bluuebunny/crossref_metadata_2025 huggingface dataset:
PRIMARY CORE VITRECTOMY TECHNIQUE BEFORE CATARACT SURGERY IN COMBINED PHACOVITRECTOMY FOR EYES WITH DENSE VITREOUS HEMORRHAGES
Authors: Shin Kyung Sup , Lim Hyung Bin , Shin Yong Il , Lee Seong Eun , Jo Young Joon , Kim Jung Yeul
Published: April 2018

Purpose:

To investigate the efficacy and safety of a primary core vitrectomy technique for combined phacovitrectomy in eyes showing a poor red reflex because of dense vitreous hemorrhage before cataract surgery.

Methods:

A total of 156 eyes from 156 patients, who underwent combined phacovitrectomy because of cataract and dense vitreous hemorrhage, and who were followed up for at least 6 months were included. The patients were divided into a primary phacoemulsification group (Group A, 80 eyes) who underwent phacoemulsification first followed by total vitrectomy and a primary vitrectomy group (Group B, 76 eyes) who underwent core vitrectomy first followed by cataract surgery and followed by total vitrectomy. A conventional 23-gauge combined phacovitrectomy was performed in all patients. The operation time, including the total continuous curvilinear capsulorhexis time and total cataract surgery time, and the incidence of surgery-related complications were evaluated in the two groups.

Results:

Diabetic retinopathy was the most common cause for vitreous hemorrhage in both groups (Group A: 51 eyes; Group B: 39 eyes). The total continuous curvilinear capsulorhexis time (P = 0.001) and total cataract surgery time (P = 0.036) were significantly shorter in Group B than in Group A. Among the complications, radial tears occurred more frequently in Group A than Group B, but these differences were not statistically significant (P = 0.211). Pupil size reduction during cataract surgery was greater in Group B than in Group A (P = 0.034). There were no significant differences in posterior capsular ruptures or posterior capsular opacities between the two groups. Other postoperative complications were not observed in either group until 6 months after surgery.

Conclusion:

Primary core vitrectomy combined with phacovitrectomy of patients who had dense vitreous hemorrhage helped to obtain a good red reflex and enabled surgeons to perform successful cataract surgery. In addition, primary core vitrectomy was an easy and safe technique, which reduced the surgery time and surgery-related complications. This surgical technique would, therefore, be helpful to vitreoretinal surgeons.
Atypical Presentation of Iridocorneal Endothelial Syndrome With Band Keratopathy but No Corneal Edema Managed With Descemet Membrane Endothelial Keratoplasty
Authors: Zygoura Vasiliki , Lavy Itay , Verdijk Robert M. , Santander-García Diana , Baydoun Lamis , Dapena Isabel , Melles Gerrit R. J.
Published: April 2018

Purpose:

To report an unusual presentation of iridocorneal endothelial (ICE) syndrome associated with band keratopathy and its management with ethylenediamine-tetraacetic acid (EDTA) chelation and Descemet membrane endothelial keratoplasty (DMEK).

Methods:

A 57-year-old female patient presented with unilateral progressive painless visual impairment, corneal band keratopathy, and morphological corneal endothelial changes without corneal edema or any previous ophthalmic, medical, or family history. Routine specular and confocal microscopy imaging, as well as biomicroscopy, best-corrected visual acuity, and pachymetry measurements were performed before and after the surgical procedures. Histopathologic and immunohistochemical evaluations of the surgically excised diseased DM–endothelium were performed.

Results:

Superficial epithelial keratectomy with EDTA chelation was performed. After an initial period of a few months of corneal clearance, the patient presented with recurrence of visually significant band keratopathy. After 1 year, she underwent retreatment with superficial epithelial keratectomy and EDTA chelation, followed by DMEK. Histopathologic and immunohistochemical analysis showed ICE syndrome. Two years after DMEK surgery, the cornea was still clear and band keratopathy had not recurred.

Conclusions:

To the best of our knowledge, this is the first case in the literature that reports the association of ICE syndrome with band keratopathy. As band keratopathy recurred shortly after EDTA chelation, endothelial keratoplasty (DMEK) may be indicated to successfully treat such cases.
Flaccid Blister
Authors: Konda Sasank , Jacob Sharon E.
Published: April 2018

Teledermatology is a term to describe the provision of dermatologic medical services through telecommunication technology. This is a teledermatology case of a flaccid blister.
Contact Alopecia
Authors: Jacob Sharon E. , Lipp Michael B.
Published: April 2018

Teledermatology is a term to describe the provision of dermatologic medical services through telecommunication technology. This is a teledermatology case of inflammatory papules and hair loss.
Long-term Hearing Outcome of Canaloplasty With Partial Ossicular Replacement in Congenital Aural Atresia
Authors: Ahn Jungmin , Ryu Gwanghui , Kang Minwoong , Cho Yang-Sun
Published: April 2018

Objective:

The aim of this study was to correlate the postoperative hearing outcomes with regard to the length of prosthesis of the partial ossicular replacement prosthesis (PORP) in patients with congenital aural atresia.

Study Design:

Retrospective review of medical records.

