected regarding risk factors for prolapse, and study subjects were asked to complete a Pelvic Organ Prolapse Distress Inventory (POPDI-6). Data were collected through retrospective chart review. The primary outcome is difference in the POPDI-6 between the groups. Statistical evaluation of responses was performed, with analysis of variance used to compare the questionnaire scores between groups and correction for risk factors with χ2 tests, with a P value of 0.05 selected for statistical significance.

Results

There were 36 postcystectomy subjects who responded to the survey, 37 subjects in the prolapse group, and 44 subjects in the incontinence group. With correction for age, body mass index, and number of vaginal deliveries, the postcystectomy group reported significantly lower scores on the POPDI-6 than both the prolapse group (P < 0.0001) and the incontinence group (P = 0.0003).

Conclusions

Radical cystectomy for uroepithelial carcinoma does not correlate with an increased risk of patient-reported symptoms of pelvic organ prolapse.
Orolingual Angioedema After Tissue Plasminogen Activator Administration in Patients Taking Angiotensin-Converting Enzyme Inhibitors
Authors: Burd Megan , McPheeters Chelsey , Scherrer Leigh Ann
Published: July 2019

Orolingual angioedema is a rare adverse effect (1%–5%) of tissue plasminogen activator (tPA) that can lead to significant morbidity in patients with acute ischemic stroke. It is thought that increased levels of bradykinin and histamine resulting from tPA administration can result in angioedema. Angiotensin-converting enzyme (ACE) inhibitors can also lead to increased levels of bradykinin and appear to be a risk factor for tPA-associated angioedema. A literature review was conducted to examine previous cases of orolingual angioedema associated with tPA administration in patients also taking ACE inhibitors to better understand the relationship between ACE inhibitors and tPA-induced angioedema. Over a 20-year period, 27 patients who experienced angioedema with tPA while on ACE inhibitor therapy were identified. In this patient population, the onset of angioedema symptoms appeared as soon as 15 min after the tPA bolus and as late as 2 hr after the tPA infusion. Most patients required a combination of supportive medications such as corticosteroids (81.5%), antihistamines (74%), and epinephrine (18.5%) for the management of angioedema. Severe presentations of orolingual angioedema resulted in intubation for airway protection (26%). Symptom resolution ranged from shortly after the administration of supportive medications to 72 hr after symptom onset. Orolingual angioedema after tPA administration has the potential to cause significant morbidity, indicating patients should be monitored closely for a few hours after administration for the development of airway compromise. ACE inhibitors should not be the preferred antihypertensive agents for patients who require blood pressure lowering prior to tPA administration.
Advanced Practice Provider Burnout in a Large Urban Medical Center
Authors: Ashooh Meredith P. , Barnette Katherine , Moran Tim P. , O'Shea James , Lall Michelle D.
Published: July 2019

Burnout is characterized by 3 facets: the presence of emotional exhaustion, depersonalization, and a lack of sense of personal accomplishment. It arises when stress becomes so severe relative to a person's own resources that he or she loses motivation to perform, and it is associated with many negative outcomes. Emergency medicine (EM) physicians ranked highest in a study of burnout rates among physician subspecialties. However, there is an overall lack of robust research examining the work-related psychological states in advanced practice providers (APPs). Because the utilization of APPs in emergency departments (EDs) is steadily increasing, we aimed to describe burnout in this understudied group. A sample of APPs employed in a large urban academic hospital was surveyed using 3 well-established questionnaires measuring burnout, resilience, and mindfulness. Responses were compared with a normative group of health care workers (HCWs). The respondents reported a significantly greater sense of personal accomplishment than other HCWs. This was greater with a perceived control over their work environment and if they self-identified as being nonjudgmental. The sense of accomplishment was less in the respondents of older age and for those with children. This group also reported an increased sense of depersonalization. Mindfulness traits of acting with awareness and having trust in their instincts were identified as potential protective factors against depersonalization. Although the respondents were not more emotionally exhausted than other HCWs, being more emotionally “reactive” did predict greater emotional exhaustion. This is an important finding for APPs working in affect-laden work environments such as EDs. These findings suggest that increasing control over the work environment, fostering trust of instincts, and reducing emotional reactiveness are prudent interventional targets for EM-APP leaders to prevent and reduce burnout in the workforce.
Using Survivors' Voices to Guide the Identification and Care of Trafficked Persons by U.S. Health Care Professionals
Authors: Armstrong Stephanie , Greenbaum V. Jordan
Published: July 2019

