Search

Abstract The recA gene, encoding Recombinase A (RecA) is one of three Mycobacterium tuberculosis (Mtb) genes encoding an in-frame intervening protein sequence (intein) that must splice out of precursor host protein to produce functional protein. Ongoing debate about whether inteins function solely as selfish genetic elements or benefit their host cells requires understanding of interplay between inteins and their hosts. We measured environmental effects on native RecA intein splicing within Mtb using a combination of western blots and promoter reporter assays. RecA splicing was stimulated in bacteria exposed to DNA damaging agents or by treatment with copper in hypoxic, but not normoxic, conditions. Spliced RecA was processed by the Mtb proteasome, while free intein was degraded efficiently by other unknown mechanisms. Unspliced precursor protein was not observed within Mtb despite its accumulation during ectopic expression of Mtb recA within E. coli. Surprisingly, Mtb produced free N-extein in some conditions, and ectopic expression of Mtb N-extein activated LexA in E. coli. These results demonstrate that the bacterial environment greatly impacts RecA splicing in Mtb, underscoring the importance of studying intein splicing in native host environments and raising the exciting possibility of intein splicing as a novel regulatory mechanism in Mtb.

Background and purpose: We aimed to systematically review studies of crosswalks for converting patient-reported outcome measure (PROM) scores used in joint replacement, and develop a database of published crosswalks. Methods: 4 electronic databases were searched from January 2000 to May 2023 to identify studies reporting the development and/or validation of crosswalks to convert PROM scores in patients undergoing elective hip, knee, or shoulder replacement surgery. Data on study and sample characteristics, source and target PROMs, and crosswalk development and validation methods were extracted from eligible studies. Study reporting was evaluated using the Mapping onto Preference-based measures reporting Standards (MAPS) checklist. Results: 17 studies describing 35 crosswalks were eligible for inclusion. Unidirectional crosswalks were available to convert hip-specific (Oxford Hip Score [OHS]) and knee-specific (Oxford Knee Score [OKS]) scores to the EQ-5D-3L/EQ-5D-5L. Similar crosswalks to convert disease-specific scores (WOMAC) to the EQ-5D-3L, EQ-5D-5L, and ICECAP-O Capability Index were identified. Bidirectional crosswalks for converting OHS and OKS to the HOOS-JR/HOOS-12 and KOOS-JR/KOOS-12, for converting WOMAC to the HOOS-JR/KOOS-JR, and for converting HOOS-Function/KOOS-Function to the PROMIS-Physical Function were also available. Additionally, crosswalks to convert generic PROM scores from the UCLA Activity Scale to the Lower Extremity Activity Scale in both directions were available. No crosswalks were identified for converting scores in shoulder replacement. Development methods varied with the type of target score; most studies used regression, item response theory, or equipercentile equating approaches. Reporting quality was variable, particularly for methods and results items, impacting crosswalk application. Conclusion: This is the first synthesis of published crosswalks for converting joint-specific (OHS, OKS, HOOS, KOOS), disease-specific (WOMAC), and generic PROMs scores (PROMIS-Physical Function, UCLA Activity Scale, Lower Extremity Activity Scale) used to assess joint replacement outcomes, providing a resource for data harmonization and pooled analysis. Crosswalks were developed using regression methods (9 studies), equipercentile equating methods (5 studies), a combination of equipercentile equating and item response theory methods (2 studies), and a combination of regression and equipercentile equating methods (1 study). A range of crosswalk validation approaches were adopted, including the use of external datasets, separate samples or subsets, follow-up data from additional time points, or bootstrapped samples. Efforts are needed to standardize crosswalk methodology and achieve consistent reporting.

PurposeThe ongoing lack of data standardization severely undermines the potential for automated learning from the vast amount of information routinely archived in electronic health records (EHRs), Radiation Oncology Information Systems (ROIS), treatment planning systems (TPSs), and other cancer care and outcomes databases. The effort sought to create a standardized ontology for clinical data, social determinants of health (SDOH), and other radiation oncology concepts and interrelationships.Methods and materialsThe American Association of Physicists in Medicine's (AAPM's) Big Data Science Committee (BDSC) was initiated July of 2019 to explore common ground from the stakeholders' collective experience of issues that typically compromise the formation of large inter- and intra- institutional databases from EHRs. The BDSC adopted an iterative, cyclical approach to engaging stakeholders beyond its membership to optimize the integration of diverse perspectives from the community.ResultsWe developed the Operational Ontology for Oncology (O3) which identified 42 key elements, 359 attributes, 144 value sets, and 155 relationships ranked in relative importance of clinical significance, likelihood of availability in EHRs, or the ability to modify routine clinical processes to permit aggregation. Recommendations are provided for best use and development of the O3 to four constituencies: device manufacturers, centers of clinical care, researchers, and professional societies.ConclusionsO3 is designed to extend and interoperate with existing global infrastructure and data science standards. The implementation of these recommendations will lower the barriers for aggregation of information that could be used creating large, representative, findable, accessible, interoperable and reusable (FAIR) datasets supporting the scientific objectives of grant programs. The construction of comprehensive "real world" datasets and application of advanced analytic techniques, including artificial intelligence (AI), holds the potential to revolutionize patient management and improve outcomes by leveraging increased access to information derived from larger, more representative datasets.