Setting, Patients, Intervention, Main Outcome Measure:

The medical records of 131 patients (132 ears) who underwent canaloplasty with PORP by a single surgeon from 2011 to 2016 were reviewed for demographic data, Jahrsdoerfer score, grade of microtia, length of prosthesis, and audiometric outcomes. Air conduction, bone conduction threshold, and air-bone gap were measured preoperatively and at 3-, 6-, 12-, and 24-months of follow-up. Patients were divided into two groups according to the postoperative hearing outcomes, and the length of PORP was compared between the two groups. Univariable and multivariable generalized estimating equations were used to investigate other favorable prognostic factors for long-term postoperative hearing results.

Results:

When the improvement of the air-bone gap within 30 dB was defined as successful hearing outcome, no significant differences were observed for prosthesis length between two groups at 3, 6, and 12 months postoperatively. However, at 2-year follow-up, mean length of prosthesis was significantly shorter (p = 0.006) for the success group (2.30 ± 0.53 mm) than for the nonsuccess group (2.77 ± 0.73 mm). Generalized estimating equations revealed PORP length as the only factor significantly associated with favorable long-term hearing results.

Conclusion:

Long-term hearing outcome of canaloplasty with PORP is likely to be affected by prosthesis length. For that reason, making the neo-annulus as medial as possible to shorten the length of the appropriate prosthesis is important for successful long-term hearing outcomes.
Short and Long-Term Outcomes of Titanium Clip Ossiculoplasty
Authors: Kahue Charissa N. , O’Connnell Brendan P. , Dedmon Matthew M. , Haynes David S. , Rivas Alejandro
Published: April 2018

Objective:

To report short (∼4 mo) and long-term (>12 mo) audiometric outcomes following ossiculoplasty using a titanium clip partial ossicular reconstruction prosthesis.

Methods:

Case series at a single tertiary referral center reviewing 130 pediatric and adult patients with conductive hearing loss (CHL) secondary to chronic otitis media (n = 121, 93%) or traumatic ossicular disruption (n = 9, 7%) who underwent partial ossiculoplasty from January 2005 to December 2015 with the CliP prosthesis.

Results:

At both short and long-term follow-up, postoperative air-bone gap (ABG) was significantly improved (18 dB HL, IQ range 13–26, p < 0.0001 and 18 dB HL, IQ range 13–29, p = 0.0002, respectively) when compared with preoperative values (29 dB HL, IQ range 19–37). No significant change in ABG was noted when comparing short and long-term intervals (18 versus 18 dB HL, p = 0.44). Fifty seven percent of cases (51/89) achieved a long-term ABG less than or equal to 20 dB at the time of their last follow-up. The extrusion and displacement rates were 1.5% (2/130), and 0.8% (1/130), respectively. There were no cases of iatrogenic sensorineural hearing loss.

Conclusions:

Partial ossiculoplasty with the titanium CliP produces good hearing outcomes with a favorable safety profile. At long-term follow-up (minimum of 12 mo), median ABG was 18 dB and remained stable when compared with short-term follow-up. The majority of patients had successful long-term results, with 57% of patients achieving an ABG is less than or equal to 20 dB. Low rates of extrusion (1.5%) and prosthesis displacement off the stapes (0.8%) support the long-term stability of the CliP prosthesis in the middle ear.
Vitamin D deficiency in hepatitis C virus infection: what is old? what is new?
Authors: Jin Chao-Nan , Chen Jing-Dan , Sheng Ji-Fang
Published: April 2018

In the past few years, a growing body of clinical evidence has highlighted the risk of vitamin D deficiency in patients with chronic hepatitis C and that vitamin D levels are associated with the course of hepatitis C virus (HCV) infection, adverse effects, and treatment response to peginterferon/ribavirin. Recently, studies have found that vitamin D status is related to drug resistance and increased risk of infection in patients with liver cirrhosis. Vitamin D-related gene polymorphisms have been found to explain the interactions between vitamin D deficiency and HCV infection, offering a new perspective toward understanding the current problems such as the development of insulin resistance and racial differences in sustained virological response. Studies have been conducted to determine whether vitamin D supplementation as an adjuvant yields a better result compared with traditional HCV treatment. Here, we provide a brief review of the past and present knowledge of vitamin D in HCV infection.
Examining Parental Medication Adherence as a Predictor of Child Medication Adherence in Pediatric Anxiety Disorders
Authors: Bushnell Greta A. , Brookhart M. Alan , Gaynes Bradley N. , Compton Scott N. , Dusetzina Stacie B. , Stürmer Til
Published: April 2018

Background:

Selective serotonin reuptake inhibitors (SSRIs) are the recommended first-line pharmacotherapy for pediatric anxiety disorders but adherence remains difficult to predict.

Objectives:

To estimate SSRI adherence in children with anxiety disorders and determine if prior parental medication adherence is predictive of child high SSRI adherence.

Methods:

We identified children (3–17 y) initiating SSRI treatment after an anxiety disorder diagnosis in a commercial claims database (2005–2014). We evaluated parent SSRI, statin, and antihypertensive adherence [6-mo proportion days covered (PDC), high adherence=PDC≥0.80] in the year before child SSRI initiation. We estimated risk differences (RD) of child high SSRI adherence (6-mo PDC) stratified by parent adherence and multivariable risk ratios using modified Poisson regression. We estimated change inc-statistic and risk reclassification when adding parent-level covariates with child-level covariates to predict child adherence.

