Effect Of Antiretroviral Drug Dolutegravir On Mitochondrial Function

Background: Though antiretroviral therapy (ART) regimens have become progressively less toxic, ART-associated toxicity is still pervasive. Dolutegravir (DTG) is an HIV integrase strand transfer inhibitor (INSTI), a class of antiretrovirals that are generally well-tolerated by patients. However, in the clinic there are reports of unexpectedly high rates of toxicity in cohorts of pregnant women such as neural tube defects, and in older patients’ adverse effects such as neuropsychiatric disorders. We hypothesized that these adverse effects could be due to DTG-induced mitochondrial toxicity in the central nervous system. Methods: Human neuroblastoma cells were treated with ART regimens that are currently considered standard of care for HIV management. The cells were passaged every 4 days with standard growth media. Neuroblastoma cells were exposed to 1X or 4X-Cmax of tenofovir, emtricitabine, and DTG in single or in combination for 24 hours. We harvested the cells after 24 hours of treatment to determine the effect of treatment on cell growth, mitochondrial protein presence, mitochondrial expression levels, and NMDA receptor protein levels. Results: Our preliminary results indicate that DTG has a potentially appreciable effect on both mitochondrial function and cholesterol biosynthesis. ATP synthase expression levels appears to be relatively unaffected by treatments while expression levels for the other mitochondrial complexes appear to be decreased from DTG treatment compared to other single treatments. Conclusion: Though DTG in clinical trials has been demonstrated to be a potent treatment for HIV viral load, have a high resistance barrier, and low interaction potential, there is still much to be understood in terms of toxicity mechanisms. Our study indicates that the clinical safety profile of DTG and DTG-combination therapies need to be further evaluated

Improving musculoskeletal model scaling using an anatomical atlas:the importance of gender and anthropometric similarity to quantify joint reaction forces

Objective: The accuracy of a musculoskeletal model relies heavily on the implementation of the underlying anatomical dataset. Linear scaling of a generic model, despite being time and cost-efficient, produces substantial errors as it does not account for gender differences and inter-individual anatomical variations. The hypothesis of this study is that linear scaling to a musculoskeletal model with gender and anthropometric similarity to the individual subject produces similar results to the ones that can be obtained from a subject-specific model. Methods: A lower limb musculoskeletal anatomical atlas was developed consisting of ten datasets derived from magnetic resonance imaging of healthy subjects and an additional generic dataset from the literature. Predicted muscle activation and joint reaction force were compared with electromyography and literature data. Regressions based on gender and anthropometry were used to identify the use of atlas. Results: Primary predictors of differences for the joint reaction force predictions were mass difference for the ankle (p<0.001) and length difference for the knee and hip (p≤0.017) . Gender difference accounted for an additional 3% of the variance (p≤0.039) . Joint reaction force differences at the ankle, knee and hip were reduced by between 50% and 67% (p=0.005) when using a musculoskeletal model with the same gender and similar anthropometry in comparison with a generic model. Conclusion: Linear scaling with gender and anthropometric similarity can improve joint reaction force predictions in comparison with a scaled generic model. Significance: The scaling approach and atlas presented can improve the fidelity and utility of musculoskeletal models for subject-specific applications

In vivo knee contact force prediction using patient-specific musculoskeletal geometry in a segment-based computational model

Segment-based musculoskeletal models allow the prediction of muscle, ligament, and joint forces without making assumptions regarding joint degrees-of-freedom (DOF). The dataset published for the “Grand Challenge Competition to Predict in vivo Knee Loads” provides directly measured tibiofemoral contact forces for activities of daily living (ADL). For the Sixth Grand Challenge Competition to Predict in vivo Knee Loads, blinded results for “smooth” and “bouncy” gait trials were predicted using a customized patient-specific musculoskeletal model. For an unblinded comparison, the following modifications were made to improve the predictions: further customizations, including modifications to the knee center of rotation; reductions to the maximum allowable muscle forces to represent known loss of strength in knee arthroplasty patients; and a kinematic constraint to the hip joint to address the sensitivity of the segment-based approach to motion tracking artifact. For validation, the improved model was applied to normal gait, squat, and sit-to-stand for three subjects. Comparisons of the predictions with measured contact forces showed that segment-based musculoskeletal models using patient-specific input data can estimate tibiofemoral contact forces with root mean square errors (RMSEs) of 0.48–0.65 times body weight (BW) for normal gait trials. Comparisons between measured and predicted tibiofemoral contact forces yielded an average coefficient of determination of 0.81 and RMSEs of 0.46–1.01 times BW for squatting and 0.70–0.99 times BW for sit-to-stand tasks. This is comparable to the best validations in the literature using alternative models.</jats:p

Identifying Health Resources and Community Perceptions in the Greater New Haven Area

As required by new laws of the Affordable Care Act, non-profit hospitals are required to produce a Community Health Needs Assessment (CHNA) on a triennial basis in order to receive Medicaid funding, among others. Identification of community health assets is now a requirement by the IRS, in order for the hospital to keep their non-profit status. Community asset mapping (CAM) is an important new component of the community health needs assessment required by the Affordable Care Act for non-profit hospitals. CAM allows these hospitals and the communities they serve to identify key fixtures in their communities that can be leveraged to promote better health and well-being, especially when external resources (e.g. grants) are not available. In partnership with Yale New Haven Health and UnitedWay 2-1-1, we compiled health assets from various towns and communities in the broad Connecticut region. They were classified into six broad areas of need. We conducted interviews with community leaders and residents from the Greater New Haven area, more specifically the West River neighborhood. We hoped to gather insight and perceptions of residents about health assets in their area. Lastly, we generated asset heat maps with GIS to visualize health asset service areas and possibly identify areas of need. Our project sought to expand upon the scope of the mandated CHNA to include community input. Outside of the list of health assets, we went a step further to try to identify possible areas of need based on low coverage by assets on the heat maps.https://elischolar.library.yale.edu/ysph_pbchrr/1028/thumbnail.jp

A method for incorporating organ motion due to breathing into 3D dose calculations

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134856/1/mp8577.pd

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead