bluuebunny/crossref_metadata_2025 huggingface dataset:
Research Capacity Strengthening in American Samoa: Fa’avaeina le Fa’atelega o le Tomai Sa’ili’ili i Amerika Samoa
Authors: Tofaeono Va’atausili , Ka’opua Lana Sue I , Sy Angela , Terada Tyran , Taliloa-Vai Purcell Rachelann , Aoelua-Fanene Salote , Tong Katherine , Tofaeono Victor , Unutoa-Mageo Tofoipupu , Scanlan Luana , Cassel Kevin , Rosario Adelaida
Published: December 2019

Capacity-building partnerships are central to the sustainable development goals (SDGs), the UN’s blueprint for achieving global health equity. The UN Permanent Forum on Indigenous Issues endorses the SDG and underscores the need for global partnerships that respect local leadership and culture. Innovations that weave or integrate Indigenous and Western knowledges are emphasised. These recommendations guided the INdigenous Samoan Partnership to Initiate Research Excellence (INSPIRE). INSPIRE is led by investigators from American Samoa and supported by US co-investigators. In project year one, INSPIRE queried: What weaving approaches are feasible for promoting community access to INSPIRE’s research hub and for training Indigenous researchers? Weaving procedures involved interlacing Samoan and Western knowledges. Cultural tailoring strategies were used to customise communications. Formative evaluation suggests the feasibility of INSPIRE’s efforts. Evidential tailoring provided information on American Samoa (A.S.) social determinants of health; trainees indicated increased research commitment. Linguistic and sociocultural relevance tailoring were positively received; trainees reported increased interest in research praxis and initiated an A.S. research capacity-strengthening model. Social work assured knowledge parity in development/delivery of the training curriculum and culturally safe discussions on social determinants of health, territorial status and Samoan survivance. Findings are context-specific yet offer considerations for capacity-strengthening partnerships seeking to advance health equity.
Development of an international standard set of outcome measures for patients with atrial fibrillation: a report of the International Consortium for Health Outcomes Measurement (ICHOM) atrial fibrillation working group
Authors: Seligman William H , Das-Gupta Zofia , Jobi-Odeneye Adedayo O , Arbelo Elena , Banerjee Amitava , Bollmann Andreas , Caffrey-Armstrong Bridget , Cehic Daniel A , Corbalan Ramon , Collins Michael , Dandamudi Gopi , Dorairaj Prabhakaran , Fay Matthew , Van Gelder Isabelle C , Goto Shinya , Granger Christopher B , Gyorgy Bathory , Healey Jeff S , Hendriks Jeroen M , Hills Mellanie True , Hobbs F D Richard , Huisman Menno V , Koplan Kate E , Lane Deirdre A , Lewis William R , Lobban Trudie , Steinberg Benjamin A , McLeod Christopher J , Moseley Spencer , Timmis Adam , Yutao Guo , Camm A John
Published: December 2019

Aims

As health systems around the world increasingly look to measure and improve the value of care that they provide to patients, being able to measure the outcomes that matter most to patients is vital. To support the shift towards value-based health care in atrial fibrillation (AF), the International Consortium for Health Outcomes Measurement (ICHOM) assembled an international Working Group (WG) of 30 volunteers, including health professionals and patient representatives to develop a standardized minimum set of outcomes for benchmarking care delivery in clinical settings.

Methods and results

Using an online-modified Delphi process, outcomes important to patients and health professionals were selected and categorized into (i) long-term consequences of disease outcomes, (ii) complications of treatment outcomes, and (iii) patient-reported outcomes. The WG identified demographic and clinical variables for use as case-mix risk adjusters. These included baseline demographics, comorbidities, cognitive function, date of diagnosis, disease duration, medications prescribed and AF procedures, as well as smoking, body mass index (BMI), alcohol intake, and physical activity. Where appropriate, and for ease of implementation, standardization of outcomes and case-mix variables was achieved using ICD codes. The standard set underwent an open review process in which over 80% of patients surveyed agreed with the outcomes captured by the standard set.

Conclusion

Implementation of these consensus recommendations could help institutions to monitor, compare and improve the quality and delivery of chronic AF care. Their consistent definition and collection, using ICD codes where applicable, could also broaden the implementation of more patient-centric clinical outcomes research in AF.
The impact of hormones and reproductive factors on the risk of bladder cancer in women: results from the Nurses’ Health Study and Nurses’ Health Study II
Authors: Abufaraj Mohammad , Shariat Shahrokh , Moschini Marco , Rohrer Florian , Papantoniou Kyriaki , Devore Elizabeth , McGrath Monica , Zhang Xuehong , Markt Sarah , Schernhammer Eva
Published: December 2019

Background

With three out of four new bladder cancer (BCa) cases occurring in men, an apparent gender disparity exists. We aimed to investigate the role of hormonal and reproductive factors in BCa risk using two large female US prospective cohorts.

Methods

Our study population comprised 118 256 and 115 383 female registered nurses who were recruited in the Nurses' Health Study (NHS) and NHS II, respectively. Reproductive and hormonal factors and other relevant data were recorded in biennial self-administered questionnaires. Cox-regression analyses were performed to estimate age- and multivariable-adjusted incidence risk ratios (IRRs) and 95% confidence intervals (CIs). Inverse-variance-weighted meta-analysis was used to pool estimates across cohorts.

