Search

Summary: Background: People with diabetes are at increased risk of hospitalisation, morbidity, and mortality following SARS-CoV-2 infection. Long-term outcomes for people with diabetes previously hospitalised with COVID-19 are, however, unknown. This study aimed to determine the longer-term physical and mental health effects of COVID-19 in people with and without diabetes. Methods: The PHOSP-COVID study is a multicentre, long-term follow-up study of adults discharged from hospital between 1 February 2020 and 31 March 2021 in the UK following COVID-19, involving detailed assessment at 5 and 12 months after discharge. The association between diabetes status and outcomes were explored using multivariable linear and logistic regressions. Findings: People with diabetes who survived hospital admission with COVID-19 display worse physical outcomes compared to those without diabetes at 5- and 12-month follow-up. People with diabetes displayed higher fatigue (only at 5 months), frailty, lower physical performance, and health-related quality of life and poorer cognitive function. Differences in outcomes between diabetes status groups were largely consistent from 5 to 12-months. In regression models, differences at 5 and 12 months were attenuated after adjustment for BMI and presence of other long-term conditions. Interpretation: People with diabetes reported worse physical outcomes up to 12 months after hospital discharge with COVID-19 compared to those without diabetes. These data support the need to reduce inequalities in long-term physical and mental health effects of SARS-CoV-2 infection in people with diabetes. Funding: UK Research and Innovation and National Institute for Health Research. The study was approved by the Leeds West Research Ethics Committee (20/YH/0225) and is registered on the ISRCTN Registry (ISRCTN10980107).

Chimeric antigen receptor (CAR) T cell therapy has become an important treatment for hematological cancers, and its success has spurred research into CAR T cell therapies for other diseases, including solid tumor cancers and autoimmune diseases. Notably, the development of CAR-based treatments for autoimmune diseases has shown great progress recently. Clinical trials for anti-CD19 and anti-BCMA CAR T cells in treating severe B cell-mediated autoimmune diseases, like systemic lupus erythematosus (SLE), have shown lasting remission thus far. CAR T cells targeting autoreactive T cells are beginning clinical trials for treating T cell mediated autoimmune diseases. Chimeric autoantigen receptor (CAAR) T cells specifically target and eliminate only autoreactive B cells, and they have shown promise in treating mucosal pemphigus vulgaris and MuSK myasthenia gravis. Regulatory CAR T cells have also been developed, which show potential in altering autoimmune affected areas by creating a protective barrier as well as helping decrease inflammation. These new treatments are only the beginning of potential CAR T cell applications in treating autoimmune disease. Novel CAR technologies have been developed that increase the safety, potency, specificity, and efficacy of CAR T cell therapy. Applying these novel modifications to autoimmune CARs has the potential to enhance the efficacy and applicability of CAR therapies to autoimmune disease. This review will detail several recently developed CAR technologies and discuss how their application to autoimmune disease will improve this emerging field. These include logic-gated CARs, soluble protein-secreting CARs, and modular CARs that enable CAR T cell therapies to be more specific, reach a wider span of target cells, be safer for patients, and give a more potent cytotoxic response. Applying these novel CAR technologies to the treatment of autoimmune diseases has the potential to revolutionize this growing application of CAR T cell therapies.

Abstract Among disabling post-traumatic stress symptoms (PTSS) are irritability, aggressive behavior, distressing memories and general impaired cognition and negative mood. Art therapy interventions, including mask-making, can potentially alleviate these symptoms. We tested the hypothesis that art conveys emotions and predicted that blinded viewers would be able to perceive changes in theoretically derived emotional profiles expressed in art made by military personnel with PTSS from the onset to the end of therapy. Five service members and veterans exhibiting PTSS were enrolled in an 8-session art therapy protocol, during which they artistically transformed papier-mâché masks at the beginning and end of the protocol. We found that blinded viewers without knowledge of the masks’ creation stage (onset or end of therapy) read initial masks as conveying more negative emotions (e.g., angry, upset, and challenged) and later masks as conveying more positive emotions (calm and pleasure). Based on the assessments from the blinded evaluators, we infer the emotional transition experienced by the participants was expressed in the masks. In an exploratory arm of the study, we also found that viewers were better able to empathize with the negative emotions experienced by participants with PTSS when asked to explicitly take their perspective.

Background The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p

Abstract Busulfan is hepatically metabolized through glutathione (GSH) conjugation; in vitro, this process depletes hepatocyte GSH stores and generates the cytotoxic metabolite γ‐glutamyldehydroalanylglycine, which is too unstable to be quantitated in vivo. We sought to evaluate if pre‐graft (i.e., immediately before allograft infusion) concentrations of busulfan metabolites' and of endogenous metabolomic compounds (EMCs) representing the glutathione pathway were associated with clinical outcomes in hematopoietic cell transplant (HCT) recipients receiving busulfan. The clinical outcomes evaluated were relapse, acute graft versus host disease (GVHD), chronic GVHD, non‐relapse mortality, and neutrophil nadir. In pre‐graft samples obtained from patients immediately before allograft infusion, our objectives were to evaluate for: (1) the presence of busulfan and its metabolites tetrahydrothiophenium ion (THT+), tetrahydrothiophene 1‐oxide, sulfolane, and 3‐hydroxysulfolane (N = 124); (2) EMCs using a global metabolomics assay (N = 77); and (3) the association of the busulfan metabolites and the EMCs with clinical outcomes. In the pre‐graft samples, busulfan and THT+ could not be detected. THT 1‐oxide, sulfolane, and 3‐hydroxysulfolane were quantitated in 9.6%, 26%, and 58% of pre‐graft samples; their concentrations were not associated with clinical outcomes. Four pre‐graft EMCs were statistically significantly associated with the neutrophil nadir. The pre‐graft EMCs were not associated with the other clinical outcomes. In conclusion, busulfan's metabolites are present in patients' plasma immediately before allograft infusion; the neutrophil nadir is associated with pre‐graft EMCs. Future research should investigate the association of clinical outcomes with the concentrations of busulfan's metabolites and EMCs in the pre‐graft plasma from allogeneic HCT recipients.