Evidence suggests that trafficked persons in the United States frequently seek health care, yet little is known of their experiences, including reasons for seeking assistance, interactions with professionals, and barriers to obtaining care. To gain a better understanding, a search was conducted for empirical data collected directly from trafficked persons about their US health care experiences, published in peer-reviewed journals within the past 10 years, and in the English language. Four databases were searched and of the 1,605 articles initially identified, 8 met all inclusion criteria. Data from 420 participants demonstrated a wide range of physical and mental health complaints and 50%–98% reported seeking health care services in diverse medical settings during their exploitation. Barriers to care occurred at various levels, and although some are not modifiable, others are amendable by changes in the behaviors of professionals. A trauma-informed, rights-based approach to care would address many of these issues and create feasible treatment plans.
International Travel for Living Donor Kidney Donation: A Proposal for Focused Screening of Vulnerable Groups
Authors: Hartsock Jane A. , Helft Paul R.
Published: July 2019

As the gap between organ donors and patients on the recipient waiting list grows, residents of the United States who are in need of kidney transplantation occasionally contract with living donors from outside the United States. Those donors then travel to the United States to undergo living donor kidney donation at US transplant centers. This practice is not limited to the United States and occurs with some regularity around the world. However, there is very little written about this practice from the perspective of the US transplant system, and there is little in the way of guidance (either legal or ethical) to assist centers that accommodate it in distinguishing between ethically permissible travel for transplant and what could potentially be human trafficking for organ removal. This article will present an ethical analysis of travel for organ donation with particular attention to lessons that can be drawn from living donor donation in other countries. This inquiry is particularly germane because Organ Procurement and Transplantation Network has promulgated guidelines with respect to obligations owed to living donors, but those guidelines appear to assume that the donor is a US resident. The critical question then is whether or to what extent those guidelines are applicable to the instant scenario in which the living donor is a nonresident. In addition, this article addresses several critical ethical concerns implicated by the often vulnerable populations from which donors are drawn. Finally, this article proposes that focused inquiry by transplant centers is necessary when donors are nonresidents.
Donor PNPLA3 and TM6SF2 Variant Alleles Confer Additive Risks for Graft Steatosis After Liver Transplantation
Authors: Míková Irena , Neřoldová Magdaléna , Hubáček Jaroslav A. , Dlouhá Dana , Jirsa Milan , Honsová Eva , Sticová Eva , Lánská Věra , Špičák Julius , Trunečka Pavel
Published: July 2019

Background.

The rs58542926 polymorphism in transmembrane 6 superfamily member 2 (TM6SF2) is a genetic factor predisposing to nonalcoholic fatty liver disease. We aimed to explore the effect of recipient and donor TM6SF2 rs58542926 genotypes on liver graft fat content after liver transplantation.

Methods.

Steatosis was evaluated in liver biopsies from 268 adult recipients. The influence of recipient and donor TM6SF2 genotypes, patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 genotypes, and nongenetic factors on the steatosis grade assessed 6–30 months after transplantation was analyzed by ordinal logistic regression.

Results.

