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Phenoscape: Identifying Candidate Genes for Evolutionary Phenotypes.
No full textPhenotypes resulting from mutations in genetic model organisms can help reveal candidate genes for evolutionarily important phenotypic changes in related taxa. Although testing candidate gene hypotheses experimentally in nonmodel organisms is typically difficult, ontology-driven information systems can help generate testable hypotheses about developmental processes in experimentally tractable organisms. Here, we tested candidate gene hypotheses suggested by expert use of the Phenoscape Knowledgebase, specifically looking for genes that are candidates responsible for evolutionarily interesting phenotypes in the ostariophysan fishes that bear resemblance to mutant phenotypes in zebrafish. For this, we searched ZFIN for genetic perturbations that result in either loss of basihyal element or loss of scales phenotypes, because these are the ancestral phenotypes observed in catfishes (Siluriformes). We tested the identified candidate genes by examining their endogenous expression patterns in the channel catfish, Ictalurus punctatus. The experimental results were consistent with the hypotheses that these features evolved through disruption in developmental pathways at, or upstream of, brpf1 and eda/edar for the ancestral losses of basihyal element and scales, respectively. These results demonstrate that ontological annotations of the phenotypic effects of genetic alterations in model organisms, when aggregated within a knowledgebase, can be used effectively to generate testable, and useful, hypotheses about evolutionary changes in morphology
Gonomics: Uniting high performance and readability for genomics with Go.
No full textMany existing software libraries for genomics require researchers to pick between competing considerations: the performance of compiled languages and the accessibility of interpreted languages. Go, a modern compiled language, provides an opportunity to address this conflict. We introduce Gonomics, an open-source collection of command line programs and bioinformatic libraries implemented in Go that unites readability and performance for genomic analyses. Gonomics contains packages to read, write, and manipulate a wide array of file formats (e.g. FASTA, FASTQ, BED, BEDPE, SAM, BAM, and VCF), and can convert and interface between these formats. Furthermore, our modular library structure provides a flexible platform for researchers developing their own software tools to address specific questions. These commands can be combined and incorporated into complex pipelines to meet the growing need for high-performance bioinformatic resources. Gonomics is implemented in the Go programming language. Source code, installation instructions, and documentation are freely available at https://github.com/vertgenlab/gonomics
1-Year Post-Operative Radiographic and Patient-Reported Outcomes following Cervical Deformity Correction are not Affected by a Short-Term Unplanned Return to the OR.
No full textStudy designRetrospective analysis of a prospectively-collected multi-center database.ObjectiveAssess the radiographic and health-related quality of life (HRQoL) impact of a short term (Summary of background dataReturns to the OR within a year of ACSD correction can be particularly devastating to these vulnerable hosts as they often involve compromise of the soft tissue envelope, neurologic deficits or hardware failure. This work sought to assess the impact of a short-term reoperation on 1-year radiographic and HRQoL outcomes.MethodsPatients operated on from 1/1/2013 to 1/1/2019 with at least 1-year of follow-up were included. The primary outcome was a short-term return to the OR. Variables of interest included patient demographics, Charlson Comorbidity Index (CCI), HRQoL measured with the Modified Japanese Orthopaedic Association (mJOA), Neck Disability Index (NDI) and EuroQuol-5D visual analogue scale (EQ-5D VAS) and radiographic outcomes, including T1-slope (TS), C2-C7 sagittal cobb angle (CL), TS-CL and cervical sagittal vertical axis (cSVA). Comparisons between those who did versus did not require a 1-year reoperation were performed using paired t-tests. A Kaplan Meier survival curve was used to estimate reoperation-free survival up to 2-years post-operatively.ResultsA total of 121 patients were included in this work (age 61.9±10.1 y, BMI 28.4±6.9, CCI 1.0±1.4, 62.8% female). A 1-year unplanned return to the OR was required for 28 (23.1%) patients, of whom 19 followed-up for at least 1-year. Indications for a return to the OR were most commonly for neurologic complications (5%), infectious/wound complications (5.8%) and junctional failure (6.6%) No differences in demographics, comorbidities, pre-operative or 1-year post-operative HRQoL or radiographic outcomes were seen between operative groups.ConclusionReoperation <1 year after ACSD surgery did not influence 1-year radiographic outcomes or HRQoL
A minimal monitoring approach for the treatment of hepatitis C virus infection (ACTG A5360 [MINMON]): a phase 4, open-label, single-arm trial.