Results

During up to 36 years of follow-up, 629 incident BCa cases were confirmed. In the NHS, 22 566 women (21.3%) were postmenopausal at baseline, compared with 2723 women (2.4%) in the NHS II. Among women in the NHS, younger age at menopause (≤45 years) was associated with an increased risk of BCa (IRR: 1.41, 95% CI: 1.11–1.81, Ptrend = 0.01) compared with those with menopause onset at age 50+ years, particularly among ever-smokers (IRR for age at menopause ≤45 years: 1.53, 95% CI: 1.15–2.04; PIntx = 0.16). Age at menarche and first birth, parity, oral-contraceptive use and postmenopausal hormone use were not associated with BCa risk.

Conclusions

Overall, we found little support for an association between female reproductive factors and BCa risk in these prospective cohort studies. Earlier age at menopause was associated with a higher risk of BCa, particularly among smokers, indicating the potential for residual confounding.
The governance of genomic biobank research in Africa: reframing the regulatory tilt
Authors: Staunton Ciara , de Vries Jantina
Published: December 2019

Genomic biobank research has experienced exponential growth in recent years. It represents a real opportunity to remedy global health inequity that has seen limited investment in diseases affecting populations from low- and middle-income countries. Previous research in Africa was limited to so-called parachute research, whereby samples were taken from local populations for use in high-income countries with no local oversight or use of the sample. These exploitative practices must be guarded against, but the current regulation of genomic research in Africa adopts a precautionary approach that at times is restrictive in nature. We argue that the regulation and oversight of genomic biobank research should guard against exploitative research, but in a manner that promotes reciprocal benefit and not restrictive research practices. To achieve this, there must be a rebalancing of the regulatory tilt.
Comminuted Femur Fracture in a Free Fall Jump: A Case Report
Authors: Bridwell Rachel E , Oliver Joshua J , Ziehl Danielle , Tannenbaum Lloyd I , McCarthy Patrick M
Published: December 2019

Military free fall or high-altitude low-opening parachute jumps play a key role in special operations tactics, though injury patterns in these operators are not well characterized. In contrast to lower-altitude static line paratroopers, free fall operators require precise parachute deployment after a prolonged descent, with the potential for high-velocity trauma. This report describes a 33-year-old Marine Corps Reconnaissance operator who sustained left comminuted basicervical femoral neck fracture requiring cephalomedullary nail internal fixation with a full recovery. This femoral neck fracture highlights the high-energy injuries experienced by these invaluable operators, especially when conducting combat or night jumps.
On the gravitational field of a point-like body immersed in a quantum vacuum
Authors: Hajdukovic Dragan Slavkov
Published: December 2019

Quantum vacuum and the matter immersed in it interact through electromagnetic, strong and weak interactions. However, we have zero knowledge of the gravitational properties of the quantum vacuum. As an illustration of the possible fundamental gravitational impact of the quantum vacuum, we study the gravitational field of an immersed point-like body. This is done under the working hypothesis, that quantum vacuum fluctuations are virtual gravitational dipoles (i.e. two gravitational charges of the same magnitude but opposite sign); coincidentally, this hypothesis makes quantum vacuum free of the cosmological constant problem. The major result is that a point-like body creates a halo of polarized quantum vacuum around itself, which acts as an additional source of gravity. There is a maximal magnitude ${g_{\rm qv\max}}$ of gravitational acceleration that can be caused by a polarized quantum vacuum; the small size of this magnitude (${g_{\rm qv\max}} < 6\ \times {10^{ - 11}}\,\mathrm{ m\,s}{^{-2}}$) is the reason why in some cases (for instance within the Solar system) the quantum vacuum can be neglected. Advanced experiments at CERN and forthcoming astronomical observations will reveal if this is true or not, but we point to already existing empirical evidence that seemingly supports this fascinating possibility.
Long-term participation of Dutch service members with combat-related injury
Authors: de Kruijff L G M , Schröder C D , Plat M-C J , van Dongen T T C F , Hoencamp R , van der Wurff P
Published: December 2019

Background

After deployment service members need to adapt to civilian life and return to participation in family, vocational and community life.

Aims

To assess the level of activity and participation of service members with combat-related injury after their rehabilitation intervention and to measure the effect of injury severity, adaptive coping, number of deployments and traumatic stress.

Methods

The physical functioning scale of the 36-Item Short Form Health Survey (SF-36 PF), the Assessment of Life Habits short version (LIFE-H), the Impact of Event Scale (IES-R) and the Cognitive Emotion Regulation Questionnaire (CERQ) were administered to service members who sustained combat-related injury. The Injury Severity Score (ISS) was calculated, and the number of deployments was noted. Correlations were calculated between the LIFE-H and ISS, IES-R, number of deployments and adaptive coping and between the SF-PF and ISS, IES-R, number of deployments and adaptive coping.

Results

The response rate was 55% (32 service members). A moderate correlation was found between LIFE-H and IES (r = −0.49) and a very weak correlation was found between LIFE-H and injury severity (r = 0.31). No correlation was found between SF-36 PF and ISS, IES, number of deployments or CERQ and between LIFE-H and number of deployments or CERQ.

Conclusions

A moderate correlation was found between level of participation and traumatic stress in service members with combat-related injury in a 5-year follow-up. Therefore, it is advisable to screen for traumatic stress symptoms and monitor these symptoms during the rehabilitation intervention.
How hard is it to maximize profit? Evidence from a 19th-century Italian state monopoly
Authors: Ciccarelli Carlo , De Fraja Gianni , Tiezzi Silvia
Published: December 2019

In this paper, we study the ability of the 19th-century Italian government to choose profit maximizing prices for a multiproduct monopolist. We use very detailed historical data on the tobacco consumption in 62 Italian provinces from 1871 to 1888 to estimate a differentiated product demand system. The demand conditions and the legal environment of the period made this market as close to a textbook monopoly as is practically possible. The government’s stated aim for this industry was profit maximization: since at the time profits from tobacco were close to 10% of the revenues for the cash-strapped government, the stated aim was very likely the true one. Our empirical application uses historical price and cost data, and suggests that the government was not wide off the mark: the tobacco prices were ‘not far’ from those dictated by the multiproduct monopoly formulae for profit maximization with interdependent demand functions.
The Effects of the Amount of Fluid Used in Epiduroscopic Laser Neural Discectomy Procedures on Intraocular Pressure and an Evaluation of the Ocular Findings
Authors: Beyaz Serbülent Gökhan , Ülgen Ali Metin , Çakir Burçin
Published: December 2019

Introduction

During epiduroscopic laser neural discectomy (ELNP) procedures, the amount of fluid used in the epidural area may cause increased intracranial pressure. This study aimed to investigate the effect of increased epidural pressure on intraocular pressure and other ocular findings due to the amount of fluid delivered to the epidural area and the rate of delivery of the fluid.

Material and Methods

After obtaining approval from the Ethics Committee of Sakarya University Faculty of Medicine, patients who underwent ELNP in the Department of Anesthesiology and Reanimation Department, Algology Clinic, between January 2017 and May 2017 were included in this retrospective study. To evaluate the ocular findings after the operation, measurements obtained using an optical coherence tomography device were retrieved from the patient files and evaluated.

Results

Data from the medical files of 52 patients from the hospital system were evaluated. There was no significant difference between preoperative and postoperative retinal nerve fiber layer (RNFL) thickness, mean central macular thickness, optic disk area, and vertical cup-to-disk ratio (P > 0.05).

Conclusions

Epiduroscopy procedures include intermittent or continuous infusion of saline into the epidural area. Currently, the volume of fluid that should be given to the epidural area in epiduroscopy procedures is very controversial. As a result of this study, we concluded that the amount of fluid used during ELNP, at 107.25 mL and 8.33 mL/min, had no effect on the intraocular pressure, optic disk diameter, macular thickness, or peripapillary RNFL thickness; thus, it was safe for ELNP.
Shining a Light Into the Black Box of Group Learning: Medical Students’ Experiences and Perceptions of Small Groups
Authors: Park Charles , Wu Claire , Regehr Glenn
Published: December 2019

Purpose

Group work is seen as serving multiple positive purposes in health professions education, such as providing an opportunity for students to master course content, transfer knowledge into clinical practice, and develop collaborative/teamwork skills. However, there have been relatively few studies exploring medical students’ experiences of the small-group learning context or what they learn in and from that context.

Method

Between January 2018 and January 2019, the authors used grounded theory methods to conduct semistructured interviews with 9 medical students to explore their perceptions of the value of the group as a mechanism for learning both content and teamwork skills. Sessions were audiorecorded and transcribed verbatim. One author coded the transcripts and identified codes, which the team then discussed, refined, and used to develop themes.

Results

Students were able to express all the expected goals for small-group learning, such as retaining course materials, mimicking future health care team interactions, and creating a collaborative environment. However, when their experiences were further explored, students seemed to have perceived that the value of group learning was as a mechanism for reviewing rather than for deepening their learning. Further, students frequently expressed the opinion that the tutor was the primary factor in the success of a group, and when group function was suboptimal, students described giving up on the group or relying on the tutor to address the problem.

Conclusions

Formal, small-group, tutor-led learning sessions, at least in the context of single-term groups, may not be accomplishing what educators might hope. Although students understand the intent of small-group learning, it cannot be assumed that such groups are deepening learning or solving the teamwork problems in health professions education.
Revealing Novel IDEAS: A Fiduciary Framework for Team-Based Prescribing
Authors: Plowman R. Scooter , Peters Stephanie R. , Brady Brian M. , Osterberg Lars G.
Published: December 2019