Objective To assess the intervention fidelity and explore contextual factors affecting the process of implementing a mobile phone text messaging intervention in improving adherence to and retention in care among adolescents living with HIV, their families and their healthcare providers in southern Ethiopia.Design A convergent mixed-methods design guided by the process evaluation theoretical framework and the Reach, Effectiveness, Adoption, Implementation and Maintenance framework was used alongside a randomised controlled trial to examine the fidelity and explore the experiences of participants in the intervention.Setting Six hospitals and five health centres provide HIV treatment and care to adolescents in five zones in southern Ethiopia.Participants Adolescents (aged 10–19), their families and their healthcare providers.Intervention Mobile phone text messages daily for 6 months or standard care (control).Results 153 participants were enrolled in the process evaluation. Among the 153 enrolled in the intervention arm, 78 (49.02%) were male and 75 (43.8%) were female, respectively. The mean and SD age of the participants is 15 (0.21). The overall experiences of implementing the text messages reminder intervention were described as helpful in terms of treatment support for adherence but had room for improvement. During the study, 30 700 text messages were sent, and fidelity was high, with 99.4% successfully delivered text messages during the intervention. Barriers such as failed text messages delivery, limitations in phone ownership and technical limitations affected fidelity. Technical challenges can hinder maintenance, but a belief in the future of digital communication permeates the experiences of the text message reminders.Conclusions Overall fidelity was high, and participants’ overall experiences of mobile phone text messages were expressed as helpful. Contextual factors, such as local telecommunications networks and local electric power, as well as technical and individual factors must be considered when planning future interventions.Trial registration number PACTR202107638293593.

Computer science students often evaluate the behavior of the code they write by running it on specific inputs and studying the outputs, and then apply their comprehension to a more general understanding of the code. While this is a good starting point in the student's career, successful graduates must be able to reason analytically about the code they create or encounter. They must be able to reason about the behavior of the code on arbitrary inputs, without running the code. Abstraction is central for such reasoning. In our quest to help students learn to reason abstractly and develop logically correct code, we have developed tools that rely on a verification engine. Code involves assignment, conditional, and loop statements, along with objects and operations. Reasoning activities involve symbolic reasoning with simple assertions and design-by-contract assertions such as pre-and post-conditions as well as loop invariants with data abstractions. Students progress from tracing and reading code to the design and implementation of code, all relying on abstraction for verification. This paper reports some key results and findings from associated studies spanning several years.

Passive outdoor localization is valuable in understanding pedestrian mobility patterns for city planning and other purposes. While there are various approaches to Wi-Fi localization, few demonstrate robustness to temporal fluctuations in RSSI measurements. In this paper, we continue the work on the Mobility Intelligence System (MobIntel) and address RSSI temporal fluctuation via two approaches. First, given a rectangular testbed bounded by four sensors, we reformulate the problem from localizing the emitters from anywhere within the testbed to classifying whether they originate from the North or South strip and estimating their East-West position on the identified strip. This change simplifies the problem, reduces the impact of RSSI fluctuations, and better resembles how pedestrians move in city streets. Second, we present a multi-stage model (InXModel) to perform localization based on the reformulated problem. Within this model, we compare the performance of four data transformation methods that further dampen the effect of RSSI fluctuation—basic standardization (STD), Kernel Principal Component Analysis (KPCA), Transfer Component Analysis (TCA), and Semi-Supervised TCA (SSTCA). Data resistant to improvements via transformation are discarded to preserve model performance. We observe that the InXModel with STD is the fastest and most accurate model, achieving a localization error $\le 4$ m in 94.3% of the cases with a 30.2% data discard rate. Finally, we compare the InXModel with a recently published method (EMDT-WKNN) specialized for handling RSSI temporal fluctuations and find that the former outperforms the latter. We discuss the causes of the difference in performance.