Abstract FeSe1−x S x remains one of the most enigmatic systems of Fe-based superconductors. While much is known about the orthorhombic parent compound, FeSe, the tetragonal samples, FeSe1−x S x with x > 0.17, remain relatively unexplored. Here, we provide an in-depth investigation of the electronic states of tetragonal FeSe0.81S0.19, using scanning tunneling microscopy and spectroscopy (STM/S) measurements, supported by angle-resolved photoemission spectroscopy (ARPES) and theoretical modeling. We analyze modulations of the local density of states (LDOS) near and away from Fe vacancy defects separately and identify quasiparticle interference (QPI) signals originating from multiple regions of the Brillouin zone, including the bands at the zone corners. We also observe that QPI signals coexist with a much stronger LDOS modulation for states near the Fermi level whose period is independent of energy. Our measurements further reveal that this strong pattern appears in the STS measurements as short range stripe patterns that are locally two-fold symmetric. Since these stripe patterns coexist with four-fold symmetric QPI around Fe-vacancies, the origin of their local two-fold symmetry must be distinct from that of nematic states in orthorhombic samples. We explore several aspects related to the stripes, such as the role of S and Fe-vacancy defects, and whether they can be explained by QPI. We consider the possibility that the observed stripe patterns may represent incipient charge order correlations, similar to those observed in the cuprates.

Background: In some jurisdictions, individuals become eligible or recommended for referral for different types of kidney care using criteria based on their estimated glomerular filtration rate (eGFR). Historically, GFR was estimated with an equation developed in 2009, which included a Black race term. An updated, race-free equation was developed in 2021. It is unclear how adoption of the 2021 equation will influence the number of individuals meeting referral criteria to receive different types of kidney care. Objective: To develop population-based estimates on how the number of individuals meeting the eGFR-based referral criteria to receive three different types of kidney care (nephrologist consultation, care in a multi-care specialty clinic, kidney transplant evaluation) changes when the 2021 versus 2009 equation is used to calculate eGFR. Design: Population-based, cross-sectional study. Setting: Ontario, Canada’s most populous province with 14.2 million residents as of 2021. Less than 5% of Ontario’s residents self-identify as being of Black race. Patients: Adults with at least one outpatient serum creatinine measurement in the 2 years prior to December 31, 2021. Measurements: Referral criteria to 3 different types of kidney care: nephrologist consultation, multi-care specialty clinic, and evaluation for a kidney transplant. The eGFR thresholds used to define referral eligibility or recommendation for these kidney health services were based on guidelines from Ontario’s provincial renal agency. Methods: The number of individuals meeting referral criteria for the 3 different healthcare services was compared between the 2009 and 2021 equations, restricted to individuals not yet receiving that level of care. As individual-level race data were not available, estimates were repeated, randomly assigning a Black race status to 1%, 5%, and 10% of the population. Results: We had an outpatient serum creatinine measurement available for 1 048 110 adults. Using the 2009 equation, 37 345 individuals met the criteria to be referred to a nephrologist, 10 019 met the criteria to receive care in a multi-care specialty clinic, and 10 178 met the criteria to be referred for kidney transplant evaluation. Corresponding numbers with the 2021 equation (and the percent relative to the 2009 equation) were 26 645 (71.3%), 9009 (89.9%), and 8615 (84.6%) individuals, respectively. These numbers were largely unchanged when Black race was assumed in up to 10% of the population. Limitations: Referral criteria based solely on urine albumin-to-creatinine ratio were not assessed. Self-reported race data were unavailable. Conclusions: For healthcare planning, in regions where a minority of the population is Black, a substantial number of individuals may no longer meet referral criteria for different types of kidney healthcare following adoption of the new 2021 eGFR equation.

Background: Guidelines in Ontario, Canada, recommend timely referral for multidisciplinary kidney care to facilitate planned dialysis initiation. Many patients do not receive recommended multidisciplinary kidney care prior to dialysis. Objective: To better understand why this gap in pre-dialysis care exists, we conducted a study to describe the pathways by which patients initiate maintenance dialysis. Design: A retrospective cohort study. Setting: Population-based, using health care administrative databases from Ontario, Canada. Patients: Adults initiating maintenance dialysis from April 2016 to March 2019. Measurements and methods: Patients were grouped based on whether they received recommended multidisciplinary kidney care prior to dialysis initiation (at least 1 year of care with at least 2 visits). For those who did not receive recommended care, we grouped patients as having no identified care gap or into the following groups: (1) lack of timely chronic kidney disease (CKD) screening, (2) late nephrology referral (

Abstract Background Physicians’ behavior may unknowingly be impacted by prejudice and thereby contribute to healthcare inequities. Despite increasingly robust data demonstrating physician implicit bias (The Office of Minority Health. Minority Population Profiles, 2021; COVID-19 Shines Light on Health Disparities, National Conference of State Legislatures 2021), the evidence behind how to change this with training programs remains unclear. This scoping review therefore reports on the implementation, outcomes, and characteristics of post-graduate physician implicit bias curricula. Methods The authors conducted a literature review using scoping review methodology. They searched 7 databases in February and November 2020 for English-language academic and gray literature on implicit bias curricula for physicians at all levels of post-graduate training. Ten reviewers screened studies for eligibility independently, then extracted data from these studies and compiled it into a chart and analytical summary. Results Of the 4,599 articles screened, this review identified 90 articles on implicit bias interventions for post-graduate physicians. Inductive data analysis revealed a spectrum of educational approaches, which were categorized int o 4 educational models called Competence, Skills-Based, Social Contact, and Critical Models. The most commonly reported strength was the interactive nature of the curricula (26%), and the most frequently identified challenges were related to time and resources available (53%). Half of the interventions discussed facilitator preparation, and the majority (62%) evaluated outcomes using pre and post self-assessments. Conclusions This review provides a comprehensive synthesis of the literature on physician implicit bias curricula. It is our goal that this supports medical educators in applying and improving aspects of these interventions in their own programs.

Summary: Background: Integrase inhibitor (INSTI) with boosted darunavir (DRV/r), a regimen with a high-resistance barrier, avoiding NRTI toxicities, might be a switching option in children living with HIV (CLWHIV). Methods: SMILE is a randomised non-inferiority trial evaluating safety and antiviral efficacy of once-daily INSTI + DRV/r vs. continuing on current standard-of-care (SOC) triple ART (2NRTI + boosted PI/NNRTI) in virologically-suppressed CLWHIV aged 6–18 years. The primary outcome is the proportion with confirmed HIV-RNA ≥50 copies/mL by week 48, estimated by Kaplan–Meier method. Non-inferiority margin was 10%. Registration number for SMILE are: ISRCTN11193709, NCT #: NCT02383108. Findings: Between 10th June 2016 and 30th August 2019, 318 participants were enrolled from Africa 53%, Europe 24%, Thailand 15% and Latin America 8%, 158 INSTI + DRV/r [153 Dolutegravir (DTG); 5 Elvitegravir (EVG)], 160 SOC. Median (range) age was 14.7 years (7.6–18.0); CD4 count 782 cells/mm3 (227–1647); 61% female. Median follow-up was 64.3 weeks with no loss to follow-up. By 48 weeks, 8 INSTI + DRV/r vs. 12 SOC had confirmed HIV-RNA ≥50 copies/mL; difference (INSTI + DRV/r-SOC) −2.5% (95% CI: −7.6, 2.5%), showing non-inferiority. No major PI or INSTI resistance mutations were observed. There were no differences in safety between arms. By week 48, difference (INSTI + DRV/r-SOC) in mean CD4 count change from baseline was −48.3 cells/mm3 (95% CI: −93.4, −3.2; p = 0.036). Difference (INSTI + DRV/r-SOC) in mean HDL change from baseline was −4.1 mg/dL (95% CI: −6.7, −1.4; p = 0.003). Weight and Body Mass Index (BMI) increased more in INSTI + DRV/r than SOC [difference: 1.97 kg (95% CI: 1.1, 2.9; p

