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Ex vivo lung perfusion (EVLP) is an excellent platform to apply novel therapeutics, such as gene and cell therapies, before lung transplantation. We investigated the concept of human donor lung engineering during EVLP by combining gene and cell therapies. Premodified cryopreserved mesenchymal stromal cells with augmented anti-inflammatory interleukin-10 production (MSCIL-10) were administered during EVLP to human lungs that had various degrees of underlying lung injury. Cryopreserved MSCIL-10 had excellent viability, and they immediately and efficiently elevated perfusate and lung tissue IL-10 levels during EVLP. However, MSCIL-10 function was compromised by the poor metabolic conditions present in the most damaged lungs. Similarly, exposing cultured MSCIL-10 to poor metabolic, and especially acidic, conditions decreased their IL-10 production. In conclusion, we found that “off-the-shelf” MSCIL-10 therapy of human lungs during EVLP is safe and feasible, and results in rapid IL-10 elevation, and that the acidic target-tissue microenvironment may compromise the efficacy of cell-based therapies., Graphical abstract, Mesenchymal stromal cells with augmented anti-inflammatory IL-10 production were administered to human lungs during ex vivo lung perfusion, a platform that enables application of novel therapeutics to donor lungs before transplantation. IL-10 production was rapid but compromised by lung injury and acidosis, indicating that the local target-tissue microenvironment affects cell-based therapies.

Alcohol and cannabis co-use is associated with negative alcohol consequences and alcohol use disorder. However, mediating and distal effects remain largely unstudied. Co-use is associated with alco...

Pelvic tilt affects acetabular anteversion, and thus total hip arthroplasty (THA) dislocation risk. The pubic symphysis-sacrococcygeal distance (PSCD) is an indicator of pelvic tilt, and a PSCD0 mm (ie, excessive posterior pelvic tilt) is associated with a 3.7-fold increase in postoperative dislocation rate. However, it is not known if the direct anterior (DA) approach might reduce this dislocation rate, specifically in high-risk populations such as negative PSCD.Standing anteroposterior radiographs were reviewed for 510 consecutive DA THAs to determine PSCD. Patients were separated into 2 groups: (1) PSCD0 mm (PSCD[+]) and (2) PSCD0 mm (PSCD[-]). Incidence of dislocation was determined. We recorded if patients had spinal deformity or lumbar fusion. Continuous variables were analyzed using Student's t-test, categorical variables were analyzed using Fisher's exact test, and a sample size calculation was performed.Three hundred fifty-eight hips (70.2%) were PSCD[+], while 152 hips (29.8%) were PSCD[-]. Three dislocations (3/510 hips, 0.6%) occurred. Two dislocators were in the PSCD[-] group (2/152 hips, 1.3%) and 1 dislocator was in the PSCD[+] group (1/358 hips, 0.3%) (P = .21). Twenty-four patients had degenerative scoliosis (24/510, 4.7%), of which 1 had a dislocation (1/24, 4.2%); 2 dislocations occurred in nonscoliosis patients (2/486, 0.4%) (P = .134). Twenty-seven patients had lumbar spinal fusion (27/510, 5.3%), of which there were no dislocations (0/27, 0.0%); all dislocations were in nonfusion patients (3/483, 0.6%) (P = 1.0).We demonstrate no increased risk for THA dislocation in patients with a PSCD0 mm who have undergone a DA approach. These data would suggest a protective effect of the DA approach against dislocation, even in historically high-risk populations.

Background: Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) is an emerging condition that was first identified in paediatrics at the onset of the COVID-19 pandemic. The condition is also known as pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (PIMS-TS or PIMS), and multiple definitions have been established for this condition that share overlapping features with Kawasaki Disease and toxic shock syndrome. Methods: A review was conducted to identify literature describing the epidemiology of MIS-C, published up until March 9, 2021. A database established at the Public Health Agency of Canada with COVID-19 literature was searched for articles referencing MIS-C, PIMS or Kawasaki Disease in relation to COVID-19. Results: A total of 195 out of 988 articles were included in the review. The median age of MIS-C patients was between seven and 10 years of age, although children of all ages (and adults) can be affected. Multisystem inflammatory syndrome in children disproportionately affected males (58% patients), and Black and Hispanic children seem to be at an elevated risk for developing MIS-C. Roughly 62% of MIS-C patients required admission to an intensive care unit, with one in five patients requiring mechanical ventilation. Between 0% and 2% of MIS-C patients died, depending on the population and available interventions. Conclusion: Multisystem inflammatory syndrome in children can affect children of all ages. A significant proportion of patients required intensive care unit and mechanical ventilation and 0%–2% of cases resulted in fatalities. More evidence is needed on the role of race, ethnicity and comorbidities in the development of MIS-C.

BACKGROUND Donor-recipient size-matching has been repeatedly reported to improve outcomes following lung transplantation (LTx). However, there is significant variability in practice and the optimal strategy for size-matching is yet to be defined. For recipients with ILD, size-matching decisions are complicated by concerns regarding the potential impact of pre-LTx pulmonary restriction. We evaluate whether a specific donor-to-recipient size-matching strategy, based on predicted total lung capacity, benefits this patient group. METHODS This retrospective, single-centre, cohort study describes the post-LTx outcomes of adults who underwent LTx for ILD between 1983 and 2020. Only patients with restrictive physiology, based on pre-LTx pulmonary function testing were included. Post-LTx outcomes were compared based on donor-recipient predicted TLC (D-R pTLC) ratio. A D-R pTLC ratio of ≥0.8 or

In this narrative review, we outline the literature describing the history, training, certification, and role of peer recovery support specialists working with people with substance use disorders at different stages of active use and recovery. We explore the impact of peer recovery support specialists serving people in various settings, including the community, hospitals and emergency departments, jails and prisons, and treatment and recovery agencies; and describes considerations for future expansion of peer recovery support services, including supervision needs, compassion fatigue and burnout, and scope of practice. Finally, we make recommendations to support the broad implementation of peer recovery support services as a sustainable, cohesive, and replicable component of harm reduction and addiction services. We also make recommendations for research to continue to evaluate peer recovery support specialist interventions across settings and outcomes.