Abstract Aims Implantable defibrillators are considered life-saving therapy in heart failure (CHF) patients. Surprisingly, the recent Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) reached an opposing conclusion from that of numerous other trials about their survival benefit in patients with advanced CHF. A critical analysis of common control trial design may explain this paradoxical finding, with important implications for future studies. Methods and Results Common control trials compare several intervention groups to a single rather than separate control groups. Though potentially requiring fewer patients than trials using separate controls, variation in the common control group will influence all comparisons and creates correlations between findings. During subgroup analyses, this dependency of outcomes may increase belief in the presence of a real subgroup effect when, in fact, it should increase skepticism. For example, a high (r = 0.92), statistically unlikely (p = 0.052) correlation between comparisons was observed across the subgroups reported in SCD-HeFT. Such concordance between amiodarone and a defibrillator across subgroups was unexpected, given how much the effects of these treatments significantly differed from one another in the main study. This suggests the study's subgroup findings (specifically the absence of benefit from defibrillators in advanced CHF) were not necessarily a consequence of treatment; more likely, they resulted from variation in what the treatments were compared against, the common control. Conclusion Common control trials can be more efficient than other designs, but induce dependence between treatment comparisons and require cautious interpretation.

Background: Coronavirus disease (COVID) created unprecedented challenges, especially for high-volume elective subspecialties like total joint arthroplasty. Limited inpatient capacity and resource conservation led to new outpatient selection criteria and site of service changes. As a Michigan Arthroplasty Registry Quality Collaborative Initiative quality project, demographic changes, complications, and differential effects on inpatient vs outpatient centers pre- and post-COVID were analyzed. Methods: The registry identified all total joint arthroplasty at hospitals and ASCs/HOPDs between 07/2019-12/2019 and 07/2020-12/2020. These intervals represented pre-COVID and post-COVID elective surgery shutdowns. Case volumes, demographics, and 90-day complications were compared. Results: Comparing 2020 to 2019, hospital volumes decreased (−9% total hip arthroplasty [THA], −17% total knee arthroplasty [TKA]), and ambulatory surgery center (ASC)/hospital outpatient department (HOPD) increased (+84% THA, +125% TKA). Entering 2020, ASC/HOPD patients were older (P = .0031, P < .0001: THA, TKA), had more American Society of Anesthesiologists score 3-4 (P = .0105, P = .0021), fewer attended joint class (P < .0001, P < .0001), and more hips were women (P = .023). Hospital patients had higher preoperative pain scores (P = .0117, P < .0001; THA, TKA), less joint education attendance (P < .0001, P < .0001), younger TKAs (P = .0169), and more American Society of Anesthesiologists score 3-4 (0.0009). After propensity matching, there were no significant differences between site of service for 90-day fractures, deep vein thromboses or pulmonary embolisms, infection, or hip dislocations. Hospital THAs had higher readmissions (P = .0003) and TKAs had higher 30-day emergency department visits (P = .005). ASC/HOPD patients were prescribed higher oral morphine equivalents (P < .0001, P < .0001; THA, TKA). Conclusions: COVID’s elective surgery shutdown caused a dramatic site of service shift. Traditional preoperative education was negatively impacted, and older and sicker patients became outpatients. But short-term complications were not increased in ASCs/HOPDs. These site of service and associated patient demographic changes may be safely sustained.

Background and purposeCavernous malformations occur most often in the brain but can occur in the spinal cord. Small studies of patients with familial cerebral cavernous malformations suggested a prevalence of spinal cord cavernous malformations of 20%-42%. We aimed to review our familial cohort and prospectively estimate the prevalence of spinal cord cavernous malformations.Materials and methodsWe initially reviewed our familial cerebral cavernous malformations cohort for spinal cord cavernous malformations and reviewed clinical spine MR imaging examinations for sequence sensitivity. We then prospectively performed research MR imaging of the spinal cord in 29 patients from the familial cohort to estimate the prevalence.ResultsGradient-based sequences identified the most spinal cord cavernous malformations on clinical MR images, forming the basis for developing our screening MR imaging. Screening spinal cord MR imaging demonstrated a prevalence of 72.4%, and a positive correlation with patient age and number of cerebral cavernous malformations.ConclusionsSpinal cord cavernous malformations occur commonly in the familial cerebral cavernous malformation population. Gradient-based sequences are the most sensitive and should be used when spinal cord cavernous malformations are suspected. This study establishes the prevalence in the familial population at around 70% and supports the idea that this condition is a progressive systemic disease that affects the entire central nervous system.