Results:

In 70,979 children with an anxiety disorder (59%=female, 14=median age), the mean 6-month SSRI PDC was 0.72, with variation by anxiety disorder. Overall 64% of children had high adherence if their parent had high SSRI adherence versus 53% of children with parents with low SSRI adherence (RD, 12%; multivariable risk ratios, 1.17; 95% confidence interval, 1.14–1.20). Findings were similar for parent statin (RD=10%) and antihypertensive adherence (RD=8%) and when stratified by child age and parent sex. There was minor improvement in risk reclassification and thec-statistic after adding parent adherence and parent-level covariates.

Conclusions:

Parental medication adherence could help providers identify children at risk of nonadherence to inform the treatment decision, reduce unnecessary medication switches, and lead to broader effective interventions.
Case-Mix for Performance Management
Authors: Gao Jian , Moran Eileen , Almenoff Peter L.
Published: April 2018

Background:

Accurate risk adjustment is the key to a reliable comparison of cost and quality performance among providers and hospitals. However, the existing case-mix algorithms based on age, sex, and diagnoses can only explain up to 50% of the cost variation. More accurate risk adjustment is desired for provider performance assessment and improvement.

Objective:

To develop a case-mix algorithm that hospitals and payers can use to measure and compare cost and quality performance of their providers.

Methods:

All 6,048,895 patients with valid diagnoses and cost recorded in the US Veterans health care system in fiscal year 2016 were included in this study. The dependent variable was total cost at the patient level, and the explanatory variables were age, sex, and comorbidities represented by 762 clinically homogeneous groups, which were created by expanding the 283 categories from Clinical Classifications Software based on ICD-10-CM codes. The split-sample method was used to assess model overfitting and coefficient stability. The predictive power of the algorithms was ascertained by comparing theR2, mean absolute percentage error, root mean square error, predictive ratios, andc-statistics.

Results:

The expansion of the Clinical Classifications Software categories resulted in higher predictive power. TheR2reached 0.72 and 0.52 for the transformed and raw scale cost, respectively.

Conclusions:

The case-mix algorithm we developed based on age, sex, and diagnoses outperformed the existing case-mix models reported in the literature. The method developed in this study can be used by other health systems to produce tailored risk models for their specific purpose.
Impact of an Advanced Imaging Utilization Review Program on Downstream Health Care Utilization and Costs for Low Back Pain
Authors: Graves Janessa M. , Fulton-Kehoe Deborah , Jarvik Jeffrey G. , Franklin Gary M.
Published: April 2018

Background:

Early magnetic resonance imaging (MRI) for acute low back pain (LBP) has been associated with increased costs, greater health care utilization, and longer disability duration in workers’ compensation claimants.

Objectives:

To assess the impact of a state policy implemented in June 2010 that required prospective utilization review (UR) for early MRI among workers’ compensation claimants with LBP.

Research Design:

Interrupted time series.

Subjects:

In total, 76,119 Washington State workers’ compensation claimants with LBP between 2006 and 2014.

Measures:

Proportion of workers receiving imaging per month (MRI, computed tomography, radiographs) and lumbosacral injections and surgery; mean total health care costs per worker; mean duration of disability per worker. Measures were aggregated monthly and attributed to injury month.

Results:

After accounting for secular trends, decreases in early MRI [level change: −5.27 (95% confidence interval, −4.22 to −6.31); trend change: −0.06 (−0.01 to −0.12)], any MRI [−4.34 (−3.01 to −5.67); −0.10 (−0.04 to −0.17)], and injection [trend change: −0.12 (−0.06 to −0.18)] utilization were associated with the policy. Radiograph utilization increased in parallel [level change: 2.46 (1.24–3.67)]. In addition, the policy resulted in significant decreasing changes in mean costs per claim, mean disability duration, and proportion of workers who received disability benefits. The policy had no effect on computed tomography or surgery utilization.

Conclusions:

The UR policy had discernable effects on health care utilization, costs, and disability. Integrating evidence-based guidelines with UR can improve quality of care and patient outcomes, while reducing use of low-value health services.
Aplastic Anemia as an Immune-mediated Complication of Thymoma: A Case Report
Authors: Toret Ersin , Demirag Bengü , Köker Sultan A. , Doyurgan Onur , Ergin Malik , Genc Sinan , Karapinar Tuba H. , Ay Yilmaz , Oymak Yeşim , Vergin Canan
Published: April 2018

Thymomas are the most common masses located in the anterior mediastinum, and they are often associated with autoimmune disorders including myasthenia gravis, polymyositis, and aplastic anemia (AA). Autoreactive T-cell clones generated by the thymoma may lead to autoimmune disorders. We report the case of a 14-year-old boy who was examined for AA, and the underlying cause was determined to be an immune-mediated complication of thymoma. He had no matched sibling donors. He underwent thymectomy, and 3 months later he was treated with immunosuppressive therapy (IST), consisting of antithymocyte globulin and cyclosporine A. The duration of the IST was determined to be a period of 12 months. He has recently been in complete response condition for 6 months since IST stopped. IST is a successful treatment choice for thymomas associated with AA in childhood.
Recurrent Severe Iron Deficiency Anemia and Thrombocytopenia in an Adolescent Male
Authors: Giordano Lisa , Llanos-Chea Alejandro , Monde Alexandra , Mulinge Ivy , Dighe Dipti
Published: April 2018