The importance of safe, effective, and cost-effective prescribing habits can hardly be overstated in the current pay-for-value environment. The prescribing process taught in most medical curricula focuses primarily on accurate medical indications. While this may be of utmost importance from the clinician’s perspective, it falls short of addressing the other key elements of highly effective prescribing. These other elements are often paramount in the minds of patients. A patient-centric framework that associates and incorporates the necessary components of optimal prescribing is overdue. Building this framework into medical curricula will foster increased teamwork among providers and enhance shared decision making between patients and clinicians. In addition to establishing accurate medical indications, prescribing teams need to assure every prescribed medication is desired, effective, affordable, and safe for patients who receive them. Prescription writing is an honorable prerogative, and doing so safely, effectively, and cost-effectively requires both teamwork and technology. Highly effective prescribing teams can implement the IDEAS (Indicated, Desired, Effective, Affordable, Safe) framework through appropriate and deliberate delegation. By empowering members of the care team to support and educate patients, this framework will allow physicians to focus on ensuring appropriate indications and real-world effectiveness. This novel IDEAS framework serves as an important mental model for medical trainees and reinforces sound prescribing habits among seasoned clinicians. High-touch and high-tech partnerships have the potential to maximize the triple aim (i.e., improving the patient’s experience of care, improving the health of populations, and reducing the per capita cost of health care). In an era when costs overwhelm quality, providing a fiduciary framework to instill responsibility for optimal prescribing, especially among young physician–leaders, is invaluable.
Associations of Intraoperative Radial Arterial Systolic, Diastolic, Mean, and Pulse Pressures with Myocardial and Acute Kidney Injury after Noncardiac Surgery
Authors: Ahuja Sanchit , Mascha Edward J. , Yang Dongsheng , Maheshwari Kamal , Cohen Barak , Khanna Ashish K. , Ruetzler Kurt , Turan Alparslan , Sessler Daniel I.
Published: December 2019

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New

Background

Arterial pressure is a complex signal that can be characterized by systolic, mean, and diastolic components, along with pulse pressure (difference between systolic and diastolic pressures). The authors separately evaluated the strength of associations among intraoperative pressure components with myocardial and kidney injury after noncardiac surgery.

Methods

The authors included 23,140 noncardiac surgery patients at Cleveland Clinic who had blood pressure recorded at 1-min intervals from radial arterial catheters. The authors used univariable smoothing and multivariable logistic regression to estimate probabilities of each outcome as function of patients’ lowest pressure for a cumulative 5 min for each component, comparing discriminative ability using C-statistics. The authors further assessed the association between outcomes and both area and minutes under derived thresholds corresponding to the beginning of increased risk for the average patient.

Results

Out of 23,140 patients analyzed, myocardial injury occurred in 6.1% and acute kidney injury in 8.2%. Based on the lowest patient blood pressure experienced for greater than or equal to 5 min, estimated thresholds below which the odds of myocardial or kidney injury progressively increased (slope P < 0.001) were 90 mmHg for systolic, 65 mmHg for mean, 50 mmHg for diastolic, and 35 mmHg for pulse pressure. Weak discriminative ability was noted between the pressure components, with univariable C-statistics ranging from 0.55 to 0.59. Area under the curve in the highest (deepest) quartile of exposure below the respective thresholds had significantly higher odds of myocardial injury after noncardiac surgery and acute kidney injury compared to no exposure for systolic, mean, and pulse pressure (all P < 0.001), but not diastolic, after adjusting for confounding.

Conclusions

Systolic, mean, and pulse pressure hypotension were comparable in their strength of association with myocardial and renal injury. In contrast, the relationship with diastolic pressure was poor. Baseline factors were much more strongly associated with myocardial and renal injury than intraoperative blood pressure, but pressure differs in being modifiable.
Metformin mediated microRNA-7 upregulation inhibits growth, migration, and invasion of non-small cell lung cancer A549 cells
Authors: Dong Jingying , Peng Heng , Yang Xiaolong , Wu Wenbing , Zhao Yanan , Chen Dan , Chen Lihong , Liu Ji
Published: December 2019

Metformin, a medication widely used in the treatment of type 2 diabetes mellitus, has a possible antitumor effect in type 2 diabetes mellitus patients. MicroRNA-7 is a significant microRNA in non-small cell lung cancer. Metformin has an inhibitory effect on lung cancer and regulates the expression of certain microRNAs, but there is no report connecting metformin with microRNA-7 in lung cancer. Thus, we used qPCR to measure microRNA-7 expression in A549 non-small cell lung cancer cells treated with metformin. We used CCK8, cell scratch, and Transwell assays to test the growth, migration, and invasion of A549 cells. Western blotting was used to measure the expression level of relevant proteins in A549 cells. We found that microRNA-7 was dramatically upregulated by metformin via AMPK in a dose- and time-dependent manner. Both metformin and microRNA-7 mimic reduced A549 cell growth, migration, and invasion. Metformin downregulated the levels of p-NF-κB p65, p-Erk1/2, p-AKT, and p-mTOR proteins. The treatment with the microRNA-7 mimic had the same result. The decrease of these proteins caused the inhibition of A549 cell growth, migration, and invasion. Our discovery revealed that metformin, via increasing the expression of microRNA-7 mediated by AMPK, regulates the AKT/mTOR, MAPK/Erk, and NF-κB signaling pathways, thereby suppressing A549 cell growth, migration, and invasion.
Band-like Lipomatous Metaplasia of the Superficial Dermis and Nonseptate Subcutaneous Tissue: A Rare Histopathological Phenomenon With Ultrasonographic Correlation
Authors: Portilla Nataly , Quintana-Codina Mónica , Olivé Marta , Pérez-Muñoz Noelia , Salleras Montse , Fernández-Figueras María Teresa
Published: December 2019