Thoracolumbar spine trauma can result in potentially life-threatening consequences and requires careful management to ensure good outcomes. The purpose of this chapter is to discuss the anatomy, diagnostic tools, non-operative, and operative treatments important when addressing thoracolumbar trauma.

Approaches for rapid reviews that focus on streamlining systematic review methods are not always suitable for exploring complex policy questions, as developing and testing theories to explain these complexities requires configuring diverse qualitative, quantitative, and mixed methods studies. Our objective was therefore to provide a guide to selecting approaches for rapidly (i.e., within days to months) addressing complex questions related to health policy and system issues. We provide a two-stage, transdisciplinary collaborative process to select a rapid review approach to address complex policy questions, which consists of scoping the breadth and depth of the literature and then selecting an optimal approach to synthesis. The first stage (scoping the literature) begins with a discussion with the stakeholders requesting evidence to identify and refine the question for the review, which is then used to conduct preliminary searches and conceptually map the documents identified. In the second stage (selection of an optimal approach), further stakeholder consultation is required to refine and tailor the question and approach to identifying relevant documents to include. The approach to synthesizing the included documents is then guided by the final question, the breadth and depth of the literature, and the time available and can include a static or evolving conceptual framework to code and analyze a range of evidence. For areas already covered extensively by existing systematic reviews, the focus can be on summarizing and integrating the review findings, resynthesizing the primary studies, or updating the search and reanalyzing one or more of the systematic reviews. The choice of approaches for conducting rapid reviews is intertwined with decisions about how to manage projects, the amount of work to be done, and the knowledge already available, and our guide offers support to help make these strategic decisions. Supplementary Information The online version contains supplementary material available at 10.1186/s13643-021-01834-y.

Purpose To systematically review past studies to determine the effect of various solutions on the color of denture teeth, thus answering the question in regards to which type of denture teeth has the best optical properties after exposure to various solutions. The method of measuring the color of artificial teeth was also evaluated as a secondary outcome. Materials and methods A search of studies that quantitatively investigated the influence of immersion solutions on the color change of denture teeth was conducted. Ovid MEDLINE, PubMed and Scopus databases were searched from 1997 to April 2021. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used during article selection. Data regarding the effect of immersion solutions, accelerated aging and surface treatments on color change were gathered. Methodologies used to assess optical properties were also summarised and compared. The modified CONSORT checklist was used to determine the risk of bias of past studied included in this review. Results 133 studies were identified after removing duplicates. Forty-one studies were selected for full-text analysis, and 35 remaining papers met the inclusion criteria and were therefore included in this systematic review. Thirty-two in vitro studies and 3 in vivo studies were included in the review. All studies reported that immersion in various solutions has a significant influence on the change in color and optical properties of denture teeth. However, the discolouration of denture teeth is still clinically acceptable in most studies. Exposure to various solution also affected the translucency parameter of denture teeth. Most studies also investigated the surface roughness and hardness along with the optical properties, and reported that immersion cycles did not cause changes in surface roughness of denture teeth, while hardness was affected. The optical properties of PMMA denture teeth have been studied extensively, whereas that of CAD/CAM and 3D printed denture teeth is limited. Conclusions Color stability of CAD/CAM milled denture teeth is comparable to conventional PMMA denture teeth. There are contradictory findings in terms of color stability of 3D printed denture teeth as compared to conventional PMMA denture teeth. Staining by coffee is worst among the common beverages and solutions investigated. Denture teeth can show color changes after immersion in staining beverages as early as one week. The degree of discoloration of denture teeth after immersion is time dependent, with the larger extent in the initial phase. This article is protected by copyright. All rights reserved.

Lentigo maligna (LM) is a common in situ melanoma subtype arising on chronically sun-damaged skin and mostly affects the head and neck region. Localisation in cosmetically sensitive areas, difficulty to obtain wide resection margins and advanced patient age/comorbidities have encouraged investigation of less invasive therapeutic strategies than surgery in managing complex cases of LM. Radiotherapy and imiquimod have emerged as alternative treatment options in this context. The treatment of LM with imiquimod cream can be challenging due to the nature of the disease including its often large size, variegated appearance, involvement of adnexal structures, poorly defined peripheral edge and frequent localisation close to sensitive structures such as the eyes and lips, and elderly patients with multiple comorbidities. Prolonged and unpredictable inflammatory reaction and side effects and compliance with a patient-delivered therapy can also be challenging. In the literature to date, studies evaluating the use of imiquimod to treat LM have utilised varying methodologies and provided short follow-up and these limitations have impaired the development of clear guidelines for dosage and management of side effects. Based on our multidisciplinary experience and review of the literature, we propose practical clinical strategies for the use of imiquimod for treating LM, detailing optimal administration procedures in various clinical scenarios and long-term management, with the aim of facilitating optimal patient outcomes.