An adolescent male presented with recurrent episodes over several years of severe iron deficiency anemia and associated severe thrombocytopenia. The anemia was secondary to chronic blood loss due to ulceration at the site of an ileocolonic anastomosis performed during infancy. We were able to demonstrate complete resolution of thrombocytopenia with the administration of iron, and without using steroids, intravenous immunoglobulin, or platelet transfusions. This is the first reported case of an individual with multiple episodes over several years of thrombocytopenia secondary to recurrent severe iron deficiency anemia, illustrating a predisposition to this complication in a unique patient.
Clinical Trial Enrollment is Associated With Improved Follow-up Rates Among Survivors of Childhood Cancer
Authors: Hutchins Kelley K. , Savaşan Süreyya , Thomas Ronald L. , Strathdee Laura A. , Wang Zhihong J. , Taub Jeffrey W.
Published: April 2018

Fortunately >80% of children diagnosed with cancer become long-term survivors; however, this population is at a significantly increased risk of morbidity and mortality as a result of their previous cancer therapy, and long-term follow-up (LTFU) is critical. Multiple barriers to receiving adequate LTFU care have been studied. We investigated whether lack of enrollment in a therapeutic clinical trial may be a barrier to receiving LTFU care. We conducted a review of 353 patient records at the Children’s Hospital of Michigan enrolled in our Children’s Oncology Group registry between January 1, 2005 and December 31, 2010. In total, 71 patients were excluded (death before follow-up, n=61; currently receiving therapy, n=5; known transfer of care, n=4; insufficient information, n=1). In total, 158 (56%) patients were enrolled in a therapeutic clinical trial. Follow-up rates at 1-, 2- and 5-years following completion of therapy for patients enrolled in a therapeutic clinical trial were 96.8% (153/158), 93.7% (148/158), and 81.7% (103/126), respectively, compared with 83.1% (103/124; P<0.001), 74.2% (92/124; P<0.001), and 66.7% (72/108; P=0.001) for patients not enrolled. Our findings suggest patients enrolled in a therapeutic clinical trial have better LTFU rates and supports the importance of patient enrollment in therapeutic clinical trials when possible. Additional resources may be warranted to improve LTFU for patients not enrolled.
Comparison between three types of prosthetic feet: a randomized double-blind single-subject multiple-rater trial
Authors: Burger Helena , Vidmar Gaj , Zdovc Branko , Erzar Dominik , Zalar Metka
Published: April 2018

There are many prosthetic feet (Pfeet) on the market, and those in the same category do not necessarily have the same properties. We assessed three different Pfeet in terms of gait patterns on various terrains, balance and walking speed in a randomized double-blind controlled single-subject multiple-rater clinical trial. The patient was a 43-year old man who was an active prosthesis user and was amputated at transtibial level because of injury 17 years ago. One Solid Ankle Cushion Heel and two Dynamic Elastic Response (DER) Pfeet were tried six times in random order. The patient walked on flat, uneven, sloped terrain and stairs. Gait pattern was rated in comparison with the patient’s previous prosthetic foot (Pfoot) by a physiatrist, physiotherapist, prosthetist and the patient; one-leg standing test on the prosthesis and 10-m walking test were also performed. The ratings differed significantly between the raters on each terrain, and there was no agreement among the raters regarding the ranking order of the Pfeet. All the Pfeet were generally rated as worse than the patient’s previous one. The patient gave lower ratings on average than the professionals and recognized the order of the tested Pfeet. The results of one-leg standing test with one DER and the Solid Ankle Cushion Heel Pfoot were statistically significant better than with the other DER and the patient’s previous Pfoot. Our study therefore indicates that rehabilitation professionals, when blinded, cannot always reliably observe differences in walking on different terrains with different Pfeet. The patient may feel the differences, but those may not match what the manufacturers declare.
Motor learning in dystonia: distorted feedback results in distorted motor learning and information-seeking compensatory behaviour
Authors: Nagy Edit
Published: April 2018

Motor learning is possible in dystonia, but distorted feedback results in distorted motor performance and information-seeking compensatory behavior, as observed in this case. With globus pallidus internal segment deep brain stimulation, the postural background of hand writing improved, but the learned left compensatory grip did not change.
Risk Factors for Pneumocystis jirovecii Pneumonia in Patients With Rheumatoid Arthritis and a Prophylactic Indication of Trimethoprim/Sulfamethoxazole
Authors: Yukawa Kazutoshi , Nagamoto Yasutsugu , Watanabe Hirofumi , Funaki Masamoto , Iwahashi Mitsuhiro , Yamana Jiro , Sasaki Rie , Yamana Seizo
Published: April 2018

Background/Objectives

Immunosuppressant medications (ISPs) increase the occurrence of Pneumocystis jirovecii pneumonia (PCP) in rheumatoid arthritis (RA) patients. The prophylactic administration of trimethoprim/sulfamethoxazole (TMP/SMX) for PCP is effective but has serious adverse effects and so should be selectively used for patients at high risk. The aims of this study were to clarify the risk factors for PCP in RA patients and to establish the indications for administering TMP/SMX.

Methods

This retrospective cohort study analyzed data from 2640 patients (2010–2014) diagnosed as having RA who had not received a prophylactic administration of TMP/SMX. The risk factors for PCP were evaluated by comparing the clinical parameters between patients with PCP (PCP group, n = 19) and those without (non-PCP group, n = 2621).