Summary: Background: The scale of COVID-19 and its well documented long-term sequelae support a need to understand long-term outcomes including frailty. Methods: This prospective cohort study recruited adults who had survived hospitalisation with clinically diagnosed COVID-19 across 35 sites in the UK (PHOSP-COVID). The burden of frailty was objectively measured using Fried's Frailty Phenotype (FFP). The primary outcome was the prevalence of each FFP group—robust (no FFP criteria), pre-frail (one or two FFP criteria) and frail (three or more FFP criteria)—at 5 months and 1 year after discharge from hospital. For inclusion in the primary analysis, participants required complete outcome data for three of the five FFP criteria. Longitudinal changes across frailty domains are reported at 5 months and 1 year post-hospitalisation, along with risk factors for frailty status. Patient-perceived recovery and health-related quality of life (HRQoL) were retrospectively rated for pre-COVID-19 and prospectively rated at the 5 month and 1 year visits. This study is registered with ISRCTN, number ISRCTN10980107. Findings: Between March 5, 2020, and March 31, 2021, 2419 participants were enrolled with FFP data. Mean age was 57.9 (SD 12.6) years, 933 (38.6%) were female, and 429 (17.7%) had received invasive mechanical ventilation. 1785 had measures at both timepoints, of which 240 (13.4%), 1138 (63.8%) and 407 (22.8%) were frail, pre-frail and robust, respectively, at 5 months compared with 123 (6.9%), 1046 (58.6%) and 616 (34.5%) at 1 year. Factors associated with pre-frailty or frailty were invasive mechanical ventilation, older age, female sex, and greater social deprivation. Frail participants had a larger reduction in HRQoL compared with before their COVID-19 illness and were less likely to describe themselves as recovered. Interpretation: Physical frailty and pre-frailty are common following hospitalisation with COVID-19. Improvement in frailty was seen between 5 and 12 months although two-thirds of the population remained pre-frail or frail. This suggests comprehensive assessment and interventions targeting pre-frailty and frailty beyond the initial illness are required. Funding: UK Research and Innovation and National Institute for Health Research.

In recent years, the interplay between oral microbiota and systemic disease has gained attention as poor oral health is associated with several pathologies. The oral microbiota plays a role in the maintenance of overall health, and its dysbiosis influences chronic inflammation and the pathogenesis of gum diseases. Periodontitis has also been associated with other diseases and health complications such as cancer, neurogenerative and autoimmune disorders, chronic kidney disease, cardiovascular diseases, rheumatic arthritis, respiratory health, and adverse pregnancy outcomes. The host microbiota can influence immune cell development and immune responses, and recent evidence suggests that changes in oral microbiota composition may also contribute to sensitization and the development of allergic reactions, including asthma and peanut allergies. Conversely, there is also evidence that allergic reactions within the gut may contribute to alterations in oral microbiota composition. Here we review the current evidence of the role of the oral microbiota in inflammatory diseases and health complications, as well as its future relevance in improving health and ameliorating allergic disease.

Abstract The skin is a barrier and part of the immune system that protects us from harmful bacteria. Because indwelling medical devices break this barrier, they greatly increase the risk of infection by microbial pathogens. To study how these infections can be prevented through improved clinical practices and medical device technology, it is important to have preclinical models that replicate the early stages of microbial contamination, ingress, and colonization leading up to infection. At present, there are no preclinical ex vivo models specifically developed to simulate conditions for indwelling medical devices. Translocation of pathogens from outside the body across broken skin to normally sterile internal compartments is a rate-limiting step in infectious pathogenesis. In this work, we report a sensitive and reproducible ex vivo porcine skin–catheter model to test how long antimicrobial interventions can delay translocation. Skin preparation was first optimized to minimize tissue damage. The presence of skin dramatically decreased bacterial migration time across the polyurethane catheter interface from > 96 h to 12 h. Using visual colony detection, fluorescence, a luminescent in vitro imaging system, and confocal microscopy, the model was used to quantify time-dependent differences in translocation for eluting and non-eluting antimicrobial catheters. The results show the importance of including tissue in preclinical biofilm models and help to explain current gaps between in vitro testing and clinical outcomes for antimicrobial devices.

Abstract Background Accurately estimating gestational age is essential to the provision of time-sensitive maternal and neonatal interventions, including lifesaving measures for imminent preterm birth and trimester-specific health messaging. Methods We explored healthcare provider perspectives on gestational age estimation in the state of Rajasthan, India, including the methods they use (last menstrual period [LMP] dating, ultrasound, or fundal height measurement); barriers to making accurate estimates; how gestational age estimates are documented and used for clinical decision-making; and what could help improve the accuracy and use of these estimates. We interviewed 20 frontline healthcare providers and 10 key informants. Thematic network analysis guided our coding and synthesis of findings. Results Health care providers reported that they determined gestational age using some combination of LMP, fundal height, and ultrasound. Their description of their practices showed a lack of standard protocol, varying levels of confidence in their capacity to make accurate estimates, and differing strategies for managing inconsistencies between estimates derived from different methods. Many frontline healthcare providers valued gestational age estimation more to help women prepare for childbirth than as a tool for clinical decision making. Feedback on accuracy was rare. The providers sampled could not offer ultrasound directly, and instead could only refer women to ultrasound at higher level facilities, and usually only in the second or third trimesters because of late antenatal care-seeking. Low recall among pregnant women limited the accuracy of LMP. Fundal height was heavily relied upon, despite its lack of precision. Conclusion The accuracy of gestational age estimates is influenced by factors at four levels: 1. health system (protocols to guide frontline workers, interventions that make use of gestational age, work environment, and equipment); 2. healthcare provider (technical understanding of and capacity to apply the gestational age estimation methods, communication and rapport with clients, and value assessment of gestational age); 3. client (time of first antenatal care, migration status, language, education, cognitive approach to recalling dates, and experience with biomedical services); and, 4. the inherent limitations and ease of application of the methods themselves.