Total hip and knee replacement are effective operations for the management of end-stage arthritis. There are increasing numbers of these operations being performed, and the rate of increase is anticipated to continue into the future (1, 2, 3, 4). There is also a substantial rise in the lifetime risk of a person receiving a total hip or knee replacement and this has been shown in several countries (5, 6, 7, 8). There are a large number of joint replacement prostheses on the market available for use and not all perform the same. Many have no published outcomes. Joint replacement registries provide an appropriate way to monitor the real-world outcomes of these procedures and can provide comparative data on the rates of revision for specific prostheses. Revisions are generally defined in joint registries as a removal or exchange of a prosthesis or part thereof and provide an unambiguous record of a problem with the joint replacement. There are many factors that affect revision rates. Non-device-related issues may include patient factors, surgical technique, surgeon experience and volume of cases. Device-related factors may contribute to the variation in the rates of revision with individual prostheses.

Abstract One of the outstanding questions in planetary science is to determine how the fundamental mechanical and physical properties of materials determine the thermal evolution of asteroids, and which properties have the greatest influence. We investigate the effects of uncertainty in the material properties of asteroid parent bodies on the ability of thermal evolution models to constrain the sizes and formation times of ordinary chondrite parent asteroids. A simple model is formulated for the thermal evolution of the parent body of asteroid 25143 Itokawa. The effects of the uncertainties in the values specified for specific heat capacity, thermal diffusivity, and aluminum abundance are determined. The uncertainties in specific heat capacity and aluminum abundance, or heat production more generally, are found to both have significant and approximately equal effects on these results, substantially widening the range of possible formation times of Itokawa’s parent body. We show that Itokawa’s parent body could have formed between 1.6 and 2.5 million years after the origin of calcium–aluminum inclusions with a radius larger than 19 km, and it could have formed as early as 1.4 millions years, as late as 3.5 million years, or with a radius as small at 17 km if more lenient definitions of uncertainty in aluminum abundance are considered. These results stress the importance of precise data required of the material properties of a suite of LL type 4-6 ordinary chondrite meteorites to place better constraints on the thermal history of Itokawa’s parent body. Graphical Abstract

Background: Obesity is associated with increased complications after total joint arthroplasty (TJA), leading some surgeons to recommend nutrition counseling and weight loss. We aim to evaluate the effect of preoperative nutritionist referral on weight loss and likelihood of surgery in obese patients seeking primary TJA. Methods: A retrospective cohort of patients seeking primary TJA who were referred to a licensed nutritionist for weight loss was matched by age, sex, and body mass index (BMI) to an unreferred control group. BMI change was compared between groups up to 1 year of follow-up. Differences were determined using 2-tailed t-tests and chi-squared tests with a significance cutoff of P < .05. Results: A total of 274 referred patients and 174 controls were included in our analysis. Patients who were referred to a nutritionist achieved significantly greater average BMI change (−1.5 kg/m2) than controls (−0.8 kg/m2) by 6 months after first contact (P = .01) although significance was lost at 1 year after first contact (P = .21). Thirty-eight percent of referred patients went on to TJA compared with 28% of controls (P < .01). Conclusions: Referral to a licensed nutritionist modestly improves early weight loss and is associated with a higher rate of surgery in obese patients seeking primary TJA.

Nova Scotia's Supportive Care Program (SCP) is an individualized funding program that provides funds for people living with dementia (PLWD) or acquired brain injuries to purchase basic home care services such as personal care, respite, cleaning and cooking. The SCP has the potential to address the Quintuple Aim of enhancing care experience, improving population health, reducing costs, improving provider experience and improving health equity, yet qualitative evidence is lacking. The aim of this study is to use participatory program evaluation methods to evaluate the SCP and consider how effective it is in addressing the Quintuple Aim. The study objectives and corresponding methods are to (1) Co-develop a SCP logic model to guide the evaluation through consultations with a diverse group of stakeholders including PLWD, caregivers, care providers, researchers, government representatives, and nongovernment organizations, with attention to gender; (2) Evaluate the SCP based on the outcomes and outputs identified in the logic model using focus groups with PLWD, caregivers and home care providers, and interviews with PLWD and their caregivers; and (3) Mobilize knowledge about the ways the SCP addresses the Quintuple Aim through integrated knowledge translation activities with public, policy and research audiences. By focusing on clinically and socially vulnerable populations of PLWD and caregivers, the proposed evaluation of the SCP offers a valuable case in assessing the effectiveness of individually-funded home care in addressing the Quintuple Aim including health equity within the context of dementia care.