Background. Wearable sensors allow for direct measurement of upper limb (UL) performance in daily life. Objective. To map the trajectory of UL performance and its relationships to other factors post-stroke. Methods. Participants (n = 67) with first stroke and UL paresis were assessed at 2, 4, 6, 8, 12, 16, 20, and 24 weeks after stroke. Assessments captured UL impairment (Fugl-Meyer), capacity for activity (Action Research Arm Test), and performance of activity in daily life (accelerometer variables of use ratio and hours of paretic limb activity), along with other potential modifying factors. We modeled individual trajectories of change for each measurement level and the moderating effects on UL performance trajectories. Results. Individual trajectories were best fit with a 3-parameter logistic model, capturing the rapid growth early after stroke within the longer data collection period. Plateaus (90% of asymptote) in impairment (bootstrap mean ± SE: 32 ± 4 days post-stroke) preceded those in capacity (41 ± 4 days). Plateau in performance, as measured by the use ratio (24 ± 5 days), tended to precede plateaus in impairment and capacity. Plateau in performance, as measured by hours of paretic activity (41 ± 6 days), occurred at a similar time to that of capacity and slightly lagged impairment. Modifiers of performance trajectories were capacity, concordance, UL rehabilitation, depressive symptomatology, and cognition. Conclusions. Upper limb performance in daily life approached plateau 3 to 6 weeks post-stroke. Individuals with stroke started to achieve a stable pattern of UL use in daily life early, often before neurological impairments and functional capacity started to stabilize.

Deep learning is a subdiscipline of artificial intelligence that uses a machine learning technique called artificial neural networks to extract patterns and make predictions from large data sets. The increasing adoption of deep learning across healthcare domains together with the availability of highly characterised cancer datasets has accelerated research into the utility of deep learning in the analysis of the complex biology of cancer. While early results are promising, this is a rapidly evolving field with new knowledge emerging in both cancer biology and deep learning. In this review, we provide an overview of emerging deep learning techniques and how they are being applied to oncology. We focus on the deep learning applications for omics data types, including genomic, methylation and transcriptomic data, as well as histopathology-based genomic inference, and provide perspectives on how the different data types can be integrated to develop decision support tools. We provide specific examples of how deep learning may be applied in cancer diagnosis, prognosis and treatment management. We also assess the current limitations and challenges for the application of deep learning in precision oncology, including the lack of phenotypically rich data and the need for more explainable deep learning models. Finally, we conclude with a discussion of how current obstacles can be overcome to enable future clinical utilisation of deep learning.

The establishment of genomics in health care systems has been occurring for the past decade. It is recognised that implementing genomics within a health service is challenging without a system-wide approach. Globally, as clinical genomics implementation programs have matured there is a growing body of information around program design and outcomes. Program structures vary depending on local ecosystems including the health system, politics and funding availability, however, lessons from other programs are important to the design of programs in different jurisdictions. Here we describe an adaptive approach to the implementation of genomics into a publicly funded health care system servicing a population of 5.1 million people. The adaptive approach enabled flexibility to facilitate substantial changes during the program in response to learnings and external factors. We report the benefits and challenges experienced by the program, particularly in relation to the engagement of people and services, and the design of both individual projects and the program as a whole.

Purpose This single institution study describes the technique, safety, and efficacy of genicular artery embolization (GAE) for treatment of refractory hemarthrosis following total knee arthroplasty (TKA) with a focus on patient-reported outcomes. Material and methods Patients who underwent GAE between January 2010 and March 2020 at the authors' institution were included if they had undergone TKA and subsequently experienced recurrent hemarthrosis. Embolization was performed using spherical microparticles. Technical success was defined as significant reduction or elimination of the hyperemic blush. Clinical success was defined as absence of clinical evidence of further hemarthrosis. Clinical follow-up was obtained 7-14 days post procedure and at 3-month intervals thereafter via telephone interview during which patients were questioned about the presence of symptoms and their satisfaction with the procedure. 82 knees were included. 117 embolizations, comprising 82 initial, 28 first repeat, and 7 second repeat, were performed. Results An average of 2.5 arteries was treated per procedure. The superior lateral genicular artery was the most commonly embolized. The most utilized particle size was 100-300 μm, although 300-500 μm particles were favored in later cases. Follow up was available for all patients, with a median duration of 21.5 months. 65.9%, 25.6%, and 8.5% of patients underwent one, two, and three treatments, respectively. Complications occurred following 12.8% of treatments, the most common of which was transient cutaneous ischemia; this was seen only in the patients who were embolized with particles smaller than 300 μm. Technical success was achieved in all cases. Clinical success was achieved in 56% of patients following the first treatment, in 79% after the second, and in 85% after the third. 83% of patients reported being either Satisfied or Very Satisfied with the overall result. Conclusion Targeted GAE with spherical particles is an effective treatment for recurrent hemarthrosis with infrequent serious complications. Repeat embolization is effective and should be considered in cases of recurrence following initial therapy.

QuestionMental disorders typically start in childhood and persist, causing high individual and collective burdens. To inform policymaking to address children’s mental health in high-income countries we aimed to identify updated data on disorder prevalence.MethodsWe identified epidemiological studies reporting mental disorder prevalence in representative samples of children aged 18 years or younger—including a range of disorders and ages and assessing impairment (searching January 1990 through February 2021). We extracted associated service-use data where studies assessed this. We conducted meta-analyses using a random effects logistic model (using R metafor package).FindingsFourteen studies in 11 countries met inclusion criteria, published from 2003 to 2020 with a pooled sample of 61 545 children aged 4–18 years, including eight reporting service use. (All data were collected pre-COVID-19.) Overall prevalence of any childhood mental disorder was 12.7% (95% CI 10.1% to 15.9%; I2=99.1%). Significant heterogeneity pertained to diagnostic measurement and study location. Anxiety (5.2%), attention-deficit/hyperactivity (3.7%), oppositional defiant (3.3%), substance use (2.3%), conduct (1.3%) and depressive (1.3%) disorders were the most common. Among children with mental disorders, only 44.2% (95% CI 37.6% to 50.9%) received any services for these conditions.ConclusionsAn estimated one in eight children have mental disorders at any given time, causing symptoms and impairment, therefore requiring treatment. Yet even in high-income countries, most children with mental disorders are not receiving services for these conditions. We discuss the implications, particularly the need to substantially increase public investments in effective interventions. We also discuss the policy urgency, given the emerging increases in childhood mental health problems since the onset of the COVID-19 pandemic (PROSPERO CRD42020157262).