The presence of the TM6SF2 c.499A allele in the donor (P = 0.014), PNPLA3 c.444G allele in the donor (P < 0.001), posttransplant body mass index (P < 0.001), and serum triglycerides (P = 0.047) independently predicted increased liver fat content on multivariable analysis, whereas noncirrhotic liver disease, as an indication for liver transplantation, was associated with lower risk of steatosis (P = 0.003). The effects of the donor TM6SF2 A and PNPLA3 G alleles were additive, with an odds ratio of 4.90 (95% confidence interval, 2.01-13.00; P < 0.001), when both minor alleles were present compared with an odds ratio of 2.22 (95% confidence interval, 1.42-3.61; P = 0.002) when only one of these alleles was present.

Conclusions.

The donor TM6SF2 c.499A allele is an independent risk factor of liver graft steatosis after liver transplantation that is additive to the effects of donor PNPLA3 c.444G allele.
Can behavioural ecologists help establish protected areas?
Authors: Caro Tim , Berger Joel
Published: July 2019

Protecting wild places is conservation's most pressing task given rapid contemporary declines in biodiversity and massive land use changes. We suggest that behavioural ecology has a valuable, albeit limited, role to play in this agenda. Behaviourally based empiricism and modelling, especially of animal movements and habitat preferences have enjoyed wide applicability in delineating reserve boundaries. In protected areas that sanction exploitation, it may also be important to understand individuals' behavioural and life-history responses to management decisions. We also argue, however, that the in-depth studies of behavioural ecologists may have an important role in conservation by elevating species’ status from mundane to charismatic and often sparking public empathy, and their mere presence in field generates local (or broader) intrigue. More generally behavioural ecologists will only be listened to, and their contributions considered of conservation importance, if they become more involved in decision-making processes as witnessed by several prominent examples that have supported the establishment of protected areas.

This article is part of the theme issue ‘Linking behaviour to dynamics of populations and communities: application of novel approaches in behavioural ecology to conservation’.
Microbiota and Health Study: a prospective cohort of respiratory and diarrheal infections and associated risk factors in Bangladeshi infants under two years
Authors: Vidal Karine , Sultana Shamima , Patron Alberto Prieto , Binia Aristea , Rahman Mahbubur , Deeba Iztiba Mallik , Brüssow Harald , Sakwinska Olga , Sarker Shafiqul Alam
Published: July 2019

Background

Early childhood respiratory and diarrheal infections are major causes of morbidity and mortality worldwide. There is a need to further assess the epidemiology through prospective and community-based studies to gain key insights that could inform preventative measures to reduce the risk of infectious disease in this vulnerable population. We aimed to analyze the burden and determinants of acute respiratory infection (ARI) and diarrhea episodes affecting infants during their first 2 years of life with state-of-the-art molecular technologies.

Methods

The ARI and diarrhea episodes were prospectively collected in a community-based, longitudinal cohort of infants (n=267) from birth to 2 years of life in Bangladesh. Women were recruited during the third trimester of pregnancy. Demographic, socioeconomic, and environmental information on the households was recorded. Nasopharyngeal and fecal samples were collected during regular scheduled visits from mother-infant pairs, and also from the infants during unscheduled visits for reported illnesses. New generation sequencing methods will be utilized to determine microbiota composition and function, supplemented by the state-of-the-art multiplex molecular detection technology for a wide range of bacterial and viral pathogens.

Discussion

This study sought to assess the epidemiology of both respiratory and gastrointestinal illnesses during the first 2 years of life in children from a peri-urban community of Dhaka, Bangladesh. Characteristics of the mothers, as well as birth characteristics of infants enrolled in the Microbiota and Health Study are presented here. We will determine any potential association between microbiota composition and the abovementioned illnesses, and also examine the influence of known and hypothesized risk factors on the occurrence of infections. Such putative factors include environmental, socioeconomic, maternal, clinical, and selected genetic factors, namely the variation of the fucosyltransferase genes (FUT2 and FUT3) of mothers and infants. This study will add to current knowledge about these early childhood infectious diseases, and will provide data to generate hypotheses for the development of nutritional approaches to be used as prevention strategies.