Abstract Background Thymidine kinase 1 (TK1) is a pyrimidine salvage pathway enzyme that is up-regulated in malignant tissues and elevated in the serum of cancer patients. While TK1 has been well established as a tumor biomarker, little has been done to explore its potential as a tumor target. Recently, we reported the membrane expression of TK1 on malignant cells, but not on normal cells. This study explores the possible use of monoclonal antibodies for the targeting of membrane associated TK1 in lung, breast, colon and prostate cancer cells. Methods We generated and evaluated a panel of monoclonal antibodies against six different epitopes exposed in the tetrameric form of TK1. Antibodies were developed with hybridoma technology and validated with Western blot, siRNA TK1 knockdown, enzyme-linked immunosorbent assay (ELISA) and flow cytometry. The therapeutic potential of the antibodies was evaluated in vitro in antibody-dependent cell-mediated-cytotoxicity (ADCC) experiments. Results Binding of the antibodies to TK1 was confirmed by Western blot in purified recombinant protein, cancer serum, and cell lysate. After a TK1 knockdown was performed, a reduction of TK1 expression was observed with five antibodies. Using indirect ELISA, we identified 3B2E11, 9C10, 7H2, 3B4, 8G2 among the most sensitive antibodies (LOD = 10.73–66.9 pg/ml). Surface expression of TK1 on the membrane of various cancer cell lines was analyzed with flow cytometry. Antibodies 8G2, 3B4, 7HD and 5F7G11 detected TK1 on the membrane of various cancer cell lines, including lung, prostate, colon and breast. No significant binding was detected on normal lymphocytes. Increased cytolysis of lung (~ 70%. p = 0.0001), breast (~ 70%, p = 0.0461) and colon (~ 50% p = 0.0216) cancer cells by effector cells was observed when anti-TK1 antibodies were added during ADCC experiments. Conclusions The antibodies developed showed potential to be used to detect and target TK1 on the membrane of various tumor cells. The targeting of TK1 in malignant cells using monoclonal antibodies may be a feasible approach for the elimination of high TK1 expressing tumor cells.

Background: While home dialysis therapies are more cost effective and may offer improved health-related quality of life, uptake compared to in-center hemodialysis remains low. Objective: To test whether a web-based interactive health communication application (IHCA) compared to usual care would increase home dialysis use. Design: Randomized control trial Setting: Patients were recruited from 3 multidisciplinary kidney clinics across Ontario, Canada (Hamilton, Kingston, London). Patients: We included adults with advanced chronic kidney disease (CKD) followed in multidisciplinary kidney clinics. Patients who had not completed dialysis modality education, who did not have access to a home computer or the internet, who had significant hearing or vision impairment, who could not read/write/speak English, who had a medical contraindication for home dialysis, or who had selected conservative kidney care were excluded. Measurements: The primary outcome was any use of home dialysis (peritoneal dialysis or home hemodialysis) within 90 days of dialysis initiation. Secondary outcomes were social support, decision conflict and dialysis knowledge measured at baseline, 6 months and 1 year. Methods: Eligible patients were randomized to either usual care or the IHCA in addition to usual care in a 1:1 ratio. As part of usual care, all patients received education about dialysis modalities and kidney transplantation delivered by clinic nurses according to local practices. Randomization was performed using a computer-generated sequence in randomly permuted block sizes, stratified by site, and allocation occurred using sequentially numbered sealed, opaque envelopes. Participants, care providers, and outcome assessors were not blinded to the intervention. All analyses were performed blinded using an intention to treat approach. We estimated the effect of the ICHA on the odds of the primary outcome using unadjusted logistic regression models. Linear mixed models for repeated measures over time were used to analyze the impact of the IHCA on the secondary outcomes of interest. Results: We randomized 140 (usual care, n = 71; IHCA, n = 69) out of a planned 264 patients (mean [SD] age 61 [14.5] years, 65% men). Among patients randomized to the IHCA group that completed 6-month and 1-year follow-up visits, 56.8% and 71.4%, respectively, had not accessed the IHCA website within the past month. There were 23 (32.4%) and 26 (37.7%) patients in the usual care and IHCA groups who received a home dialysis therapy within 90 days of dialysis initiation (odds ratio, OR = 1.3, 95% CI = [0.6-2.5], P = .5). Among the 78 patients who initiated dialysis (n = 38 usual care, n = 40 IHCA), 60.5% and 65% in the usual care and IHCA groups received a home therapy within 90 days of dialysis initiation (OR = 1.2, 95% CI = [0.5-3.0], P = .7). Secondary outcomes did not differ by intervention group over time. Limitations: The trial was underpowered due to poor recruitment and use of the IHCA was low. Conclusions: We did not find evidence of a difference in home dialysis uptake with IHCA use, but our analyses were notably underpowered. The incorporation of greater patient engagement, qualitative research and design research, and pilot implementation may help future evaluations of strategies to improve home dialysis uptake. Trial Registration: ClinicalTrials.gov # NCT01403454, registration date: Jul 21, 2011

For nearly three decades, chimeric antigen receptors (CARs) have captivated the interest of researchers seeking to find novel immunotherapies to treat cancer. CARs were first designed to work with T cells, and the first CAR T cell therapy was approved to treat B cell lymphoma in 2017. Recent advancements in CAR technology have led to the development of modified CARs, including multi-specific CARs and logic gated CARs. Other immune cell types, including natural killer (NK) cells and macrophages, have also been engineered to express CARs to treat cancer. Additionally, CAR technology has been adapted in novel approaches to treating autoimmune disease and other conditions and diseases. In this article, we review these recent advancements in alternative CAR therapies and design, as well as their mechanisms of action, challenges in application, and potential future directions.