Objective To investigate in a large global sample of patients with retinoblastoma whether sex predilection exists for this childhood eye cancer. Methods A cross-sectional analysis including 4351 treatment-naive retinoblastoma patients from 153 countries who presented to 278 treatment centers across the world in 2017. The sex ratio (male/female) in the sample was compared to the sex ratio at birth by means of a two-sided proportions test at global level, country economic grouping, continent, and for selected countries. Results For the entire sample, the mean retinoblastoma sex ratio, 1.20, was higher than the weighted global sex ratio at birth, 1.07 (p n = 1940), 1.23 vs. 1.07 (p = 0.019); Asia (n = 2276), 1.28 vs. 1.06 (p n = 558), 1.52 vs. 1.11 (p = 0.008). Sensitivity analysis, excluding data from India, showed that differences remained significant for the remaining sample (χ2 = 6.925, corrected p = 0.025) and for Asia (χ2 = 5.084, corrected p = 0.036). Excluding data from Asia, differences for the remaining sample were nonsignificant (χ2 = 2.205, p = 0.14). Conclusions No proof of sex predilection in retinoblastoma was found in the present study, which is estimated to include over half of new retinoblastoma patients worldwide in 2017. A high male to female ratio in Asian countries, India in specific, which may have had an impact on global-level analysis, is likely due to gender discrimination in access to care in these countries, rather than a biological difference between sexes.

Background Children who experience traumatic physical injuries are at risk of developing acute stress disorder and posttraumatic stress disorder (PTSD). Early identification and treatment of these high-risk children can lead to improved mental health outcomes in this population. Objective This study assesses the feasibility of a study protocol that compares 3 screening tools for identifying patients at a high risk of later development of acute stress disorder or PTSD among pediatric trauma patients. Methods This pilot study compared 3 questionnaires used as screening tools for predictors of later development of PTSD in a convenience sample of pediatric trauma patients aged 7-17 years. Patients were randomized to one of 3 screening tools. Families were contacted at 30, 60, and 90-120 days postinjury to complete the Child Report of Post-Traumatic Symptoms questionnaire. The sensitivity and negative predictive value of the screening tools were compared for the diagnosis of PTSD defined using the Child Report of Post-Traumatic Symptoms questionnaire. Results Of the 263 patients identified for possible enrollment, 52 patients met full inclusion criteria and agreed to participate. Only 29 (55.7%) patients completed at least one follow-up questionnaire. The prevalence of acute stress disorder and PTSD in our population was 41% (95% CI [24, 61]) and 31% (95% CI [15, 51]), respectively. Conclusions In this pilot study, we sought to determine the utility of the 3 commonly used screening instruments for measuring traumatic stress symptoms in pediatric trauma patients to predict the diagnosis of acute stress disorder or PTSD. Limitations include the use of the Child Report of Post-Traumatic Symptoms screening tool as the gold standard for calculating test characteristics and lack of 24/7 enrollment capabilities. As such, a significant portion of patients were discharged prior to our teams' engagement for enrollment.

A new polymorph of 2,3,5,6-tetra­fluoro-7,7,8,8-tetra­cyano­quinodi­methane (F4TCNQ) has been characterized using single-crystal X-ray diffraction and is presented in com­parison with the previously reported structure of the com­pound., During the course of research into the structure of 2,3,5,6-tetra­fluoro-7,7,8,8-tetra­cyano­quinodi­methane (F4TCNQ), C12F4N4, an important com­pound in charge-transfer and organic semiconductor research, a previously unreported polymorph of F4TCNQ was grown concomitantly with the known polymorph from a saturated solution of di­chloro­methane. The structure was elucidated using single-crystal X-ray diffraction and it was found that the new polymorph packs with mol­ecules in parallel layers, in a similar manner to the layered structure of F2TCNQ. The structure was analysed using Hirshfeld surface analysis, fingerprint plots and pairwise inter­action energies, and com­pared to existing data. The structure of a toluene solvate of F4TCNQ is also reported.

Aims Traditionally, acetabular component insertion during total hip arthroplasty (THA) is visually assisted in the posterior approach and fluoroscopically assisted in the anterior approach. The present study examined the accuracy of a new surgeon during anterior (NSA) and posterior (NSP) THA using robotic arm-assisted technology compared to two experienced surgeons using traditional methods. Methods Prospectively collected data was reviewed for 120 patients at two institutions. Data were collected on the first 30 anterior approach and the first 30 posterior approach surgeries performed by a newly graduated arthroplasty surgeon (all using robotic arm-assisted technology) and was compared to standard THA by an experienced anterior (SSA) and posterior surgeon (SSP). Acetabular component inclination, version, and leg length were calculated postoperatively and differences calculated based on postoperative film measurement. Results Demographic data were similar between groups with the exception of BMI being lower in the NSA group (27.98 vs 25.2; p = 0.005). Operating time and total time in operating room (TTOR) was lower in the SSA (p < 0.001) and TTOR was higher in the NSP group (p = 0.014). Planned versus postoperative leg length discrepancy were similar among both anterior and posterior surgeries (p > 0.104). Planned versus postoperative abduction and anteversion were similar among the NSA and SSA (p > 0.425), whereas planned versus postoperative abduction and anteversion were lower in the NSP (p < 0.001). Outliers > 10 mm from planned leg length were present in one case of the SSP and NSP, with none in the anterior groups. There were no outliers > 10° in anterior or posterior for abduction in all surgeons. The SSP had six outliers > 10° in anteversion while the NSP had none (p = 0.004); the SSA had no outliers for anteversion while the NSA had one (p = 0.500). Conclusion Robotic arm-assisted technology allowed a newly trained surgeon to produce similarly accurate results and outcomes as experienced surgeons in anterior and posterior hip arthroplasty. Cite this article: Bone Jt Open 2021;2(6):365–370.