Trial registration

The study was retrospectively registered at clinicaltrials.gov as NCT02361164 (February 11, 2015).
The ansa subthalamica: a neglected fiber tract
Authors: Lopes Alho Eduardo Joaquim , Di Lorenzo Alho Ana Tereza , Horn Andreas , M. Martin Maria da Graca , Edlow Brian L , Fischl Bruce , Nagy József , Fonoff Erich T , Hamani Clement , Heinsen Helmut
Published: July 2019

Background

The pallidofugal pathways are classically subdivided into ansa lenticularis, lenticular fasciculus, and subthalamic fasciculus. In addition to these three subsystems, we characterize an anatomical structure that connects the antero-medial pole of the subthalamic nucleus to the ventral portions of the pallidum, both related to limbic processing of information. This bundle has been previously considered to form a part of the ansa lenticularis, however, it shows striking differences on histology and MRI features compared to the ansa lenticularis, and therefore we suggest to denominate it ansa subthalamica.

Objectives

To describe the ansa subthalamica as a different structure than the ansa lenticularis, that can be recognized by different methods (histology, high-field MRI and connectome tractography), including current 3T clinical imaging.

Methods

A complete human brain was histologically processed and submitted to registration procedures to correct for tissue deformations and normalization to MNI space. Coordinates of histological structures were then comparable to high-field (7T) post-mortem and in vivo MRIs, 13 pre-operative 3T imaging of parkinsonian patients and normative connectome tractography. Mean intensity gray values for different structures were measured in Susceptibility-Weighted Images.

Results

It was possible to characterize this structure with different methods and there was significant difference in signal intensity in the ansa subthalamica (hypointense), compared to the ansa lenticularis (hyperintense).

Conclusions

The ansa subhtalamica may represent the anatomical pathway that connects limbic regions of the STN and pallidum, and should be investigated as a possible substrate for limbic effects of stereotactic surgery of the subthalamic region.
Considerations in the deployment of novel universal vaccines against epidemic and pandemic influenza
Authors: Arinaminpathy N , Riley S , Barclay W.S , Saad-Roy C , Grenfell B
Published: July 2019

There is increasing interest in the development of new, ‘universal’ influenza vaccines (UIV) that - unlike current vaccines - are effective against a broad range of seasonal influenza strains, as well as against novel pandemic viruses. Even where these vaccines do not block infection, they can moderate clinical severity, reducing morbidity and mortality while potentially also reducing opportunities for transmission. Previous modelling studies have illustrated the potential epidemiological benefits of UIVs, including their potential to mitigate pandemic burden. However, these new vaccines could shape population immunity in complex ways. Here, using mathematical models of influenza transmission, we illustrate two types of unintended consequences that could arise from their future deployment. First, by reducing the amount of infection-induced immunity in a population without fully replacing it, a seasonal UIV programme may permit larger pandemics than in the absence of vaccination. Second, the more successful a future UIV programme is in reducing transmission of seasonal influenza, the more vulnerable the population could become to the emergence of a vaccine-escape variant. These risks could be mitigated by optimal deployment of any future UIV vaccine: namely, the use of a combined vaccine formulation (incorporating conventional as well as multiple universal antigenic targets), and by achieving sufficient population coverage to compensate for reductions in infection-induced immunity. As early candidates of UIVs approach advanced clinical trials, there is a need to monitor their characteristics in such a way that is focused on their potential impact. This work offers a first step in this direction.
Maintenance of adaptive dynamics and no detectable load in a range-edge out-crossing plant population
Authors: Takou Margarita , Hämälä Tuomas , Koch Evan M. , Steige Kim A. , Dittberner Hannes , Yant Levi , Genete Mathieu , Sunyaev Shamil , Castric Vincent , Vekemans Xavier , Savo-lainen Outi , de Meaux Juliette
Published: July 2019