No full textBackgroundDespite widespread availability of direct-acting antivirals including generic formulations, limited progress has been made in the global adoption of hepatitis C virus (HCV) treatment. Barriers to treatment scale-up include availability and access to diagnostic and monitoring tests, health-care infrastructure, and requirement for frequent visits during treatment.MethodsACTG A5360 was a phase 4, open-label, single-arm trial across 38 sites in Brazil, South Africa, Thailand, Uganda, and the USA. Key inclusion criteria were age of 18 years or older, evidence of active HCV infection (HCV RNA >1000 IU/mL) and HCV treatment-naive; patients with compensated cirrhosis and HIV/HCV co-infection were included but their enrolment was capped. All participants received a fixed dose combination of oral sofosbuvir (400 mg) and velpatasvir (100 mg) once daily for 12 weeks. The minimal monitoring (MINMON) approach consisted of four components: (1) there was no pre-treatment genotyping; (2) the entire treatment course (84 tablets) was dispensed at entry; (3) there were no scheduled visits or laboratory monitoring; and (4) there were two points of remote contact, at week 4 for adherence and week 22, to schedule outcome assessment at week 24 (-2 weeks to +4 weeks). Participants who missed the week 24 window could return for a visit to assess treatment response any time before week 72. Unplanned visits for any reason were permissible before the week 24 visit. The primary efficacy outcome was sustained virological response (SVR), defined as HCV RNA less than the lower limit of quantification measured at least 22 weeks post-treatment initiation; the primary safety outcome was serious adverse events. The primary efficacy analysis included all participants who initiated treatment, using a missing=failure approach. The primary safety analysis included all participants who initiated treatment and had at least one post-treatment assessment. This trial is registered at ClinicalTrials.gov, NCT03512210.FindingsBetween Oct 22, 2018, and July 19, 2019, 400 participants were enrolled across all 38 sites; 399 initiated treatment. At the SVR assessment visit, 355 (89%) of 397 participants reported taking 100% of the trial medication during the 12-week treatment period; two patients did not have any follow-up visits after the entry visit and were excluded from the safety analyses. Overall, 379 of the 399 who initiated treatment had an SVR (95·0%, 95% CI 92·4-96·7). 14 (4%) of 397 participants reported serious adverse events between treatment initiation and week 28; none were treatment related or led to treatment discontinuation or death. 15 (4%) of 399 participants had unplanned visits; none were related to treatment.InterpretationIn this diverse global population of people with HCV, the MINMON approach with sofosbuvir-velpatasvir treatment was safe and achieved SVR comparable to standard monitoring observed in real-world data. Coupled with innovative case finding strategies, this strategy could be crucial to the global HCV elimination agenda.FundingUS National Institutes of Health and Gilead Sciences
Mathematical Analysis of High-Dimensional Algorithms and Models
No full textHigh-dimensional data and problems are ubiquitous in recent research in scientific computing, machine learning, and their applications. Although many algorithms and models have been proposed and examined as efficient in practice, mathematical theories supporting their reliability and efficiency are relatively scarce. In this dissertation, we establish theoretical foundations for three classes of high-dimensional algorithms and models, using analytical tools.(i) Randomized coordinate gradient descent algorithm displays some advantages in high dimensions due to the sparse update and larger stepsize. We prove under generic assumptions that the algorithm almost surely escapes from strict saddle points and converges to local minima for nonconvex optimization. The proof is based on viewing the randomized algorithm as a nonlinear random dynamical system and a quantitative finite block analysis of its linearization around saddle points. (ii) Neural-network-based methods have achieved great success in solving high-dimensional partial differential equations (PDEs) numerically. We establish an approximation theory of two-layer neural networks without the curse of dimensionality for general second-order elliptic PDEs and a regularity theory for static Schr\"odinger equations, via functional analysis in Barron spaces. (iii) Graph neural networks (GNNs) are considered as suitable for representing mixed-integer linear programs (MILPs) due to the permutation-invariant/equivariant property. We show that MILPs suffer from a fundamental limitation of GNNs in separation power, while linear programs (LPs) without integer constraints enjoy the universal approximation. Several remedies are proposed for MILPs.</p
Pre-Existing Diseases of Patients Increase Susceptibility to Hypoxemia during Gastrointestinal Endoscopy
No full textThe impact of baseline cervical malalignment on the development of proximal junctional kyphosis following surgical correction of thoracolumbar adult spinal deformity.