Background To shape priorities for health and health care outcomes, it is essential for nurse leaders to be influential. The application and impact of influence are readily recognized, but not its characteristics. Purpose The purpose of this project was to conduct a concept analysis of influence relative to nurse leaders. Methods The Walker and Avant method of concept analysis was utilized. Findings Attributes of influence include advocacy, communications skills, competency, confidence, credibility, and engagement. Antecedents of influence are authority, collaboration, integrity, and mentorship. Consequences of influence are action, change, commitment, compliance, decision-making, motivation, and resistance. Discussion By drawing upon a systematic understanding of the concept of influence, nurse leaders are urged to develop and leverage the attributes of influence to drive and achieve collective good for the future of health and health care in society.

Aims “Get It Right First Time” (GIRFT) and NHS England’s Best Practice Tariff (BPT) have published directives advising that patients over the ages of 65 (GIRFT) and 69 years (BPT) receiving total hip arthroplasty (THA) should receive cemented implants and have brought in financial penalties if this policy is not observed. Despite this, worldwide, uncemented component use has increased, a situation described as a ‘paradox’. GIRFT and BPT do, however, acknowledge more data are required to support this edict with current policies based on the National Joint Registry survivorship and implant costs. Methods This study compares THA outcomes for over 1,000 uncemented Corail/Pinnacle constructs used in all age groups/patient frailty, under one surgeon, with identical pre- and postoperative pathways over a nine-year period with mean follow-up of five years and two months (range: nine months to nine years and nine months). Implant information, survivorship, and regular postoperative Oxford Hip Scores (OHS) were collected and two comparisons undertaken: a comparison of those aged over 65 years with those 65 and under and a second comparison of those aged 70 years and over with those aged under 70. Results Overall revision rate was 1.3% (13/1,004). A greater number of revisions were undertaken in those aged over 65 years, but numbers were small and did not reach significance. The majority of revisions were implant-independent. Single component analysis revealed a 99.9% and 99.6% survival for the uncemented cup and femoral component, respectively. Mean patient-reported outcome measures (PROMs) improvement for all ages outperformed the national PROMs and a significantly greater proportion of those aged over 65/69 years reached and maintained a meaningful improvement in their OHS earlier than their younger counterparts (p < 0.05/0.01 respectively). Conclusion This study confirms that this uncemented THA system can be used safely and effectively in patient groups aged over 65 years and those over 69 years, with low complication and revision rates. Cite this article: Bone Jt Open 2021;2(5):293–300.

To assess total and allergic rhinitis (AR)-related healthcare costs among AR patients residing in the United States with a focus on patients persisting with AIT.AR patients were identified in the IBM MarketScan database between 1 January 2014 to 31 March 2017. Patients receiving allergy immunotherapy (AIT) were identified with relevant billing codes (earliest AIT claim = index date); non-AIT patients were identified with claims containing a diagnosis code for AR (earliest AR claim = index date). AIT patients reaching 25+ injection claims were analyzed as a separate maintenance cohort. All patients were required to have continuous enrollment for 12 months preceding and following index.A total of 2,334,530 AR patients were included; 103,207 had at least 1 AIT claim, with 45,279 (43.9%) of these patients reaching maintenance, and 24,640 AIT patients (23.9%) never presenting a single injection claim. Compared to non-AIT patients, patients initiating AIT presented higher rates of baseline comorbidities, including asthma (30.1% vs. 7.5%) and conjunctivitis (21.7% vs. 4.4%). During the follow-up period, patients reaching the maintenance phase of AIT incurred lower total costs than the overall AIT cohort ($10,431±$16,606 vs. $11,612±$24,797), and also presented lower follow-up hospitalization costs ($698±$7,248 vs. $1,281±$12,991) and total medical costs ($7950±$13,844 vs. $8989±$22,019).Continued efforts are needed to increase patient awareness of available options and adherence to AIT, along with reducing wastage. Despite AIT patients presenting fairly progressed disease at the time of treatment initiation, this therapy remains an economical treatment option, as it was not accompanied by substantial increases in overall healthcare expenditure, and may promote positive societal impacts beyond the direct medical costs.What is known on this topicThe prevalence of allergic diseases has increased over the past 50 years and affects between 10-30% of the world population.Allergic rhinitis (AR) poses a significant economic burden in the form of both direct and indirect costsAllergy immunotherapy (AIT) is the only treatment option able to modify the underlying course of the disease.What this study addsSpecific all-cause and AR-related healthcare costs decreased following the initiation of AIT among patients diagnosed with AR, with the largest decreases observed among AIT patients reaching the maintenance phase of treatment, while non-AIT patients showed increases in all categories assessed over a similar follow-up period.Cost decreases among AIT patients were observed despite increased levels of comorbidities compared to non-AIT patients, as the AIT cohort presented elevated rates of atopic dermatitis (7.1% vs. 2.7%), conjunctivitis (21.7% vs. 4.4%), asthma (30.1% vs. 7.5%), and chronic sinusitis (22.6% vs. 4.9%).An analysis of patients' index subcutaneous AIT consultation revealed substantial variability in the initial treatment costs, with nearly 20% of paid amounts exceeding $1,000; given nearly 1 in 4 AIT patients who get AIT mixed never came back for their first injection, this highlights an opportunity to target frontloaded billing practices and the timing of mixing/injection as an area to minimize healthcare waste.