During range expansion, edge populations are expected to face increased genetic drift, which in turn can alter and potentially compromise adaptive dynamics, preventing the removal of deleterious mutations and slowing down adaptation. Here, we contrast populations of the European sub-speciesArabidopsis lyratassppetraea, which expanded its Northern range after the last glaciation. We document a sharp decline in effective population size in the range-edge population and observe that non-synonymous variants segregate at higher frequencies. We detect a 4.9% excess of derived non-synonymous variants per individual in the range-edge population, suggesting an increase of the genomic burden of deleterious mutations. Inference of the fitness effects of mutations and modeling of allele frequencies under the explicit demographic history of each population predicts a depletion of rare deleterious variants in the range-edge population, but an enrichment for fixed ones, consistent with the bottleneck effect. However, the demographic history of the range-edge population predicts a small net decrease in per-individual fitness. Consistent with this prediction, the range-edge population is not impaired in its growth and survival measured in a common garden experiment. We further observe that the allelic diversity at the self-incompatibility locus, which ensures strict outcrossing and evolves under negative frequency-dependent selection, has remained unchanged. Genomic footprints indicative of selective sweeps are broader in the Northern population but not less frequent. We conclude that the outcrossing speciesA. lyratassppetraeashows a strong resilience to the effect of range expansion.
Template plasmid integration in germline genome-edited cattle
Authors: Norris Alexis L. , Lee Stella S. , Greenlees Kevin J. , Tadesse Daniel A. , Miller Mayumi F. , Lombardi Heather
Published: July 2019

We analyzed publicly available whole genome sequencing data from cattle which were germline genome-edited to introduce polledness. Our analysis discovered the unintended heterozygous integration of the plasmid and a second copy of the repair template sequence, at the target site. Our finding underscores the importance of employing screening methods suited to reliably detect the unintended integration of plasmids and multiple template copies.
Transpeptidase PBP2 governs initial localization and activity of major cell-wall synthesis machinery inEscherichia coli
Authors: Wollrab Eva , Özbaykal Gizem , Vigouroux Antoine , Cordier Baptiste , Simon Francois , Chaze Thibault , Matondo Mariette , van Teeffelen Sven
Published: July 2019

Bacterial shape is physically determined by the peptidoglycan cell wall. The cell-wall-synthesis machinery responsible for rod shape inEscherichia coliis the processive ‘Rod complex’. Previously, cytoplasmic MreB filaments were thought to govern formation and localization of Rod complexes based on local cell-envelope curvature. However, using single-particle tracking of the transpeptidase PBP2, we found strong evidence that PBP2 initiates new Rod complexes by binding to a substrate different from MreB or any known Rod-complex component. This substrate is likely the cell wall. Consistently, we found only weak correlations between MreB and envelope curvature in the cylindrical part of cells. Residual correlations do not require any curvature-based Rod-complex initiation but can be attributed to persistent rotational motion. Therefore, local cell-wall architecture likely provides the cue for PBP2 binding and subsequent Rod-complex initiation. We also found that PBP2 has a limiting role for Rod-complex activity, thus supporting its central role.
Pathogenic and uncertain genetic variants have clinical cardiac correlates in diverse biobank participants
Authors: Pottinger Tess D. , Puckelwartz Megan J. , Pesce Lorenzo L. , Robinson Avery , Kearns Samuel , Pacheco Jennifer A. , Rasmussen-Torvik Laura J. , Smith Maureen E. , Chisholm Rex , McNally Elizabeth M.
Published: July 2019

Background

Genome sequencing coupled with electronic heath record data can uncover medically important genetic variation. Interpretation of rare genetic variation and its role in mediating cardiovascular phenotypes is confounded by variants of uncertain significance.