Non-tuberculous mycobacteria (NTM) are widespread in the environment and are a public health concern due to their resistance to antimicrobial agents. The colonization of surgical heater-cooler devices (HCDs) by the slow-growing NTM species Mycobacterium chimaera has recently been linked to multiple invasive infections in patients worldwide. The resistance of M. chimaera to antimicrobials may be aided by a protective biofilm matrix of extracellular polymeric substances (EPS). This study explored the hypothesis that M. chimaera can form biofilms on medically relevant materials. Several M. chimaera strains, including two HCD isolates, were used to inoculate a panel of medical device materials. M. chimaera colonization of the surfaces was monitored for 6 weeks. M. chimaera formed a robust biofilm at the air-liquid interface of borosilicate glass tubes, which increased in mass over time. M. chimaera was observed by 3D Laser Scanning Microscopy to have motility during colonization, and form biofilms on stainless steel, titanium, silicone and polystyrene surfaces during the first week of inoculation. Scanning electron microscopy (SEM) of M. chimaera biofilms after 4 weeks of inoculation showed that M. chimaera cells were enclosed entirely in extracellular material, while cryo-preserved SEM samples further revealed that an ultrastructural component of the EPS matrix was a tangled mesh of 3D fiber-like projections connecting cells. Considering that slow-growing M. chimaera typically has culture times on the order of weeks, the microscopically observed ability to rapidly colonize stainless steel and titanium surfaces in as little as 24 h after inoculation is uncharacteristic. The insights that this study provides into M. chimaera colonization and biofilm formation of medical device materials are a significant advance in our fundamental understanding of M. chimaera surface interactions and have important implications for research into novel antimicrobial materials, designs and other approaches to help reduce the risk of infection.

CD4+ T cells are crucial for effective repression and elimination of cancer cells. Despite a paucity of CD4+ T cell receptor (TCR) clinical studies, CD4+ T cells are primed to become important therapeutics as they help circumvent tumor antigen escape and guide multifactorial immune responses. However, because CD8+ T cells directly kill tumor cells, most research has focused on the attributes of CD8+ TCRs. Less is known about how TCR affinity and CD4 expression affect CD4+ T cell activation in full length TCR (flTCR) and TCR single chain signaling (TCR-SCS) formats. Here, we generated an affinity panel of TCRs from CD4+ T cells and expressed them in flTCR and three TCR-SCS formats modeled after chimeric antigen receptors (CARs) to understand the contributions of TCR-pMHCII affinity, TCR format, and coreceptor CD4 interactions on CD4+ T cell activation. Strikingly, the coreceptor CD4 inhibited intermediate and high affinity TCR-construct activation by Lck-dependent and -independent mechanisms. These inhibition mechanisms had unique affinity thresholds dependent on the TCR format. Intracellular construct formats affected the tetramer staining for each TCR as well as IL-2 production. IL-2 production was promoted by increased TCR-pMHCII affinity and the flTCR format. Thus, CD4+ T cell therapy development should consider TCR affinity, CD4 expression, and construct format.

Introduction: Silica gel packets are commonly used desiccants for medication products; these packets generally only pose a choking risk in young children. However, new cylindrical desiccant canisters have been developed, which may increase the risk for obstruction in adults. Case Report: An elderly male presented to the emergency department complaining of difficulty swallowing after taking his morning medications. Through a diligent work-up a desiccant canister was found lodged in the lower esophageal sphincter. The patient was endotracheally intubated and a Roth Net retriever was used to remove the canister. Conclusion: Cylindrical desiccant canisters pose an increased risk of esophageal obstruction.

Abstract Background India’s accredited social health activist (ASHA) programme consists of almost one million female community health workers (CHWs). Launched in 2005, there is now an ASHA in almost every village and across many urban centres who support health system linkages and provide basic health education and care. This paper examines how the programme is seeking to address gender inequalities facing ASHAs, from the programme's policy origins to recent adaptations. Methods We reviewed all publically available government documents (n = 96) as well as published academic literature (n = 122) on the ASHA programme. We also drew from the embedded knowledge of this paper’s government-affiliated co-authors, triangulated with key informant interviews (n = 12). Data were analysed thematically through a gender lens. Results Given that the initial impetus for the ASHA programme was to address reproductive and child health issues, policymakers viewed volunteer female health workers embedded in communities as best positioned to engage with beneficiaries. From these instrumentalist origins, where the programme was designed to meet health system demands, policy evolved to consider how the health system could better support ASHAs. Policy reforms included an increase in the number and regularity of incentivized tasks, social security measures, and government scholarships for higher education. Residential trainings were initiated to build empowering knowledge and facilitate ASHA solidarity. ASHAs were designated as secretaries of their village health committees, encouraging them to move beyond an all-female sphere and increasing their role in accountability initiatives. Measures to address gender based violence were also recently recommended. Despite these well-intended reforms and the positive gains realized, ongoing tensions and challenges related to their gendered social and employment status remain, requiring continued policy attention and adaptation. Conclusions Gender trade offs and complexities are inherent to sustaining CHW programmes at scale within challenging contexts of patriarchal norms, health system hierarchies, federal governance structures, and evolving aspirations, capacities, and demands from female CHWs. Although still grappling with significant gender inequalities, policy adaptations have increased ASHAs’ access to income, knowledge, career progression, community leadership, and safety. Nonetheless, these transformative gains do not mark linear progress, but rather continued adaptations.

Background: One of the key components of multidisciplinary CKD clinics is education; however, kidney disease knowledge among patients followed in these clinics is not routinely measured. Objective: The aim of this study was to determine objective and perceived kidney disease knowledge and patient characteristics associated with knowledge among patients followed in a multi-care kidney clinic. Design: This is a cross-sectional survey study. Setting: This study was conducted in a multi-care kidney clinic in Ontario, Canada. Patients: Patients who did not speak English, who were unable to read due to significant vision impairment, or who had a known history of dementia or significant cognitive impairment were excluded. Measurements: Perceived kidney disease knowledge was evaluated using a previously validated 9-item survey (PiKS). Each question on the perceived knowledge survey had 4 possible responses, ranging from “I don’t know anything” (1) to “I know a lot” (4). Objective kidney disease knowledge was evaluated using a previously validated survey (KiKS). Methods: The association between patient characteristics and perceived and objective kidney disease knowledge was determined using linear regression. Results: A total of 125 patients were included, 57% were male, the mean (SD) age and eGFR were 66 (13) years and 16 (5.9) mL/min/1.73 m 2 , respectively. The median (IQR) objective and perceived knowledge survey scores were 19 out of 27 (16, 21) and 2.9 out of 4 (2.4, 3.2), respectively. Only 25% of patients answered correctly that CKD can be associated with no symptoms, and 64% of patients identified correctly that the kidneys make urine. More than 60% of patients perceived themselves to know nothing or only a little about medications that help or hurt the kidney. Older age was independently associated with lower perceived and objective knowledge, but sex, income, and educational attainment were not. Limitations: This is a single-center study. Cognitive impairment was based on the treating team’s informal assessment or prior documentation in the chart; formal cognitive testing was not performed as part of this study. Conclusions: Despite resource-intensive care, CKD knowledge of patients followed in a multidisciplinary clinic was found to be modest. Whether enhanced educational strategies can improve knowledge and whether increasing knowledge improves patient outcomes warrants further study.