Lipomatous metaplasia of the upper dermis is a rare phenomenon scarcely described in the literature which has always been identified in the context of inflammatory or neoplastic processes. Microscopically, it should be distinguished from pseudolipomatosis cutis, dermal lipoma, nevus lipomatosus, and focal dermal hypoplasia (Goltz syndrome). This is the first report of the histologic and ultrasound evaluation of a patient with extensive involvement and the description of the coincidental finding of an anomalous nonseptate subcutaneous tissue.
Fragmented Elastic Fibers in Focal Dermal Hypoplasia (Goltz–Gorlin Syndrome) Without Focal Dermal Hypoplasia: Report of a Male Case and Review of the Literature
Authors: Rohdenburg Christina , Liersch Julia , Kutsche Kerstin , Schaller Joerg
Published: December 2019

Goltz–Gorlin syndrome (GGS) (focal dermal hypoplasia) is a very rare developmental disorder affecting ectodermal and mesodermal structures. The syndrome is inherited in an X-linked manner, with the majority of affected individuals being female. We report the case of a 51-year-old man presenting with congenital skin lesions, syndactyly, facial and thoracic asymmetry, inguinal and laryngeal papillomas, cryptorchidism, polythelia, and dental anomalies. Molecular genetic analysis confirmed the clinically suspected diagnosis of GGS by detecting a known pathogenic mutation in the PORCN gene, c.502G>A [p.(Gly168Arg)] in the mosaic state. Histopathological examinations of skin biopsies of affected individuals typically show focal dermal hypoplasia and fat herniation; despite numerous skin biopsies, these characteristics were not found in the patient involved. Instead, we observed a notable reduction and fragmentation of the elastic fibers in the upper dermis. A systematic literature review regarding the histopathological presence or absence of dermal hypoplasia and/or information on elastic fibers revealed 240 histopathological descriptions of 173 individuals. Absence of dermal hypoplasia was found in 21 biopsies (8.8%). Information on elastic fibers was given in 47 cases (19.6%), showing decrease/absence in 31 cases and fragmentation of elastic fibers in 11 cases. Therefore, the histopathological absence of dermal hypoplasia does not exclude the diagnosis of the GGS. Decrease and fragmentation of elastic fibers may represent new histopathological clues to the diagnosis of this rare syndrome. At the same time, GGS should be included in the histopathological differential diagnoses of elastolytic disorders.
Cytokine release syndrome: a primer for generalists
Authors: Soares Tiago , Fok Henry
Published: December 2019

Cytokine release syndrome (CRS) is an adverse drug reaction that is poorly understood but is likely to be increasingly common as more immunotherapeutics are being developed and licensed, principally in the treatment of cancer. Early recognition and aggressive treatment of this potentially rapidly fatal systemic inflammatory response syndrome (SIRS) is the key to a better outcome for this adverse drug reaction.
Comparison of 5-Year Clinical Results of Descemet and Non-Descemet Stripping Automated Endothelial Keratoplasty
Authors: Omoto Takashi , Toyono Tetsuya , Inoue Tatsuya , Shirakawa Rika , Yoshida Junko , Miyai Takashi , Yamagami Satoru , Usui Tomohiko
Published: December 2019

Purpose:

To compare 5-year clinical results of non-Descemet stripping automated endothelial keratoplasty (nDSAEK) and DSAEK.

Methods:

A retrospective chart review involving patients with non–Fuchs-type bullous keratoplasty who underwent nDSAEK or DSAEK 5 years before the review was performed on demographics, graft survival rate, endothelial cell density (ECD), best-corrected visual acuity (BCVA), and complications.

Results:

Fifty eyes (nDSAEK 28, DSAEK 22) were included in this study. Common indications for surgery were bullous keratopathy due to glaucoma, cataract surgeries, or laser iridotomy. The graft survival rates in nDSAEK and DSAEK eyes at 1, 3, and 5 years were 0.75 and 0.86, 0.67 and 0.81, and 0.59 and 0.74, respectively. The mean donor ECDs of nDSAEK and DSAEK eyes were 2638 and 2503 cells/mm2, respectively; these decreased to 1654 and 1406, 1503 and 1218, and 1108 and 1020 cells/mm2 at 1, 3, and 5 years, respectively. The mean preoperative BCVAs of nDSAEK and DSAEK eyes were 1.08 and 1.11 LogMAR, respectively; these improved to 0.238 and 0.190, 0.126 and 0.157, and 0.097 and 0.070 LogMAR at 1, 3, and 5 years, respectively. The most common complication was intraocular pressure elevation. There were no statistically significant differences between nDSAEK and DSAEK in graft survival rates, changes in ECD and BCVA, or the occurrence of postoperative complications, with the exception of the change in ECD at 2 years (1173 and 1193 cells/mm2, P = 0.0159).