Methods and Results

We analyzed the whole genome sequence of 900 racially and ethnically diverse biobank participants selected from a single US center. Participants were equally divided among European, African, Hispanic, and mixed race/ethnicities. We evaluated the American College of Medical Genetics and Genomics medically actionable list of 59 genes focusing on the cardiac genes. Variation was interpreted using the most recent reports in ClinVar, a database of medically relevant human variation. We identified 19 individuals with pathogenic/likely pathogenic variants in cardiac actionable genes (2%) and found evidence for clinical correlates in the electronic health record. African ancestry participants had more variants of uncertain significance in the medically actionable genes including the 30 cardiac actionable genes, even when normalized to total variant count per person. Longitudinal measures of left ventricle size, corrected for body surface area, from approximately 400 biobank participants (1,723 patient years) correlated with genetic findings. The presence of one or more uncertain variants in the actionable cardiac genes and a cardiomyopathy diagnosis correlated with increased left ventricular internal diameter in diastole and in systole. In particular, MYBPC3 was identified as a gene with excess variants of uncertain significance.

Conclusions

These data indicate a subset of uncertain variants may confer risk and should not be considered benign.
Efficient RNP-directed human gene targeting reveals SPDEF is required for IL-13-induced mucostasis
Authors: Koh Kyung Duk , Siddiqui Sana , Cheng Dan , Bonser Luke R. , Sun Dingyuan I. , Zlock Lorna T. , Finkbeiner Walter E. , Woodruff Prescott G. , Erle David J.
Published: July 2019

Primary human bronchial epithelial cell (HBEC) cultures are a useful model for studies of lung health and major airway diseases. However, mechanistic studies have been limited by our ability to selectively disrupt specific genes in these cells. Here we optimize methods for gene targeting in HBECs by direct delivery of single guide RNA (sgRNA) and recombinant Cas9 (rCas9) complexes by electroporation, without a requirement for plasmids, viruses, or antibiotic selection. Variations in the method of delivery, sgRNA and rCas9 concentrations, and sgRNA sequences all had effects on targeting efficiency, allowing for predictable control of the extent of gene targeting and for near complete disruption of gene expression. To demonstrate the value of this system, we targeted SPDEF, which encodes a transcription factor previously shown to be essential for the differentiation of MUC5AC-producing goblet cells in mouse models of asthma. Targeting SPDEF led to proportional decreases in MUC5AC expression in HBECs stimulated with IL-13, a central mediator of allergic asthma. Near-complete targeting of SPDEF abolished IL-13-induced MUC5AC expression and goblet cell differentiation. In addition, targeting of SPDEF prevented IL-13-induced impairment of mucociliary clearance, which is likely to be an important contributor to airway obstruction, morbidity, and mortality in asthma. We conclude that direct delivery of sgRNA and rCas9 complexes allows for predictable and efficient gene targeting and enables mechanistic studies of disease-relevant pathways in primary HBECs.
Sleep regulates the glial engulfment receptor Draper to promote Wallerian degeneration
Authors: Stahl Bethany A. , Jaggard James B. , Keene Alex C.
Published: July 2019

Sleep, a universal behavior, is critical for diverse aspects of brain function. Chronic sleep disturbance is associated with numerous health consequences, including neurodegenerative disease and cognitive decline. Neurite damage due to apoptosis, trauma, or genetic factors is a common feature of aging, and clearance of damaged neurons is essential for maintenance of brain function. In the central nervous system, damaged neurites are cleared by Wallerian degeneration, in which activated microglia and macrophages engulf damaged neurons. The fruit fly Drosophila melanogaster provides a powerful model for investigating the relationship between sleep and Wallerian degeneration. Several lines of evidence suggest that glia influence sleep duration, sleep-mediated neuronal homeostasis, and clearance of toxic substances during sleep, raising the possibility that glial engulfment of damaged axons is regulated by sleep. To explore this possibility, we axotomized olfactory receptor neurons and measured the effects of sleep loss or gain on the clearance of damaged neurites. Mechanical sleep deprivation impaired the clearance of damaged neurites, whereas the sleep-promoting drug gaboxadol accelerated clearance. In sleep-deprived animals, multiple markers of glial activation were delayed, including activation of the JAK/STAT pathway, upregulation of the cell corpse engulfment receptor Draper, and innervation of the antennal lobe by glial membranes. These markers were all enhanced when sleep was induced in gaboxadol-treated flies. Taken together, these findings reveal a critical role for sleep in regulation glial activation and engulfment following axotomy, providing a platform for further investigations of the molecular mechanisms underlying sleep-dependent modulation of glial function and neurite clearance.