Results

The PCP group was older (70 vs. 64 years), received higher doses of prednisolone (6.2 vs. 2.4 mg/d) and methotrexate (7.7 vs. 5.2 mg/wk), and had a greater number of ISPs (1.3 vs. 0.8) (p < 0.05). We stratified the PCP risk using a scoring system based on odds ratios (ORs) calculated for these parameters (methotrexate ≥6 mg/wk OR = 4.5, 1 point; age ≥65 years, OR = 3.7, 1 point; ≥2 ISPs, OR = 3.7, 1 point; prednisolone ≥5 mg/d, OR = 12.4, 3 points). The incidence of PCP among patients scoring 0 to 2 points was 0.04%; 3 to 4 points, 2.3%; and 5 points or more, 5.8%.

Conclusions

The prophylactic administration of TMP/SMX for PCP is recommended for RA patients who score at least 5 points with our system.
Exons as units of phenotypic impact for truncating mutations in autism
Authors: Chiang Andrew H. , Chang Jonathan , Wang Jiayao , Vitkup Dennis
Published: April 2018

Autism spectrum disorders (ASD) are a group of related neurodevelopmental diseases displaying significant genetic and phenotypic heterogeneity1–4. Despite recent progress in understanding ASD genetics, the nature of phenotypic heterogeneity across probands remains unclear5, 6. Notably, likely gene-disrupting (LGD) de novo mutations affecting the same gene often result in substantially different ASD phenotypes. Nevertheless, we find that truncating mutations that affect the same exon frequently lead to strikingly similar intellectual phenotypes in unrelated ASD probands. Analogous patterns are observed for two independent proband cohorts and several other important ASD-associated phenotypes. We find that exons biased towards prenatal and postnatal expression preferentially contribute to ASD cases with lower and higher IQ phenotypes, respectively. These results suggest that exons, rather than genes, often represent a unit of effective phenotypic impact for truncating mutations in autism. The observed phenotypic effects are likely mediated by nonsense-mediated decay (NMD) of splicing isoforms, with autism phenotypes usually triggered by relatively mild (15-30%) decreases in overall gene dosage. We find that each gene with recurrent ASD mutations can be described by a parameter, phenotype dosage sensitivity (PDS), which characterizes the quantitative relationship between changes in a gene’s dosage and changes in a given disease phenotype. We further demonstrate analogous relationships between LGD mutations and changes in gene expression across human tissues. Therefore, similar phenotypic patterns may be also observed in multiple other systems and genetic disorders.
Whole-brain calcium imaging during physiological vestibular stimulation in larval zebrafish
Authors: Migault Geoffrey , Panier Thomas , Candelier Raphaël , Debrégeas Georges , Bormuth Volker
Published: April 2018

During in vivo functional imaging, animals are head-fixed and thus deprived from vestibular inputs, which severely hampers the design of naturalistic virtual environments. To overcome this limitation, we developed a miniaturized ultra-stable light-sheet microscope that can be dynamically rotated during imaging along with a head-restrained zebrafish larva. We demonstrate that this system enables whole-brain functional imaging at single-cell resolution under controlled vestibular stimulation. We recorded for the first time the dynamic whole-brain response of a vertebrate to physiological vestibular stimulation. This development largely expands the potential of virtual-reality systems to explore complex multisensory-motor integration in 3D.
Festa: FLexible EXon-Based SPlicing And TRanscription ANnotation
Authors: Alfredo Rago , John K. Cobourne
Published: April 2018

We introduce FESTA, an R based algorithm that allows detection of alternative splicing based on experiment-specific exon expression data. FESTA disentangles alternative splicing signal from whole-gene transcription, facilitating the discovery and characterization of novel regulatory events even in the absence of transcript annotations or paired-end data. We also include customization options to increase its applicability on different platforms and experimental designs as well as a tool for the conversion from transcript expression to inclusion ratios.
Direct Small Molecule Activation of Mitofusins
Authors: Zacharioudakis Emmanouil , Biris Nikolaos , Garner Thomas P. , Chen Yun , Pekson Ryan , Dhingra Rimpy , Santulli Gaetano , Kirshenbaum Lorrie A. , Kitsis Richard N. , Gavathiotis Evripidis
Published: April 2018

Mitochondrial fusion is a physiological process that is regulated by mitofusins on the outer mitochondrial membrane. Conformational plasticity between anti- and pro-tethering conformations of mitofusins permits mitochondrial tethering and subsequent fusion. Here we developed a pharmacophore-based model to rationally manipulate the conformational plasticity of mitofusin 2 and perfomed an in silico small-molecule screen. This enabled the discovery of a direct activator of mitofusins, MASM7, capable of potently promoting mitochondrial fusion. The specificity of the MASM7-mitofusin 2 interaction is highlighted by structure-activity relationships of MASM7 analogues, FRET, NMR and mitochondrial fusion studies using mitofusin mutants. Our study identified the first-in-class direct activator of mitofusins, demonstrating a new paradigm for chemical modulation of mitochondrial fusion and downstream processes.
Development and validation of a triplex qPCR assay to detect efflux pump-mediated antibiotic resistance inBurkholderia pseudomallei
Authors: Webb Jessica R. , Price Erin P. , Somprasong Nawarat , Schweizer Herbert P. , Baird Robert W. , Currie Bart J. , Sarovich Derek S.
Published: April 2018