Background: Research studies comparing antibody response from coronavirus disease 2019 (COVID-19) cases that retested positive (RP) using reverse transcription polymerase chain reaction (RT-PCR) and those who did not retest positive (NRP) were used to investigate a possible relationship between antibody response and retesting status. Methods: Seven data bases were searched. Research criteria included cohort and case-control studies, carried out worldwide and published before September 9, 2020, that compared the serum antibody levels of hospitalized COVID-19 cases that RP after discharge to those that did NRP. Results: There is some evidence that immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody levels in RP cases were lower compared with NRP cases. The hypothesis of incomplete clearance aligns with these findings. The possibility of false negative reverse transcription polymerase chain reaction (RT-PCR) test results during viral clearance is also plausible, as concentration of the viral ribonucleic acid (RNA) in nasopharyngeal and fecal swabs fluctuate below the limits of RT-PCR detection during virus clearance. The probability of reinfection was less likely to be the cause of retesting positive because of the low risk of exposure where cases observed a 14 day-quarantine after discharge. Conclusion: More studies are needed to better explain the immune response of recovered COVID-19 cases retesting positive after discharge.

Rasch and classification analyses on a field-test version of the third edition of the Assessment, Evaluation, and Programming System (AEPS-3), a curriculum-based assessment used to assess young children birth to age 6 years, were conducted. First, an evaluation of the psychometric properties of data from each developmental area of an AEPS-3 field-test version was conducted. Next, cutoff scores at 6-month age intervals were created and then the validity of the cutoff scores was evaluated. Results using Rasch modeling indicated acceptable model fit statistics with reasonable reliability estimates within each developmental area. Classification results showed cutoff scores accurately classified a high percentage of eligible children. Findings suggest that scores from a field-test version of the AEPS-3 are reliable within developmental areas. To the extent allowed by state criteria, early childhood interventionists could possibly use a new field-test version of the AEPS-3 to determine or corroborate eligibility for special education services.

Evaluating genes involved in the pharmacodynamics and pharmacokinetics of epilepsy drugs is critical to better understand pharmacoresistant epilepsy. We reviewed the pharmacogenetics literature on six antiseizure medicines (carbamazepine, perampanel, lamotrigine, levetiracetam, sodium valproate and zonisamide) and compared the genes found with those present on epilepsy gene panels using a functional annotation pathway analysis. Little overlap was found between the two gene lists; pharmacogenetic genes are mainly involved in detoxification processes, while epilepsy panel genes are involved in cell signaling and gene expression. Our work provides support for a specific pharmacoresistant epilepsy gene panel to assist antiseizure medicine selection, enabling personalized approaches to treatment. Future efforts will seek to include this panel in genomic analyses of pharmacoresistant patients, to determine clinical utility and patient treatment responses.

For complex machine learning (ML) algorithms to gain widespread acceptance in decision making, we must be able to identify the features driving the predictions. Explainability models allow transparency of ML algorithms, however their reliability within high-dimensional data is unclear. To test the reliability of the explainability model SHapley Additive exPlanations (SHAP), we developed a convolutional neural network to predict tissue classification from Genotype-Tissue Expression (GTEx) RNA-seq data representing 16,651 samples from 47 tissues. Our classifier achieved an average F1 score of 96.1% on held-out GTEx samples. Using SHAP values, we identified the 2423 most discriminatory genes, of which 98.6% were also identified by differential expression analysis across all tissues. The SHAP genes reflected expected biological processes involved in tissue differentiation and function. Moreover, SHAP genes clustered tissue types with superior performance when compared to all genes, genes detected by differential expression analysis, or random genes. We demonstrate the utility and reliability of SHAP to explain a deep learning model and highlight the strengths of applying ML to transcriptome data.

An explosion in the volume of Industrial Internet of Things (IIoT) research has failed to fully resonate with industry. Better communication of requirements to researchers will help avoid wasteful IIoT research using attractively priced but functionally dead-end hardware. A robust and systematic evaluation of popular low-cost IIoT devices based on fitment for purpose will increase industry adoption of new technology built on that hardware. Specific hardware examples that have already been adopted by industry are presented. Based on that evaluation, general traits to consider when selecting IIoT hardware for research and development purposes are outlined; we propose that projects built with these criteria in mind are far more likely to be applied by industry and further developed.

The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma.In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331.Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2-34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3-not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55-0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7-18·9] vs 11·1 months [9·1-12·5]; 0·71 [0·60-0·84], p0·0001). The most frequent (≥10% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis.With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma.Merck SharpDohme Corp, a subsidiary of MerckCo, Inc.

BackgroundInhaled tobramycin powder/solution (TIP/S) use has resulted in improved clinical outcomes in patients with cystic fibrosis (CF) with chronic Pseudomonas aeruginosa. However, TIP/S effect on the CF sputum microbiome has not been explored. We hypothesised that TIP/S has additional ‘off-target’ effects beyond merely P. aeruginosa and that baseline microbiome prior to initiation of therapy is associated with subsequent patient response.MethodsWe drew sputum samples from a prospectively collected biobank. Patients were included if they had one sputum sample in the 18 months before and after TIP/S. Bacterial 16S rRNA gene profiling was used to characterise the sputum microbiome.ResultsForty-one patients met our inclusion criteria and 151 sputum samples were assessed. At baseline, median age was 30.4 years (IQR 24.2–35.2) and forced expiratory volume in 1 (FEV1) second was 57% predicted (IQR 44–74). Nineteen patients were defined a priori as responders having no net decrease in FEV1 in the year following TIP/S. No significant changes were observed in key microbiome metrics of alpha (within-sample) or beta (between-sample) diversity for samples collected before and after TIP/S. However, significant beta-diversity (Bray-Curtis) differences were noted at baseline between patients based on response status. Notably, responders were observed to have a higher abundance of Staphylococcus in pretherapy baseline samples.ConclusionsOur longitudinal study demonstrates that the sputum microbiome of patients with CF is relatively stable following inhaled tobramycin over many months. Intriguingly, our findings suggest that baseline microbiome may associate with patient response to TIP/S—suggesting the sputum microbiome could be used to personalise therapy.