Metabolic function plays a key role in immune cell activation, destruction of foreign pathogens, and memory cell generation. As T cells are activated, their metabolic profile is significantly changed due to signaling cascades mediated by the T cell receptor (TCR) and co-receptors found on their surface. CD5 is a T cell co-receptor that regulates thymocyte selection and peripheral T cell activation. The removal of CD5 enhances T cell activation and proliferation, but how this is accomplished is not well understood. We examined how CD5 specifically affects CD4+ T cell metabolic function and systemic metabolome by analyzing serum and T cell metabolites from CD5WT and CD5KO mice. We found that CD5 removal depletes certain serum metabolites, and CD5KO T cells have higher levels of several metabolites. Transcriptomic analysis identified several upregulated metabolic genes in CD5KO T cells. Bioinformatic analysis identified glycolysis and the TCA cycle as metabolic pathways promoted by CD5 removal. Functional metabolic analysis demonstrated that CD5KO T cells have higher oxygen consumption rates (OCR) and higher extracellular acidification rates (ECAR). Together, these findings suggest that the loss of CD5 is linked to CD4+ T cell metabolism changes in metabolic gene expression and metabolite concentration.

Abstract Background Patients should receive follow-up serum creatinine tests after an initial abnormal result to diagnose chronic kidney disease. However, half of the time this fails to occur in primary care. We interviewed primary care providers to better understand their perceptions of enablers and barriers to following this guideline-recommended care. Methods We performed a qualitative descriptive study guided by the Theoretical Domains Framework (TDF), a framework for behavioural change. We used purposeful sampling to recruit primary care providers (physicians and nurse practitioners) based on provider and practice characteristics (rural, solo versus team practice, etc.) from Ontario, Canada. We completed one-on-one interviews with providers using a semi-structured and open-ended interview guide based on the 14 TDF domains. We alternated between data collection and analysis, where we used directed content analysis to identify frequent, important, and conflicting enablers and barriers. Results We completed 13 interviews with nine primary care physicians and four nurse practitioners. Nine themes related to the TDF emerged from the data: 1) environmental context and resources, 2) knowledge, 3) memory, attention, and decision processes, 4) beliefs about consequences, 5) goals, 6) social or professional role, 7) behavioural regulation, 8) skills, and 9) optimism. Within these themes, we identified 16 enablers and five barriers. Some enablers included, providers’ knowledge on appropriate testing, their motivation to order these tests, and their use of tools and resources to help order follow-up serum creatinine tests. However, providers perceived some barriers including that ordering confirmatory laboratory tests for chronic kidney disease was not always a priority in regards to other care they wish to provide. Providers also noted that a perceived barrier is patients not going to the laboratory to complete the test. Conclusions We identified novel enablers and barriers to primary care providers completing guideline recommended repeat testing for the diagnosis of chronic kidney disease. Similar research is needed to understand the views of patients. These research findings can be used to inform strategies to improve the quality of care.

Abstract Background Lung, breast, and colorectal malignancies are the leading cause of cancer-related deaths in the world causing over 2.8 million cancer-related deaths yearly. Despite efforts to improve prevention methods, early detection, and treatments, survival rates for advanced stage lung, breast, and colon cancer remain low, indicating a critical need to identify cancer-specific biomarkers for early detection and treatment. Thymidine kinase 1 (TK1) is a nucleotide salvage pathway enzyme involved in cellular proliferation and considered an important tumor proliferation biomarker in the serum. In this study, we further characterized TK1’s potential as a tumor biomarker and immunotherapeutic target and clinical relevance. Methods We assessed TK1 surface localization by flow cytometry and confocal microscopy in lung (NCI-H460, A549), breast (MDA-MB-231, MCF7), and colorectal (HT-29, SW620) cancer cell lines. We also isolated cell surface proteins from HT-29 cells and performed a western blot confirming the presence of TK1 on cell membrane protein fractions. To evaluate TK1’s clinical relevance, we compared TK1 expression levels in normal and malignant tissue through flow cytometry and immunohistochemistry. We also analyzed RNA-Seq data from The Cancer Genome Atlas (TCGA) to assess differential expression of the TK1 gene in lung, breast, and colorectal cancer patients. Results We found significant expression of TK1 on the surface of NCI-H460, A549, MDA-MB-231, MCF7, and HT-29 cell lines and a strong association between TK1’s localization with the membrane through confocal microscopy and Western blot. We found negligible TK1 surface expression in normal healthy tissue and significantly higher TK1 expression in malignant tissues. Patient data from TCGA revealed that the TK1 gene expression is upregulated in cancer patients compared to normal healthy patients. Conclusions Our results show that TK1 localizes on the surface of lung, breast, and colorectal cell lines and is upregulated in malignant tissues and patients compared to healthy tissues and patients. We conclude that TK1 is a potential clinical biomarker for the treatment of lung, breast, and colorectal cancer.

Estimates of potential harmful effects on ecosystems in the Canadian provinces of Alberta and Saskatchewan due to acidifying deposition were calculated, using a 1-year simulation of a high-resolution implementation of the Global Environmental Multiscale-Modelling Air-quality and Chemistry (GEM-MACH) model, and estimates of aquatic and terrestrial ecosystem critical loads. The model simulation was evaluated against two different sources of deposition data: total deposition in precipitation and total deposition to snowpack in the vicinity of the Athabasca oil sands. The model captured much of the variability of observed ions in wet deposition in precipitation (observed versus model sulfur, nitrogen and base cation R2 values of 0.90, 0.76 and 0.72, respectively), while being biased high for sulfur deposition, and low for nitrogen and base cations (slopes 2.2, 0.89 and 0.40, respectively). Aircraft-based estimates of fugitive dust emissions, shown to be a factor of 10 higher than reported to national emissions inventories (Zhang et al., 2018), were used to estimate the impact of increased levels of fugitive dust on model results. Model comparisons to open snowpack observations were shown to be biased high, but in reasonable agreement for sulfur deposition when observations were corrected to account for throughfall in needleleaf forests. The model–observation relationships for precipitation deposition data, along with the expected effects of increased (unreported) base cation emissions, were used to provide a simple observation-based correction to model deposition fields. Base cation deposition was estimated using published observations of base cation fractions in surface-collected particles (Wang et al., 2015).Both original and observation-corrected model estimates of sulfur, nitrogen, and base cation deposition were used in conjunction with critical load data created using the NEG-ECP (2001) and CLRTAP (2017) methods for calculating critical loads, using variations on the Simple Mass Balance model for terrestrial ecosystems, and the Steady State Water Chemistry and First-order Acidity Balance models for aquatic ecosystems. Potential ecosystem damage was predicted within each of the regions represented by the ecosystem critical load datasets used here, using a combination of 2011 and 2013 emissions inventories. The spatial extent of the regions in exceedance of critical loads varied between 1  ×  104 and 3.3  ×  105 km2, for the more conservative observation-corrected estimates of deposition, with the variation dependent on the ecosystem and critical load calculation methodology. The larger estimates (for aquatic ecosystems) represent a substantial fraction of the area of the provinces examined.Base cation deposition was shown to be sufficiently high in the region to have a neutralizing effect on acidifying deposition, and the use of the aircraft and precipitation observation-based corrections to base cation deposition resulted in reasonable agreement with snowpack data collected in the oil sands area. However, critical load exceedances calculated using both observations and observation-corrected deposition suggest that the neutralization effect is limited in spatial extent, decreasing rapidly with distance from emissions sources, due to the rapid deposition of emitted primary dust particles as a function of their size. We strongly recommend the use of observation-based correction of model-simulated deposition in estimating critical load exceedances, in future work.