Background: Information on the revision risk of implants is useful for improving the quality of care for elective hip and knee arthroplasty. The purpose of this study was to report on the revision risk of implants using a state-wide registry in the United States. Methods: The Michigan Arthroplasty Registry Collaborative Quality Initiative systematically collects data on elective primary and revision hip and knee arthroplasty cases in Michigan. It contained data on 139,970 hip and 245,499 knee arthroplasty cases from February 15, 2012, to December 31, 2021. Kaplan-Meier estimates of revision risk were computed using time to first revision as the dependent variable, and the results were computed and expressed as the cumulative percent revision (CPR). CPR estimates were computed for all implants having at least 500 cases in the Michigan Arthroplasty Registry Collaborative Quality Initiative dataset. Results: At 5-years postoperatively, elective primary conventional total hip arthroplasty implant stem/cup combinations had CPR values from 0.95% (0.39%-2.30%, 95% confidence intervals [CI]) to 5.77% (4.22%-7.85%, 95% CI), and elective primary total knee arthroplasty CPR ranged from 1.10% (0.64%-1.89%, 95% CI) to 12.52% (8.37%-18.50%, 95% CI). Unicondylar knee arthroplasty CPR at 5-years went from 4.23% (3.54%-5.06%, 95% CI) to 7.13% (6.20%-8.20%, 95% CI). Conclusions: The wide variation in CPR points to the need for surgeons to choose implants wisely to improve quality of care.

ABSTRACT This learning activity teaches the difficult concept of V(D)J recombination as it occurs in B cells. Following the traditional lecture, this hands-on activity uses pipe cleaners of various colors representing variable, joining, and diversity gene segments and recombination signal sequences. Students are provided with instructions for using the pipe cleaners to assemble specific light and heavy immunoglobulin chains. Students each assemble their own light and heavy chains and compare the products made by classmates. This activity uses materials that are easy and affordable to acquire and provides a tactile approach to reinforcing concepts that students often struggle to visualize and master from lecture and textbook material alone.

Byline: Henrietha. Adandom, Samuel. Ofori-Dei, Lars. Hallstrom Introduction: This article describes the health and lifestyle profile of Hutterite farmers in Alberta who participated in a health literacy education program. Methods: [...]

New treatments are required to enhance current therapies for lung cancer. Mesothelin is a surface protein overexpressed in non-small cell lung cancer (NSCLC) that shows promise as an immunotherapeutic target in phase I clinical trials. However, the immunosuppressive environment in NSCLC may limit efficacy of these therapies. We applied time-of-flight mass cytometry to examine the state of circulating mononuclear cells in fourteen patients undergoing treatment for unresectable lung cancer. Six patients had earlier stage NSCLC (I-IVA) and eight had highly advanced NSCLC (IVB). The advanced NSCLC patients relapsed with greater frequency than the earlier stage patients. Before treatment, patients with very advanced NSCLC had a greater proportion of CD14- myeloid cells than patients with earlier NSCLC. These patients also had fewer circulating natural killer (NK) cells bearing an Fc receptor, CD16, which is crucial to antibody-dependent cellular cytotoxicity. We designed a high affinity tri-specific killer engager (TriKE®) to enhance NK cytotoxicity against mesothelin+ targets in this environment. The TriKE consisted of CD16 and mesothelin binding elements linked together by IL-15. TriKE enhanced proliferation of lung cancer patient NK cells in vitro. Lung cancer lines are refractory to NK cell killing, but the TriKE enhanced cytotoxicity and cytokine production by patient NK cells when challenged with tumor. Importantly, TriKE triggered NK cell responses from patients at all stages of disease and treatment, suggesting TriKE can enhance current therapies. These pre-clinical studies suggest mesothelin-targeted TriKE has the potential to overcome the immunosuppressive environment of NSCLC to treat disease.

Computer science students often evaluate the behavior of the code they write by running it on specific inputs and studying the outputs, and then apply their comprehension to a more general understanding of the code. While this is a good starting point in the student’s career, successful graduates must be able to reason analytically about the code they create or encounter. They must be able to reason about the behavior of the code on arbitrary inputs, without running the code. Abstraction is central for such reasoning. In our quest to help students learn to reason abstractly and develop logically correct code, we have developed tools that rely on a verification engine. Code involves assignment, conditional, and loop statements, along with objects and operations. Reasoning activities involve symbolic reasoning with simple assertions and design-by-contract assertions such as pre-and post-conditions as well as loop invariants with data abstractions. Students progress from tracing and reading code to the design and implementation of code, all relying on abstraction for verification. This paper reports some key results and findings from associated studies spanning several years.