This study prospectively reports survivorship and radiographic and clinical outcomes following primary elective total hip arthroplasty (THA) using a novel single hemispherical, porous-coated acetabular cup with five different bearing combinations and a minimum of five year follow-up. Continuing post-market release monitoring of this cup, we prospectively enrolled 108 patients (121 THA) between 2009 and 2015. We followed this cohort by examining survivorship, in addition to clinical and radiological outcomes for metal-on-metal (MoM) compared with non-MoM bearing combinations (ceramic-on-ceramic, oxinium-on-polyethylene, ceramic-on-metal, and metal-on-polyethylene). All 108 (121 hips) patients were followed up. Average age at time of surgery was 45.1 years (range 19 to 71 years) of which 42.1% were males. A total of seven (5.8%) cups were revised, all of which were MoM. No osteolysis was observed in any of the patients at the latest visit with a mean follow-up of 9.1 ± 1.7 years (range 4.4–10.7 years). With MoM excluded, survivorship of the cup at five years is 97.8%. Survivorship for MoM implants was 90.0%. Validated hip scores showed significant improvements for all bearing types and no significant difference between groups at latest follow-up (p = 0.614). There was no cup migration with any bearing surface. This cup showed excellent survivorship at five year follow-up, except for patients receiving a MoM articulation. While there were concerns over the early survivorship of this cup, our cohort and joint registry data confirm excellent outcomes.

Normative values for heart-rate corrected repolarisation length are not available in children and are scarce in adults. We wished to define repeatability and normative values of Holter recording measurements of repolarisation length in healthy individuals using a commercially available system, and compare measurements with those from 12-lead electrocardiograms (ECGs).Twenty-four-hour (24-) Holter recordings were made on 99 Healthy volunteers: 52 children (7 months to 14 years) and 47 adults (≥15 yrs). Mean and peak values of QTc, and RTPc (R-wave to peak T-wave) were assessed. Bazett heart rate correction was employed for each measurement and only heart rates between 40 and 120 bpm were analysed. The end of the T-wave was defined from the zero-crossing point. QTc was also determined from 12-lead ECGs from the same population by manual measurement recording the longest QTc of leads 2 and V5. The tangent technique was used to define the end of the T-wave.Interobserver repeatability: mean QTc ±15 ms (CI 3.5%), peak QTc ±25 ms (CI 4.5%), mean RTPc ±3 ms (CI 1%), peak RTPc ±44 ms (CI 11%). Mean values were very similar for15 years and all females and were therefore amalgamated: mean (±2 SD); mean QTc 424 ms (394-454), mean RTPc 291ms (263-319). Values were lower in males ≥15 years; (mean QTc 408 ms (370-446), p0.01; mean RTPc 274 ms (234-314), p0.01. The highest mean QTc value was 467 ms in an adult female. QTc from 12-lead ECG: females15 years 409 ms (384-434) males15 years 408 ms (383-433), females ≥15 years 426 ms (401-451), males ≥15 years 385 ms (362-408).Holter measurements of mean QTc and RTPc are highly repeatable. Males ≥15 years have shorter mean repolarisation length over 24 hours than males15 years and all females. Mean QTc Holter values were on average 15-17 ms longer than QTc from 12-lead ECGs except in females15 years.

Background Bilirubin is produced by the breakdown of hemoglobin and is normally catabolized and excreted. Neurotoxic accumulation of serum bilirubin often occurs in premature infants. The homozygous Gunn rat lacks uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), the enzyme needed to biotransform bilirubin. This rodent model of hyperbilirubinemia emulates many aspects of bilirubin toxicity observed in the human infant. We demonstrate that choline supplementation in early postnatal development is neuroprotective in the choline-restricted Gunn rat, when hyperbilirubinemia is induced on postnatal day 5. Methods We first compared behaviors and cerebellar weight of pups born to dams consuming regular rat chow to those of dams consuming choline-restricted diets. Second, we measured behaviors and cerebellar weights of pups born to choline-restricted dams, reared on a choline-restricted diet, supplemented with or without choline, and treated with or without sulfadimethoxine (SDMX). Results A choline-restricted diet did not change the behavioral outcomes, but cerebellar weight was reduced in the choline-restricted group regardless of genotype or SDMX administration. SDMX induced behavioral deficits in jj pups, and choline supplementation improved most behavioral effects and cerebellar weight in SDMX-treated jj rats. Conclusions These results suggest that choline may be used as a safe and effective neuroprotective intervention against hyperbilirubinemia in the choline-deficient premature infant. Impact This article investigates the effect of neonatal jaundice/bilirubin neurotoxicity on cerebellar-mediated behaviors. This article explores the potential use of choline as an intervention capable of ameliorating the effect of bilirubin on the choline-restricted developing brain. This article opens the door for future studies on the action of choline in the presence of hyperbilirubinemia, especially in preterm neonates.

For children with autism spectrum disorder (ASD), a lifelong neurodevelopmental condition, assessment and treatment services vary widely across Canada—potentially creating inequities. To highlight this, the Preschool Autism Treatment Impact study compared children’s services and outcomes in New Brunswick (NB) and Nova Scotia (NS). Diagnostic practices, service delivery models, wait times, and treatment approaches differed, as did children’s 1-year outcomes and costs for families and the public sector. Considering NB and NS strengths, we suggest that an optimal system would include: rapid access to high-quality diagnostic and intervention services; adherence to research-informed practice guidelines; interventions to enhance parents’ skills and self-efficacy; and measures to minimize financial burdens for families. Our results also suggest that provinces/territories must do more to ensure equitable access to effective services, including sharing and reporting on national comparative data. Canadian children with ASD deserve access to effective and consistent services, no matter where they live.