Purpose: High-dose chemotherapy with autologous stem-cell rescue (SCR) is a key component of high-risk neuroblastoma (HRNB) therapy. Carboplatin, etoposide, and melphalan (CEM) or busulfan and melphalan (Bu/Mel) are the most evaluated, effective high-dose chemotherapy for HRNB on the basis of results from major cooperative group studies. Toxicity profiles vary between these regimens, and practice variation exists regarding the preferred high-dose therapy (HDT). We sought to evaluate the safety of HDT and autologous SCR for HRNB in a resource-limited country (Egypt) compared with the resource-rich United States. Patients and Methods: We performed a retrospective comparative review of single CEM-based HDT/SCR outcomes through day 100 for HRNB at the Fred Hutchinson Cancer Research Center (FH) in the United States (2005 to 2015) versus Bu/Mel-based HDT at El-Sheikh Zayed Specialized Hospital (SZ) in Egypt (2009 to 2015). Results: Forty-four patients at FH and 77 patients at SZ were reviewed. Pretransplant hepatic comorbidities were significantly higher at SZ (29 of 77 v nine of 44; P = .05), with 19 of 77 patients at SZ having hepatitis infection. Engraftment was delayed after SZ-Bu/Mel therapy compared with FH-CEM therapy for neutrophils (median 12 days v 10 days, respectively; P < .001) and platelets (median 20 days v 18 days, respectively; P < .001). Sinusoidal obstruction syndrome occurred later, after SZ-Bu/Mel therapy (median 19 days v 7 days; P = .033), and four of eight cases were fatal (six of eight patients had underlying hepatitis infection), whereas three of three cases after FH-CEM therapy were moderately severe. Resource utilization associated with the number of days with fever, antibiotic use, and the number of transfusions administered was significantly higher after FH-CEM therapy than after SZ-Bu/Mel therapy. Conclusion: Use of autologous stem-cell transplantation is feasible in the context of a resource-limited country.

Background: Multidisciplinary chronic kidney disease (CKD) clinics improve patient outcomes but their optimal design is unclear. Objective: To perform a scoping review to identify and describe current practices (structure, function) associated with multidisciplinary CKD clinics. Design: Scoping review. Setting: Databases included Medline, EMBASE, Cochrane, and CINAHL. Patients: Patients followed in multidisciplinary CKD clinics globally. Measurements: Multidisciplinary CKD clinic composition, entry criteria, follow-up, and outcomes. Methods: We systematically searched the literature to identify randomized controlled trials, non-randomized interventional studies, or observational studies of multidisciplinary CKD clinics defined by an outpatient setting where two or more allied health members (with or without a nephrologist) provided longitudinal care to 50 or more adult or pediatric patients with CKD. Included studies were from 2002 to present. Searches were completed on August 10, 2018. Title, abstracts, and full texts were screened independently by two reviewers with disagreements resolved by a third. We abstracted data from included studies to summarize multidisciplinary CKD clinic team composition, entry criteria, follow-up, and processes. Results: 40 studies (8 randomized controlled trials and 32 non-randomized interventional studies or observational studies) involving 23 230 individuals receiving multidisciplinary CKD care in 12 countries were included. Thirty-eight focused on adults (27 with CKD, 10 incident dialysis patients, one conservative therapy) while two studies focused on adolescents or children with CKD. The multidisciplinary team included a mean of 4.6 (SD 1.5) members consisting of a nephrologist, nurse, dietician, social worker, and pharmacist in 97.4%, 86.8%, 84.2%, 57.9%, and 42.1% of studies respectively. Entry criteria to multidisciplinary CKD clinics ranged from glomerular filtration rates of 20 to 70 mL/min/1.73m 2 or CKD stages 1 to 5 without any proteinuria or risk equation-based criteria. Frequency of follow-up was variable by severity of kidney disease. Team member roles and standardized operating procedures were infrequently reported. Limitations: Unstandardized definition of multidisciplinary CKD care, studies limited to CKD defined by glomerular filtration rate, and lack of representation from countries other than Canada, Taiwan, the United States, and the United Kingdom. Conclusions: There is heterogeneity in multidisciplinary CKD team composition, entry criteria, follow-up, and processes with inadequate reporting of this complex intervention. Additional research is needed to determine the best model for multidisciplinary CKD clinics. Trial registration: Not applicable.

Survivorship Care Plans (SCPs) may facilitate long-term care for cancer survivors, but their effectiveness has not been established in hematopoietic cell transplantation recipients. We evaluated the impact of individualized SCPs on patient-reported outcomes among transplant survivors. Adult (≥18 years at transplant) survivors who were 1-5 years post transplantation, proficient in English, and without relapse or secondary cancers were eligible for this multicenter randomized trial. SCPs were developed based on risk-factors and treatment exposures using patient data routinely submitted by transplant centers to the Center for International Blood and Marrow Transplant Research and published guidelines for long-term follow up of transplant survivors. Phone surveys assessing patient-reported outcomes were conducted at baseline and at 6 months. The primary end point was confidence in survivorship information, and secondary end points included cancer and treatment distress, knowledge of transplant exposures, health care utilization, and health-related quality of life. Of 495 patients enrolled, 458 completed a baseline survey and were randomized (care plan=231, standard care=227); 200 (87%) and 199 (88%) completed the 6-month assessments, respectively. Patients’ characteristics were similar in the two arms. Participants on the care plan arm reported significantly lower distress scores at 6 months and an increase in the Mental Component Summary quality of life score assessed by the Short Form 12 (SF-12) instrument. No effect was observed on the end point of confidence in survivorship information or other secondary outcomes. Provision of individualized SCPs generated using registry data was associated with reduced distress and improved mental domain of quality of life among 1-5 year hematopoietic cell transplantation survivors. Trial registered at clinicaltrials.gov 02200133.