No full textObjectiveThe objective of this study was to identify the effect of baseline cervical deformity (CD) on proximal junctional kyphosis (PJK) and proximal junctional failure (PJF) in patients with adult spinal deformity (ASD).MethodsThis study was a retrospective analysis of a prospectively collected, multicenter database comprising ASD patients enrolled at 13 participating centers from 2009 to 2018. Included were ASD patients aged > 18 years with concurrent CD (C2-7 kyphosis 35°, C2-7 sagittal vertical axis > 4 cm, chin-brow vertical angle > 25°, McGregor's slope > 20°, or C2-T1 kyphosis > 15° across any three vertebrae) who underwent surgery. Patients were grouped according to four deformity classification schemes: Ames and Passias CD modifiers, sagittal morphotypes as described by Kim et al., and the head versus trunk balance system proposed by Mizutani et al. Mean comparison tests and multivariable binary logistic regression analyses were performed to assess the impact of these deformity classifications on PJK and PJF rates up to 3 years following surgery.ResultsA total of 712 patients with concurrent ASD and CD met the inclusion criteria (mean age 61.7 years, 71% female, mean BMI 28.2 kg/m2, and mean Charlson Comorbidity Index 1.90) and underwent surgery (mean number of levels fused 10.1, mean estimated blood loss 1542 mL, and mean operative time 365 minutes; 70% underwent osteotomy). By approach, 59% of the patients underwent a posterior-only approach and 41% underwent a combined approach. Overall, 277 patients (39.1%) had PJK by 1 year postoperatively, and an additional 189 patients (26.7%) developed PJK by 3 years postoperatively. Overall, 65 patients (9.2%) had PJF by 3 years postoperatively. Patients classified as having a cervicothoracic deformity morphotype had higher rates of early PJK than flat neck deformity and cervicothoracic deformity patients (p = 0.020). Compared with the head-balanced patients, trunk-balanced patients had higher rates of PJK and PJF (both p ConclusionsIn patients with concurrent cervical and thoracolumbar deformities undergoing isolated thoracolumbar correction, the use of CD classifications allows for preoperative assessment of the potential for PJK and PJF that may aid in determining the correction of extending fusion levels
An Analysis of Patient-Reported Outcomes Measurement Information System (PROMIS) in Non-operative Posterolateral Elbow Dislocations.
No full textIntroductionThe purpose of our study is to analyze the outcomes of traumatic posterolateral elbow dislocations using patient-reported outcomes measurement information system (PROMIS). We hypothesized that physical function (PF) and upper extremity (UE) scores in PROMIS will significantly improve over six months of follow-up and correlate with a positive change in the patient-acceptable symptom state (PASS).MethodsThis is a seven-year retrospective study of 165 consecutive adult patients with traumatic posterolateral elbow dislocations. Demographic information, PROMIS PF, PROMIS UE, PROMIS pain interference (PI), PROMIS depression, and PASS were recorded over six months of follow-up.ResultsAt the time of injury, mean PROMIS scores were PF 41.24 (SD 11.16), UE 34.27 (SD 11.87), PI 60.44 (SD 8.07), and depression 49.82 (SD 10.42). At six months, the mean PROMIS scores were PF 39.71 (SD 9.71), UE 33.95 (SD 9.09), PI 57.35 (SD 8.59), and depression 51.43 (SD 10.62). The overall six-month changes in PROMIS scores were PF -1.53, UE -0.32, PI -3.09, and depression +1.61. At the 6-month follow-up, 41.7% responded positively on the PASS, which correlated only with PROMIS PI.ConclusionsAmong patients who improved from negative to positive response on PASS, the PROMIS PF, UE, and depression scores did not significantly improve. Only PROMIS PI correlated with PASS at the six-month follow-up; PROMIS PI significantly improved among simple posterolateral elbow dislocation patients at both short-term and long-term follow-up points. PROMIS PF, UE, and depression did not significantly differ between time of injury and short-term and long-term follow-up points
Antibacterial Utilization for Febrile Illnesses and Laboratory-confirmed Bloodstream Infections in Northern Tanzania