Burkholderia pseudomallei, the causative agent of the deadly tropical disease melioidosis, is intrinsically resistant to many antibiotics, leaving few effective treatment options. Trimethoprim-sulfamethoxazole (SXT), meropenem (MEM) and doxycycline (DOX) are valuable antibiotics for melioidosis treatment due to inherently low or no primary resistance. Although considered rare, upregulation of one or more resistance-nodulation-division (RND) efflux pumps is now known to lead to acquired resistance towards these drugs inB. pseudomallei.Here, we developed a triplex quantitative PCR assay to detect upregulation of the three clinically relevant RND efflux systems: AmrAB-OprA, BpeB-OprB and BpeEF-OprC. The triplex assay was tested on seven clinically-derivedB. pseudomalleiisogenic pairs, where the latter strain of each pair had altered regulator activity and exhibited reduced susceptibility to SXT, MEM or DOX. The triplex assay accurately detected efflux pump upregulation between isogenic pairs, which corresponded with decreased antibiotic susceptibility. We further verified assay performance on eight laboratory-generatedB. pseudomalleimutants encoding efflux pump regulator mutations. Targeting antibiotic resistance inB. pseudomalleiusing molecular genotyping provides clinicians with a rapid tool to identify potential treatment failure in near real-time, enabling informed alteration of treatment during an infection and improved patient outcomes.

IMPORTANCE

The melioidosis bacteriumBurkholderia pseudomalleiis intrinsically resistant to many antibiotics, limiting treatment options to a handful of drugs including meropenem, doxycycline and trimethoprim-sulfamethoxazole. Although rare, there have now been several documented melioidosis cases where resistance to these antibiotics has developed during an infection, leading to treatment failure and increased mortality rates. Interestingly, all strains resistant to these drugs exhibit increased efflux pump expression, representing a shared molecular signature that can be exploited for rapid diagnostic purposes. Here, we developed and validated a single-tube real-time qPCR assay to detect clinically relevant efflux pump upregulation inB. pseudomallei, an important first step towards high-level resistance. This triplex assay offers a drastically reduced turn-around-time compared to current methodology, enabling earlier detection of resistance emergence. Implementation of this new diagnostic will aid clinicians in the selection of appropriate therapy, thereby minimizing resistance development and treatment failure for this high-mortality disease.
The mechanical impact of col11a2 loss on joints; col11a2 mutant zebrafish show changes to joint development and function, which leads to early onset osteoarthritis
Authors: Lawrence Elizabeth A , Kague Erika , Aggleton Jessye A , Harniman Robert L , Roddy Karen A , Hammond Chrissy L
Published: April 2018

Abstract (max 200 words)

Collagen is the major structural component of cartilage and mutations in the genes encoding Type XI collagen are associated with severe skeletal dysplasias (Fibrochondrogenesis and Stickler syndrome) and early onset osteoarthritis. The impact of the lack of Type XI collagen on cell behaviour and mechanical performance during skeleton development is unknown. We studied a zebrafish mutant for col11a2 and evaluated cartilage, bone development and mechanical properties to address this. We show that in col11a2 mutants Type II collagen is made but is prematurely degraded in maturing cartilage and ectopically expressed in the joint. These changes are correlated with increased stiffness of both bone and cartilage; quantified using Atomic Force Microscopy. In the mutants, the skeletal rudiment terminal region in the jaw joint are broader and the interzone smaller. These differences in shape and material properties impact on joint function and mechanical performance, which we modelled using Finite Element Analyses. Finally, we show that col11a2 heterozygous carriers reach adulthood but show signs of severe early onset osteoarthritis. Taken together our data demonstrate a key role for Type XI collagen in maintaining the properties of cartilage matrix; which when lost leads to alterations to cell behaviour that give rise to joint pathologies.
Dissecting indirect genetic effects from peers in laboratory mice
Authors: Baud Amelie , Casale Francesco Paolo , Barkley-Levenson Amanda M. , Farhadi Nilgoun , Montillot Charlotte , Yalcin Binnaz , Nicod Jerome , Palmer Abraham A. , Stegle Oliver
Published: April 2018

The phenotype of one individual can be affected not only by the individual’s own genotypes (direct genetic effects, DGE) but also by genotypes of interacting partners (indirect genetic effects, IGE). IGE have been detected using polygenic models in multiple species, including laboratory mice and humans. However, the underlying mechanisms remain largely unknown. Genome-wide association studies of IGE (igeGWAS) can point to IGE genes, but have not yet been applied to non-familial IGE arising from “peers” and affecting biomedical phenotypes. In addition, the extent to which igeGWAS will identify loci not identified by dgeGWAS remains an open question. Finally, findings from igeGWAS have not been confirmed by experimental manipulation.

We leveraged a dataset of 170 behavioural, physiological and morphological phenotypes measured in 1,812 genetically heterogeneous laboratory mice to study IGE arising between same-sex, adult, unrelated laboratory mice housed in the same cage. We developed methods for igeGWAS in this context and identified 24 significant IGE loci for 17 phenotypes (FDR < 10%). There was no overlap between IGE loci and DGE loci for the same phenotype, which was consistent with the moderate genetic correlations between DGE and IGE for the same phenotype estimated using polygenic models. Finally, we fine-mapped seven significant IGE loci to individual genes and confirmed, in an experiment with a knockout model, that Epha4 gives rise to IGE on stress-coping strategy and wound healing.