Highlights

Sleep deprivation impairs Wallerian degeneration in fruit flies.

Pharmacological induction of sleep accelerates Wallerian degeneration.

Sleep promotes innervation surrounding damaged neurites by phagocytic glia.

Sleep increases levels of the glial activation markers Draper and Stat92E.
Deep sampling of HawaiianCaenorhabditis elegansreveals high genetic diversity and admixture with global populations
Authors: Crombie Timothy A. , Zdraljevic Stefan , Cook Daniel E. , Tanny Robyn E. , Brady Shannon C. , Wang Ye , Evans Kathryn S. , Hahnel Steffen , Lee Daehan , Rodriguez Briana C. , Zhang Gaotian , van der Zwaag Joost , Kiontke Karin C. , Andersen Erik C.
Published: July 2019

Recent efforts to understand the natural niche of the keystone model organismCaenorhabditis eleganshave suggested that this species is cosmopolitan and associated with rotting vegetation and fruits. However, most of the strains isolated from nature have low genetic diversity likely because recent chromosome-scale selective sweeps contain alleles that increase fitness in human-associated habitats. Strains from the Hawaii Islands are highly divergent from non-Hawaiian strains. This result suggests that Hawaiian strains might contain ancestral genetic diversity that was purged from most non-Hawaiian strains by the selective sweeps. To characterize the genetic diversity and niche of HawaiianC. elegans, we sampled across the Hawaiian Islands and isolated 100 newC. elegansstrains. We found thatC. elegansstrains are not associated with any one substrate but are found in cooler climates at high elevations. These Hawaiian strains are highly diverged compared to the rest of the global population. Admixture analysis identified 11 global populations, four of which are from Hawaii. Surprisingly, one of the Hawaiian populations shares recent ancestry with non-Hawaiian populations, including portions of globally swept haplotypes. This discovery provides the first evidence of gene flow between Hawaiian and non-Hawaiian populations. Most importantly, the high levels of diversity observed in Hawaiian strains might represent the complex patterns of ancestral genetic diversity in theC. elegansspecies before human influence.
Tunable hetero-assembly of a plant pseudoenzyme-enzyme complex
Authors: Novikova Irina V. , Zhou Mowei , Du Chen , Parra Marcelina , Kim Doo Nam , VanAernum Zachary L. , Shaw Jared B. , Hellmann Hanjo , Wysocki Vicki H. , Evans James E.
Published: July 2019

Pseudoenzymes have emerged as key regulatory elements in all kingdoms of life despite being catalytically non-active. Yet many factors defining why one protein is active while its homolog is inactive remain uncertain. For pseudoenzyme-enzyme pairs, the similarity of both subunits can often hinder conventional characterization approaches. In plants, a pseudoenzyme PDX1.2 positively regulates vitamin B6 production by association with its active catalytic homologs such as PDX1.3 through an unknown mechanism. Here we used an integrative experimental approach to learn that such pseudoenzyme-enzyme pair associations result in hetero-complexes of variable stoichiometry, which are unexpectedly tunable. We also present the atomic structure of the PDX1.2 pseudoenzyme as well as the population averaged PDX1.2-PDX1.3 pseudoenzyme-enzyme pair. Finally, we dissected hetero-dodecamers of each stoichiometry to understand the arrangement of monomers in the hetero-complexes and identified symmetry- imposed preferences in PDX1.2-PDX1.3 interactions. Our results provide a new model of pseudoenzyme-enzyme interactions and their native heterogeneity.