No full textAntibacterial management of febrile patients in low-resource settings is challenging and adherence to treatment guidelines is variable. We describe antibacterial use in febrile patients, use of effective therapy for laboratory-confirmed bloodstream infections, and adherence to published guidelines for common febrile illnesses among patients enrolled in prospective hospital-based fever surveillance studies in Moshi, Tanzania.We compared data from two hospital-based prospective cohort studies, Cohort 1 (2011–2014) and Cohort 2 (2016–2019), that enrolled febrile infants, children, and adults. A study team member administered a standardized questionnaire, performed a physical examination, and collected blood cultures on all participants. Ceftriaxone, ciprofloxacin, amoxicillin-clavulanate, or azithromycin were categorized as broad-spectrum antibacterials based on published frameworks and local antimicrobial availability. Participants with laboratory-confirmed bloodstream infections were categorized as receiving effective or ineffective antibacterials based on culture and susceptibility data. Antimicrobials prescribed for preliminary or final diagnosis of pneumonia, urinary tract infection, or presumed sepsis were compared with syndrome-specific recommendations from the World Health Organization (WHO) and the Tanzania Standard Treatment Guidelines. We used descriptive statistics and logistic regression to describe factors associated with antibacterial use.We analyzed data from 2175 participants. The median age of participants in Cohort 1 was 29 (IQR: 5-41) and 22 in Cohort 2 (IQR: 2-45). Among all participants, 50% were female. There were 430 (42.0%) and 501 (45.1%) participants who reported use of antibacterials prior to admission in Cohort 1 and Cohort 2, respectively. There were 989 (91.4%) participants who received antibacterials during admission for febrile illness in Cohort 1 versus 1060 (93.6%) in Cohort 2 (p Receipt of antibacterials prior to and after hospital admission were high and use of broad-spectrum medications was common. A large proportion of participants with culture-confirmed bloodstream infections were treated with ineffective antibacterials but consistency of antibacterial prescribing with WHO and Tanzanian treatment guidelines improved over time. Our results highlight the need for improved diagnostics for febrile illness, data on local antimicrobial resistance patterns, institution-specific clinical guidelines, and provider education to improve prescribing practices and rational use of antimicrobials in Tanzania.</p
Prevalence and type of cervical deformity among 470 adults with thoracolumbar deformity.
No full textStudy designMulticenter, prospective, consecutive case series.ObjectiveTo assess prevalence and type of cervical deformity among adults with thoracolumbar (TL) deformity and to assess for associations between cervical deformities and different types of TL deformities.Summary of background dataCervical deformity can present concomitantly with TL deformity and have implications for the management of TL deformity.MethodsMulticenter, prospective, consecutive series of adult (age >18 yr) patients with TL deformity. Parameters included pelvic tilt (PT), pelvic incidence (PI), lumbar lordosis (LL), C2-C7 sagittal vertical axis (C2-C7SVA), C7-S1SVA, and C2-C7 lordosis. Cervical deformity was defined as cervical lordosis more than 0° (cervical kyphosis [CK]) or C2-C7SVA more than 4 cm (cervical positive sagittal malalignment [CPSM]). Patients were stratified by the Scoliosis Research Society-Schwab classification of adult TL deformity, including curve type (N = sagittal deformity, T = thoracic scoliosis, L = lumbar scoliosis, and D = T + L scoliosis) and modifier grades: PT (0: 30°), C7-S1SVA (0: 9.5 cm), and PI-LL mismatch (0: 20°).ResultsA total of 470 patients met criteria (mean age = 52 yr). Mean cervical lordosis and C2-C7SVA were -8° and 3.2 cm, respectively. CK and CPSM prevalence were 31% and 29%, respectively, and prevalence of CK and/or CPSM was 53%. CK prevalence differed by curve type (N = 15%, L = 27%, D = 37%, T = 49%; P ConclusionCervical deformity is highly prevalent (53%) in adult TL deformity. C7-S1SVA, PT, and PI-LL modifiers are associated with cervical deformity prevalence. These findings suggest that TL deformity evaluation should include assessment for concomitant cervical deformity and that further study is warranted to define their potential clinical impact.Level of evidence3