Our results demonstrate the potential for igeGWAS to identify IGE genes and shed some light into the mechanisms of peer influence.
bmotif: a package for motif analyses of bipartite networks
Authors: Simmons Benno I. , Sweering Michelle J. M. , Schillinger Maybritt , Dicks Lynn V. , Sutherland William J. , Clemente Riccardo Di
Published: April 2018

Bipartite networks are widely-used to represent a diverse range of species interactions, such as pollination, herbivory, parasitism and seed dispersal. The structure of these networks is usually characterised by calculating one or more metrics that capture different aspects of network architecture. While these metrics capture useful properties of networks, they only consider structure at the scale of the whole network (the macro-scale) or individual species (the micro-scale). ‘Meso-scale’ structure between these scales is usually ignored, despite representing ecologically-important interactions. Network motifs are a framework for capturing this meso-scale structure and are gaining in popularity. However, there is no software available in R, the most popular programming language among ecologists, for conducting motif analyses in bipartite networks. Similarly, no mathematical formalisation of bipartite motifs has been developed.

Here we introduce bmotif: a package for counting motifs, and species positions within motifs, in bipartite networks. Our code is primarily an R package, but we also provide MATLAB and Python code of the core functionality. The software is based on a mathematical framework where, for the first time, we derive formal expressions for motif frequencies and the frequencies with which species occur in different positions within motifs. This framework means that analyses with bmotif are fast, making motif methods compatible with the permutational approaches often used in network studies, such as null model analyses.

We describe the package and demonstrate how it can be used to conduct ecological analyses, using two examples of plant-pollinator networks. We first use motifs to examine the assembly and disassembly of an Arctic plant-pollinator community, and then use them to compare the roles of native and introduced plant species in an unrestored site in Mauritius.

bmotif will enable motif analyses of a wide range of bipartite ecological networks, allowing future research to characterise these complex networks without discarding important meso-scale structural detail.
Genomic consequences of a recent three-way admixture in supplemented wild brown trout populations revealed by ancestry tracts
Authors: Leitwein Maeva , Gagnaire Pierre-Alexandre , Desmarais Erick , Berrebi Patrick , Guinand Bruno
Published: April 2018

Understanding the evolutionary consequences of human-mediated introductions of domestic strains into the wild and their subsequent admixture with natural populations is of major concern in conservation biology. In the brown troutSalmo trutta, decades of stocking practices have profoundly impacted the genetic makeup of wild populations. Small local Mediterranean populations in the Orb River watershed (Southern France) have been subject to successive introductions of domestic strains derived from the Atlantic and Mediterranean lineages. However, the genomic impacts of two distinct sources of stocking (locally-derived vs divergent) on the genetic integrity of wild populations remain poorly understood. Here, we evaluate the extent of admixture from both domestic strains within three wild populations of this watershed, using 75,684 mapped SNPs obtained from double-digest restriction-site-associated DNA sequencing (dd-RADseq). Using a local ancestry inference approach, we provide a detailed picture of admixture patterns across the brown trout genome at the haplotype level. By analysing the chromosomal ancestry profiles of admixed individuals, we reveal a wider diversity of hybrid and introgressed genotypes than estimated using classical methods for inferring ancestry and hybrid pedigree. In addition, the length distribution of introgressed tracts retained different timings of introgression between the two domestic strains. We finally reveal opposite consequences of admixture on the level of polymorphism of the recipient populations between domestic strains. Our study illustrates the potential of using the information contained in the genomic mosaic of ancestry tracts in combination with classical methods based on allele frequencies for analysing multiple-way admixture with population genomic data.
Genetic contributions to ectopic sperm cell migration inCaenorhabditisnematodes
Authors: Ting Janice J. , Tsai Caressa N. , Cutter Asher D.
Published: April 2018

Reproductive barriers involving gametic incompatibilities can act to enhance population divergence and promote the persistence of species boundaries. Observing gametic interactions in internal fertilizing organisms, however, presents a considerable practical challenge to characterizing mechanisms of such gametic isolation. Here we exploit the transparency ofCaenorhabditisnematodes to investigate gametic isolation mediated by sperm that can migrate to ectopic locations, with this sperm invasion capable of inducing female sterility and premature death. As a step toward identifying genetic factors and mechanisms associated with female susceptibility to sperm invasion, we characterized a panel of 25C. elegansgenetic mutants to test for effects on the incidence and severity of sperm invasion in both conspecific and interspecies matings. We found genetic perturbations to contribute to distinct patterns of susceptibility that identify ovulation dynamics and sperm guidance cues as modulators of ectopic sperm migration incidence and severity. Genotypes confer distinctive phenotypic sensitivities to the sperm from conspecificC. elegansmales versus heterospecificC. nigonimales, implicating evolution of functional divergence in the history of these species for components of sperm-reproductive tract interactions. Sexually-antagonistic co-evolution within species that drives divergent trait and molecular evolution between species provides a working model to explain mismatched species-specific gametic interactions that promote or mitigate ectopic sperm migration.

Article Summary

Here we exploit the transparency ofC. elegansroundworms to investigate reproductive barriers between species resulting from sperm-cell invasion into ectopic tissues, causing female sterility and premature death. We quantify female sensitivity to sperm invasion from conspecific and interspecific matings in a panel of 25C. elegansgenetic mutants, to demonstrate how ovulation dynamics and sperm guidance cues act as modulators of ectopic sperm-cell migration incidence and severity. We observe both conserved and divergent responses to different species, implicating evolution of functional divergence for components of sperm-reproductive tract interactions consistent with the outcome of sexually-antagonistic co-evolution.
integRATE: a desirability-based data integration framework for the prioritization of candidate genes across heterogeneous omics and its application to preterm birth
Authors: Eidem Haley R. , Steenwyk Jacob , Wisecaver Jennifer , Capra John A. , Abbot Patrick , Rokas Antonis
Published: April 2018

Background

The integration of high-quality, genome-wide analyses offers a robust approach to elucidating genetic factors involved in complex human diseases. Even though several methods exist to integrate heterogeneous omics data, most biologists still manually select candidate genes by examining the intersection of lists of candidates stemming from analyses of different types of omics data that have been generated by imposing hard (strict) thresholds on quantitative variables, such as P-values and fold changes, increasing the chance of missing potentially important candidates.