The spontaneous death or loss of a fetus during pregnancy is termed a fetal death. In the United States, national data on fetal deaths are available for losses at ≥20 weeks' gestation.* Deaths occurring during this period of pregnancy are commonly known as stillbirths. In 2017, approximately 23,000 fetal deaths were reported in the United States (1). Racial/ethnic disparities exist in the fetal mortality rate; however, much of the known disparity in fetal deaths is unexplained (2). CDC analyzed 2015-2017 U.S. fetal death report data and found that non-Hispanic Black (Black) women had more than twice the fetal mortality rate compared with non-Hispanic White (White) women and Hispanic women. Fetal mortality rates also varied by maternal state of residence. Cause of death analyses were conducted for jurisdictions where >50% of reports had a cause of death specified. Still, even in these jurisdictions, approximately 31% of fetal deaths had no cause of death reported on a fetal death report. There were differences by race and Hispanic origin in causes of death, with Black women having three times the rate of fetal deaths because of maternal complications compared with White women. The disparities suggest opportunities for prevention to reduce the U.S. fetal mortality rate. Improved documentation of cause of death on fetal death reports might help identify preventable causes and guide prevention efforts.

Background Clinical studies have reported that epicardial adipose tissue (EpAT) accumulation associates with the progression of atrial fibrillation (AF) pathology and adversely affects AF management. The role of local cardiac EpAT deposition in disease progression is unclear, and the electrophysiological, cellular, and molecular mechanisms involved remain poorly defined. Objectives The purpose of this study was to identify the underlying mechanisms by which EpAT influences the atrial substrate for AF. Methods Patients without AF undergoing coronary artery bypass surgery were recruited. Computed tomography and high-density epicardial electrophysiological mapping of the anterior right atrium were utilized to quantify EpAT volumes and to assess association with the electrophysiological substrate in situ. Excised right atrial appendages were analyzed histologically to characterize EpAT infiltration, fibrosis, and gap junction localization. Co-culture experiments were used to evaluate the paracrine effects of EpAT on cardiomyocyte electrophysiology. Proteomic analyses were applied to identify molecular mediators of cellular electrophysiological disturbance. Results Higher local EpAT volume clinically correlated with slowed conduction, greater electrogram fractionation, increased fibrosis, and lateralization of cardiomyocyte connexin-40. In addition, atrial conduction heterogeneity was increased with more extensive myocardial EpAT infiltration. Cardiomyocyte culture studies using multielectrode arrays showed that cardiac adipose tissue-secreted factors slowed conduction velocity and contained proteins with capacity to disrupt intermyocyte electromechanical integrity. Conclusions These findings indicate that atrial pathophysiology is critically dependent on local EpAT accumulation and infiltration. In addition to myocardial architecture disruption, this effect can be attributed to an EpAT-cardiomyocyte paracrine axis. The focal adhesion group proteins are identified as new disease candidates potentially contributing to arrhythmogenic atrial substrate.

Background Spinal cord injury (SCI) has a significant impact on the quality of life (QoL) of affected patients. The aim of this review was to determine whether colostomy formation improves QoL in patients with SCI. Methods The Cochrane Register, MEDLINE, Embase and CINAHL were searched using medical subject headings. The search was extended to the reference lists of identified studies, ClinicalTrials.gov and the WHO International Clinical Trials Registry. All clinical trials that included spinal injury and QoL, time spent on bowel care, and patient satisfaction with stoma were assessed. Results A total of 15 studies were found (including 488 patients with a stoma), of which 13 were retrospective cross‐sectional studies and two were case–control studies, one of which was prospective research. Nine of 11 studies focusing on QoL reported that patients' QoL was improved by the stoma, whereas the remaining two studies found no difference. Time spent on bowel care was significantly reduced in all 13 studies that considered this outcome, with patients reducing the average time spent on bowel care from more than 1 h to less than 15 min per day. All 12 studies assessing patient satisfaction with their stoma reported high patient satisfaction. Conclusion Stoma formation improves QoL, reduces time spent on bowel care, and increases independence. Stoma is an option that could be discussed and offered to patients with spinal cord injury., In this systematic review to determine whether colostomy formation improved the quality of life (QoL) in patients with spinal cord injury, outcomes assessed were QoL, time spent on bowel care, and patient satisfaction with the stoma. A total of 15 studies were included; colostomy formation improved QoL and time spent on bowel care, and more than 90 per cent of patients were satisfied with having a stoma. Stoma and spinal cord injury

BackgroundThe rise of antimicrobial drug resistance in Mycobacterium tuberculosis coupled with the shortage of new antibiotics has elevated TB to a major global health priority. Repurposing drugs developed or used for other conditions has gained special attention in the current scenario of accelerated drug development for several global infectious diseases. In a similar effort, previous studies revealed that carprofen, a non-steroidal anti-inflammatory drug, selectively inhibited the growth of replicating, non-replicating and MDR clinical isolates of M. tuberculosis.ObjectivesWe aimed to reveal the whole-cell phenotypic and transcriptomic effects of carprofen in mycobacteria.MethodsIntegrative molecular and microbiological approaches such as resazurin microtitre plate assay, high-throughput spot-culture growth inhibition assay, whole-cell efflux inhibition, biofilm inhibition and microarray analyses were performed. Analogues of carprofen were also synthesized and assessed for their antimycobacterial activity.ResultsCarprofen was found to be a bactericidal drug that inhibited mycobacterial drug efflux mechanisms. It also restricted mycobacterial biofilm growth. Transcriptome profiling revealed that carprofen likely acts by targeting respiration through the disruption of membrane potential. The pleiotropic nature of carprofen’s anti-TB action may explain why spontaneous drug-resistant mutants could not be isolated in practice.ConclusionsThis immunomodulatory drug and its chemical analogues have the potential to reverse TB antimicrobial drug resistance, offering a swift path to clinical trials of novel TB drug combinations.