Conclusions:

Our 5-year clinical results of nDSAEK and DSAEK did not show significant differences at almost all points.
Disentangling the intertwined roles of mutation, selection and drift in the mitochondrial genome
Authors: Schaack Sarah , Ho Eddie K. H. , Macrae Fenner
Published: December 2019

Understanding and quantifying the rates of change in the mitochondrial genome is a major component of many areas of biological inquiry, from phylogenetics to human health. A critical parameter in understanding rates of change is estimating the mitochondrial mutation rate (mtDNA MR). Although the first direct estimates of mtDNA MRs were reported almost 20 years ago, the number of estimates has not grown markedly since that time. This is largely owing to the challenges associated with time- and labour-intensive mutation accumulation (MA) experiments. But even MA experiments do not solve a major problem with estimating mtDNA MRs—the challenge of disentangling the role of mutation from other evolutionary forces acting within the cell. Now that it is widely understood that any newly generated mutant allele in the mitochondria will initially be at very low frequency (1/N, whereNis the number of mtDNA molecules in the cell), the importance of understanding the effective population size (Ne) of the mtDNA and the size of genetic bottlenecks during gametogenesis and development has come into the spotlight. In addition to these factors regulating the role of genetic drift, advances in our understanding of mitochondrial replication and turnover allow us to more easily envision how natural selection within the cell might favour or purge mutations in multi-copy organellar genomes. Here, we review the unique features of the mitochondrial genome that pose a challenge for accurate MR estimation and discuss ways to overcome those challenges. Estimates of mtDNA MRs remain one of the most widely used parameters in biology, thus accurate quantification and a deeper understanding of how and why they may vary within and between individuals, populations and species is an important goal.

This article is part of the theme issue ‘Linking the mitochondrial genotype to phenotype: a complex endeavour’.
Faraway, so close. The comparative method and the potential of non-model animals in mitochondrial research
Authors: Milani Liliana , Ghiselli Fabrizio
Published: December 2019

Inference from model organisms has been the engine for many discoveries in life science, but indiscriminate generalization leads to oversimplifications and misconceptions. Model organisms and inductive reasoning are irreplaceable: there is no other way to tackle the complexity of living systems. At the same time, it is not advisable to infer general patterns from a restricted number of species, which are very far from being representative of the diversity of life. Not all models are equal. Some organisms are suitable to find similarities across species, other highly specialized organisms can be used to focus on differences. In this opinion piece, we discuss the dominance of the mechanistic/reductionist approach in life sciences and make a case for an enhanced application of the comparative approach to study processes in all their various forms across different organisms. We also enlist some rising animal models in mitochondrial research, to exemplify how non-model organisms can be chosen in a comparative framework. These taxa often do not possess implemented tools and dedicated methods/resources. However, because of specific features, they have the potential to address still unanswered biological questions. Finally, we discuss future perspectives and caveats of the comparative method in the age of ‘big data’.

This article is part of the theme issue ‘Linking the mitochondrial genotype to phenotype: a complex endeavour’.
Transcriptome analysis of Brucella abortus S19∆per immunized mouse spleen revealed activation of MHC-I and MHC-II pathways
Authors: Solanki Khushal Singh , Gandham Ravi Kumar , Thomas Prasad , Chaudhuri Pallab
Published: December 2019

The mouse (Mus musculus) has been extensively used for studying brucellosis, regarding pathogenesis, immunity and the evaluation of vaccines and therapeutics. In this work, RNA-seq was applied to explore the immunological potential of a live

Brucella abortus

S19∆per, a perosamine synthetase gene mutant of

B. abortus

S19. Comparison of transcriptome data was carried out for identifying differentially expressed genes among PBS (control) and

B. abortus

S19∆per immunized mice at 15 days post-immunization. Functional analysis revealed 545 significant differentially expressed genes related to mouse immunity. Specific activation of MHC-I and MHC-II antigen-processing pathways were identified as the highly enriched pathways based on Kyoto Encyclopedia of Genes and Genomes annotation. Other major immune response pathways regulated within the host were NF-kappa B signalling, chemokine signalling, T-cell receptor pathway, apoptosis, TNF signalling and nucleotide-binding oligomerization domain-like receptor signalling. These data provided new insights into the molecular mechanisms of

B. abortus

S19∆per-induced immune response in mice spleen that might facilitate the development of a highly immunogenic vaccine against brucellosis.
Functional characterisation of novel oxidative stress protection proteins in the pathogenic yeast Candida glabrata
Authors: Usher Jane
Published: December 2019

Candida species are important pathogens of humans and are the fourth most commonly isolated pathogen from nosocomial blood stream infections. Although Candida albicans is the principle causative agent of invasive candidiasis, the incidence of C. glabrata infection has grown rapidly. The reason for this increase is not fully understood but it is clear that the species has a higher innate tolerance to commonly administered azole antifungals, in addition to being highly tolerance to combinatorial stresses. Using S. cerevisiae, as a model due to its intrinsic sensitivity to combinatorial stress and hypothesizing that the expression of mediators of Candida glabrata combinatorial stress resistance (CSR) in S. cerevisiae would lead to induced resistance. To test this we transformed, en-masse, the Candida glabrata ORFeome into S. cerevisiae. This resulted in 1,500 CSR colonies and recovered plasmids of 118 ORFS. Sanger sequencing of these plasmids revealed a total of 29 different C. glabrata ORFS. The recovery of genes encoding known stress protectant proteins e.g. GPD1, GPD2 and TRX3 was predicted and validated the integrity of the screen. Through this screen we identified four C. glabrata unique ORFs that confer CSR and we are in the process of characterising.
Development of a new high-throughput method for screening large yeast libraries for use in the beverage industry
Authors: Aguiar-Cervera Jose , Severn Oliver
Published: December 2019

High-throughput techniques have become crucial for the discovery of new strains suitable for the beverage industry. These approaches allow assessment of critical traits for fermented beverages such as; stress tolerance, growth, viability, vitality and aromatic compound production in a fast and effective manner.