Methods

To better facilitate the unbiased integration of heterogeneous omics data collected from diverse platforms and samples, we propose a desirability function framework for identifying candidate genes with strong evidence across data types as targets for follow-up functional analysis. Our approach is targeted towards disease systems with sparse, heterogeneous omics data, so we tested it on one such pathology: spontaneous preterm birth (sPTB).

Results

We developed the software integRATE, which uses desirability functions to rank genes both within and across studies, identifying well-supported candidate genes according to the cumulative weight of biological evidence rather than based on imposition of hard thresholds of key variables. Integrating 10 sPTB omics studies identified both genes in pathways previously suspected to be involved in sPTB as well as novel genes never before linked to this syndrome. integRATE is available as an R package on GitHub (https://github.com/haleyeidem/integRATE).

Conclusions

Desirability-based data integration is a solution most applicable in biological research areas where omics data is especially heterogeneous and sparse, allowing for the prioritization of candidate genes that can be used to inform more targeted downstream functional analyses.
Evidence for a Solenoid Phase of Supercoiled DNA
Authors: Dittmore Andrew , Neuman Keir C.
Published: April 2018

In mechanical manipulation experiments, a single DNA molecule overwound at constant force undergoes a discontinuous drop in extension as it buckles and forms a superhelical loop (a plectoneme). Further overwinding the DNA, we observe an unanticipated cascade of highly regular discontinuous extension changes associated with stepwise plectoneme lengthening. This phenomenon is consistent with a model in which the force-extended DNA forms barriers to plectoneme lengthening caused by topological writhe. Furthermore, accounting for writhe in a fluctuating solenoid gives an improved description of the measured force-dependent effective torsional modulus of DNA, providing a reliable formula to estimate DNA torque. Our data and model thus provide context for further measurements and theories that capture the structures and mechanics of supercoiled biopolymers.
DECODER: A probabilistic approach to integrate big data reveals mitochondrial Complex I as a potential therapeutic target for Alzheimer’s disease
Authors: Celik Safiye , Russell Josh C. , Pestana Cezar R. , Lee Ting-I , Mukherjee Shubhabrata , Crane Paul K. , Keene C. Dirk , Bobb Jennifer F. , Kaeberlein Matt , Lee Su-In
Published: April 2018

Identifying gene expression markers for Alzheimer’s disease (AD) neuropathology through meta-analysis is a complex undertaking because available data are often from different studies and/or brain regions involving study-specific confounders and/or region-specific biological processes. Here we introduce a novel probabilistic model-based framework, DECODER, leveraging these discrepancies to identify robust biomarkers for complex phenotypes. Our experiments present: (1) DECODER’s potential as a general meta-analysis framework widely applicable to various diseases (e.g., AD and cancer) and phenotypes (e.g., Amyloid-β (Aβ) pathology, tau pathology, and survival), (2) our results from a meta-analysis using 1,746 human brain tissue samples from nine brain regions in three studies — the largest expression meta-analysis for AD, to our knowledge —, and (3)in vivovalidation of identified modifiers of Aβ toxicity in a transgenicCaenorhabditis elegansmodel expressing AD-associated Aβ, which pinpoints mitochondrial Complex I as a critical mediator of proteostasis and a promising pharmacological avenue toward treating AD.
Poly-Target Selection Identifies Broad-Spectrum RNA Aptamers
Authors: Alam Khalid K. , Chang Jonathan L. , Lange Margaret J. , Nguyen Phuong D.M. , Sawyer Andrew W. , Burke Donald H.
Published: April 2018

Aptamer selections often yield distinct subpopulations, each with unique phenotypes that can be leveraged for specialized applications. RNA aptamers that bind HIV-1 reverse transcriptase (RT) exhibit potent RT inhibition and suppress viral replication when targeting the strain-specific RT that they were originally selected to bind, but some of these same aptamers fail against single-point mutant and phylogenetically-diverse RTs. We hypothesized that a subset of the total aptamer population in libraries pre-enriched against a single RT may exhibit broad-spectrum RT binding and inhibition, and we devised a multiplexed Poly-Target selection approach to elicit those phenotypes against a panel of diverse primate lentiviral RTs. High-throughput sequencing of starting, negative, and final libraries, followed by analysis of coenrichment and codepletion in parallel and duplicate selection trajectories, narrowed the list of candidate aptamers by orders of magnitude. Biochemical characterization of candidates identified a novel aptamer motif and several rare and unobserved variants of previously-known motifs that inhibited recombinant RTs from HIV-1, HIV-2 and SIV to varying degrees. These broad-spectrum aptamers also suppressed replication of viral constructs carrying phylogenetically-diverse RTs. The Poly-Target selection and coenrichment approach described herein is a generalizable strategy for identifying broad-spectrum behavior and cross-reactivity among related targets from combinatorial libraries.