The growth rate of 24 Saccharomyces and non-Saccharomyces yeast strains were evaluated in industrially relevant media. High-throughput robotic platforms, the ROTOR HDA and PIXL, were used to pin colonies on solidified synthetic apple juice (SAJ), malt extract (ME), apple juice (AJ) and wort (WO) media. During incubation at 20 and 25 °C for up to 240 hours, the plates were imaged, and analysed via PhenoBooth and the ggplot2 R package. The results were corroborated via liquid growth.

Pichia scullata Y-7663 and Hanseniaspora vineae Y-17530 showed the highest growth values in ME, WO and AJ; with final colony diameters double that of the Saccharomyces cerevisiae ESM356-1 control. However, the former two strains displayed defective growth in SAJ. Kluyveromyces lactis Y-1140 exhibited high growth performance, especially in ME and WO. Interestingly, the ale strain S. cerevisiae Y-11875, showed significantly higher growth in SAJ and AJ medium than in ME and WO. Better adaptation to growth in wort conditions was expected.

This trial shows that the fitness of yeast strains can be assessed in solid media representing industrial conditions. The method can be up-scaled to a wider format, opening the possibility of screening a thousand-fold libraries of industrially relevant and/or novel yeast isolates in a fast, cost-effective manner.
Another look at microbe–metabolite interactions: how scale invariant correlations can outperform a neural network
Authors: Quinn Thomas P. , Erb Ionas
Published: December 2019

Many scientists are now interested in studying the correlative relationships between microbes and metabolites. However, these kinds of analyses are complicated by the compositional (i.e., relative) nature of the data. Recently, Morton et al. proposed a neural network architecture called mmvec to predict metabolite abundances from microbe presence. They introduce this method as a scale invariant solution to the integration of multi-omics compositional data, and claim that “mmvec is the only method robust to scale deviations”. We do not doubt the utility of mmvec, but write in defense of simple linear statistics. In fact, when used correctly, correlation and proportionality can actually outperform the mmvec neural network.
Classic oncogene family Myc defines unappreciated distinct lineage states of small cell lung cancer
Authors: Patel Ayushi S. , Yoo Seungyeul , Kong Ranran , Sato Takashi , Sinha Abhilasha , Bao Li , Fridrikh Maya , Emoto Katsura , Nudelman German , Powell Charles A. , Beasley Mary Beth , Zhu Jun , Watanabe Hideo
Published: December 2019

Comprehensive genomic analyses of small cell lung cancer (SCLC), the most aggressive form of lung cancer, have revealed near universal loss of tumor suppressors (RB1 and TP53) and frequent genomic amplification of all three MYC family members. The amplification of each Myc family member is mutually exclusive; hence it had been long suggested that they are functionally equivalent. However, their expression has more recently been associated with specific neuroendocrine markers and distinct histopathology. In this study, we explored a novel role of c-Myc and L-Myc as lineage determining factors contributing to SCLC molecular subtypes and histology. Integrated analyses of a gene regulatory network generated from mRNA expression of primary SCLC tumor and chromatin state profiling of SCLC cell lines showed that Myc family members impart distinct transcriptional programs associated with lineage state; wherein the L-Myc signature was enriched for neuronal pathways while the c-Myc signature was enriched for Notch signaling and epithelial-to-mesenchymal transition. We investigated the functional redundancy and distinction of c-Myc and L-Myc, and noted the insufficiency of L-Myc to induce lineage switch in contrast to the potential of c-Myc to induce trans-differentiation. c-Myc rewires the Myc-accessible landscape and activates neuron al repressor, Rest to mediate transition from ASCL1-SCLC to NeuroD1-SCLC characterized by distinct LCNEC-like histopathology. Collectively, our findings reveal a previously undescribed role of historically defined general oncogenes, c-Myc and L-Myc, for regulating lineage plasticity across molecular subtypes as well as histological subclasses.
Accurate modeling of replication rates in genome-wide association studies by accounting for Winner’s Curse and study-specific heterogeneity
Authors: Zou Jennifer , Zhou Jinjing , Faller Sarah , Brown Robert P , Sankararaman Sriram S , Eskin Eleazar
Published: December 2019

Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with complex human traits, but only a fraction of variants identified in discovery studies achieve significance in replication studies. Replication in GWAS has been well-studied in the context of Winner’s Curse, which is the inflation of effect size estimates for significant variants due to statistical chance. However, Winner’s Curse is often not sufficient to explain lack of replication. Another reason why studies fail to replicate is that there are fundamental differences between the discovery and replication studies. A confounding factor can create the appearance of a significant finding while actually being an artifact that will not replicate in future studies. We propose a statistical framework that utilizes GWAS and replication studies to jointly model Winner’s Curse and study-specific heterogeneity due to confounding factors. We apply this framework to 100 GWAS from the Human GWAS Catalog and observe that there is a large range in the level of estimated confounding. We demonstrate how this framework can be used to distinguish when studies fail to replicate due to statistical noise and when they fail due to confounding.
The impact of leadered and leaderless gene structures on translation efficiency, transcript stability, and predicted transcription rates inMycobacterium smegmatis
Authors: Nguyen Tien G. , Vargas-Blanco Diego A. , Roberts Louis A. , Shell Scarlet S.
Published: December 2019

Regulation of gene expression is critical for the pathogenMycobacterium tuberculosisto tolerate stressors encountered during infection, and for non-pathogenic mycobacteria such asMycobacterium smegmatisto survive stressors encountered in the environment. Unlike better studied models, mycobacteria express ∼14% of their genes as leaderless transcripts. However, the impacts of leaderless transcript structures on mRNA half-life and translation efficiency in mycobacteria have not been directly tested. For leadered transcripts, the contributions of 5’ UTRs to mRNA half-life and translation efficiency are similarly unknown. In bothM. tuberculosisandM. smegmatis, the essential sigma factor, SigA, is encoded by an unstable transcript with a relatively short half-life. We hypothesized thatsigA’s long 5’ UTR caused this instability. To test this, we constructed fluorescence reporters and then measured protein abundance, mRNA abundance, and mRNA half-life. From these data we also calculated relative transcription rates. We found that thesigA5’ UTR confers an increased transcription rate, a shorter mRNA half-life, and a decreased translation rate compared to a synthetic 5’ UTR commonly used in mycobacterial expression plasmids. Leaderless transcripts produced less protein compared to any of the leadered transcripts. However, translation rates were similar to those of transcripts with thesigA5’ UTR, and the protein levels were instead explained by lower transcript abundance. A global comparison ofM. tuberculosismRNA and protein abundances failed to reveal systematic differences in protein:mRNA ratios for natural leadered and leaderless transcripts, consistent with the idea that variability in translation efficiency among mycobacterial genes is largely driven by factors other than leader status. The variability in mRNA half-life and predicted transcription rate among our constructs could not be explained by their different translation efficiencies, indicating that other factors are responsible for these properties and highlighting the myriad and complex roles played by 5’ UTRs and other sequences downstream of transcription start sites.
Cortical activity at different time scales: high-pass filtering separates motor planning and execution
Authors: Eriksson David , Heiland Mona , Schneider Artur , Diester Ilka
Published: December 2019

The smooth conduction of movements requires simultaneous motor planning and execution according to internal goals. So far it is not known how such movement plans can be modified without being distorted by ongoing movements. Previous studies have isolated planning and execution related neuronal activity by separating behavioral planning and movement periods in time by sensory cues1–7. Here, we introduced two novel tasks in which motor planning developed intrinsically. We separated this continuous self-paced motor planning statistically from motor execution by experimentally minimizing the repetitiveness of the movements. Thereby, we found that in the rat sensorimotor cortex, neuronal motor planning processes evolved with slower dynamics than movement related responses both on a sorted unit and population level. The fast evolving neuronal activity preceded skilled forelimb movements while it coincided with movements in a locomotor task. We captured this fast evolving movement related activity via a high-pass filter approach and confirmed the results with optogenetic stimulations. As biological mechanism underlying such a high pass filtering we suggest neuronal adaption. The differences in dynamics combined with a high pass filtering mechanism represents a simple principle for concurrent motor planning and execution in which planning will result in relatively slow dynamics that will not produce movements.
Phenotypically distinct human sequence is widespread in publicly archived microbial reads: an evaluation of methods for its detection
Authors: Bush Stephen J. , Connor Thomas R. , Peto Tim E. A. , Crook Derrick W. , Walker A. Sarah
Published: December 2019

Sequencing data from host-associated microbes can often be contaminated by the body of the investigator or research subject. Human DNA is typically removed from microbial reads either by subtractive alignment (dropping all reads that map to the human genome) or using a read classification tool to predict those of human origin, and then discarding them. To inform best practice guidelines, we benchmarked 8 alignment-based and 2 classification-based methods of human read detection using simulated data from 10 clinically prevalent bacteria and 3 viruses, into which contaminating human reads had been added.

While the majority of methods successfully detected > 99% of the human reads, they were distinguishable by variance. The most precise methods, with negligible variance, were Bowtie2 and SNAP, both of which misclassified few, if any, bacterial reads (and no viral reads) as human. While correctly detecting a similar number of human reads, methods based on taxonomic classification, such as Kraken2 and Centrifuge, often misclassified bacterial reads as human, the extent of which was species-specific. Among the most sensitive methods of human read detection was BWA, although this also made the greatest number of false positive classifications. Across all methods, the set of human reads not identified as such, although often representing < 0.1% of the total reads, were non-randomly distributed along the human genome with many originating from the repeat-rich sex chromosomes.

For viral reads and longer (> 300bp) bacterial reads, the highest performing approaches were classification-based, using Kraken2 or Centrifuge. For shorter (150-300bp) bacterial reads, combining multiple methods of human read detection maximised the recovery of human reads from contaminated short read datasets without being compromised by false positives. The highest-performing approach with shorter bacterial reads was a two-stage classification using Bowtie2 followed by SNAP. Using this approach, we re-examined 11,577 publicly archived bacterial readsets for hitherto undetected human contamination. We were able to extract a sufficient number of reads to call known human SNPs, including those with clinical significance, in 6% of the samples. These results show that phenotypically-distinct human sequence is widespread in publicly-archived (and nominally pure) bacterial datasets.