Background: Unplanned dialysis initiation is common in patients with chronic kidney disease (CKD). Objective: To determine common definitions and patient risk factors for unplanned dialysis. Design: Systematic review. Setting: MEDLINE, EMBASE, and the Cochrane Library were searched from inception to February 2018. Patients: Studies that included incident chronic dialysis patients or patients with CKD that cited a definition or examined risk factors for unplanned dialysis were included. Measurements: Definitions and criteria for unplanned dialysis reported across studies. Patient characteristics associated with unplanned dialysis. Methods: Two reviewers independently extracted data using a standardized data abstraction form and assessed study quality using a modified New Castle Ottawa Scale. Results: From 2797 citations, 48 met eligibility criteria. Reported definitions for unplanned dialysis were variable. Most publications cited dialysis initiation under emergency conditions and/or with a central venous catheter. The association of patient characteristics with unplanned dialysis was reported in 26 studies, 18 were retrospective and 21 included incident dialysis patients. The most common risk factors in univariate analyses were (number of studies) increased age (n = 7), cause of kidney disease (n = 6), presence of cardiovascular disease (n = 7), lower serum hemoglobin (n = 9), lower serum albumin (n = 10), higher serum phosphate (n = 6), higher serum creatinine or lower estimated glomerular filtration rate (eGFR) at dialysis initiation (n = 7), late referral (n = 5), lack of dialysis education (n = 6), and lack of follow-up in a predialysis clinic prior to dialysis initiation (n = 5). A minority of studies performed multivariable analyses (n = 10); the most common risk factors were increased age (n = 4), increased comorbidity score (n = 3), late referral (n = 5), and lower eGFR at dialysis initiation (n = 3). Limitations: Comparison of results across studies was limited by inconsistent definitions for unplanned dialysis. High-quality data on patient risk factors for unplanned dialysis are lacking. Conclusions: Well-designed prospective studies to determine modifiable risk factors are needed. The lack of a consensus definition for unplanned dialysis makes research and quality improvement initiatives in this area more challenging.

Accurately modeled biogenic volatile organic compound (BVOC) emissions are an essential input to atmospheric chemistry simulations of ozone and particle formation. BVOC emission models rely on basal emission factor (BEF) distribution maps based on emission measurements and vegetation land-cover data but these critical input components of the models as well as model simulations lack validation by regional scale measurements. We directly assess isoprene emission-factor distribution databases for BVOC emission models by deriving BEFs from direct airborne eddy covariance (AEC) fluxes (Misztal et al., 2014) scaled to the surface and normalized by the activity factor of the Guenther et al. (2006) algorithm. The available airborne BEF data from approx. 10 000 km of flight tracks over California were averaged spatially over 48 defined ecological zones called ecoregions. Consistently, BEFs used by three different emission models were averaged over the same ecoregions for quantitative evaluation. Ecoregion-averaged BEFs from the most current land cover used by the Model of Emissions of Gases and Aerosols from Nature (MEGAN) v.2.1 resulted in the best agreement among the tested land covers and agreed within 10 % with BEFs inferred from measurement. However, the correlation was sensitive to a few discrepancies (either overestimation or underestimation) in those ecoregions where land-cover BEFs are less accurate or less representative for the flight track. The two other land covers demonstrated similar agreement (within 30 % of measurements) for total average BEF across all tested ecoregions but there were a larger number of specific ecoregions that had poor agreement with the observations. Independently, we performed evaluation of the new California Air Resources Board (CARB) hybrid model by directly comparing its simulated isoprene area emissions averaged for the same flight times and flux footprints as actual measured area emissions. The model simulation and the observed surface area emissions agreed on average within 20 %. We show that the choice of model land-cover input data has the most critical influence on model-measurement agreement and the uncertainty in meteorology inputs has a lesser impact at scales relevant to regional air quality modeling.

Coagulase-negative staphylococci (CoNS) are an important group of opportunistic pathogenic microorganisms that cause infections in hospital settings and are generally resistant to many antimicrobial agents. We report on phenotypic and genotypic virulence characteristics of a select group of clinical, mecA-positive (encoding penicillin-binding protein 2a) CoNS isolates. All CoNS were resistant to two or more antimicrobials with S. epidermidis strain 214EP, showing resistance to fifteen of the sixteen antimicrobial agents tested. Aminoglycoside-resistance genes were the ones most commonly detected. The presence of megaplasmids containing both horizontal gene transfer and antimicrobial resistance genetic determinants indicates that CoNS may disseminate antibiotic resistance to other bacteria. Staphylococcus sciuri species produced six virulence enzymes, including a DNase, gelatinase, lipase, phosphatase, and protease that are suspected to degrade tissues into nutrients for bacterial growth and contribute to the pathogenicity of CoNS. The PCR assay for the detection of biofilm-associated genes found the eno (encoding laminin-binding protein) gene in all isolates. Measurement of their biofilm-forming ability and Spearman’s rank correlation coefficient analyses revealed that the results of crystal violet (CV) and extracellular polymeric substances (EPS) assays were significantly correlated (ρ = 0.9153, P = 3.612e-12). The presence of virulence factors, biofilm-formation capability, extracellular enzymes, multidrug resistance, and gene transfer markers in mecA-positive CoNS clinical strains used in this study makes them powerful opportunistic pathogens. The study also warrants a careful evaluation of nosocomial infections caused by CoNS and may be useful in studying the mechanism of virulence and factors associated with their pathogenicity in vivo and developing effective strategies for mitigation.

Background: Depression and anxiety are common and underrecognized in end-stage renal disease (ESRD), are associated with poor outcomes and reduced health-related quality of life, and are potentially treatable. Simple, accurate screening tools are needed. Objective: We examined the operating characteristics of single questions for anxiety and depression from the Edmonton Symptom Assessment System (ESAS) in hemodialysis. Design: Cross-sectional study. Setting: Two outpatient hemodialysis units (1 tertiary, 1 community) in Hamilton, Canada. Patients: Adult prevalent hemodialysis patients. Measurements: ESAS and Hospital Anxiety and Depression Scale (HADS). Methods: Participants were asked the degree to which they experienced anxiety and depression using the ESAS. ESAS single questions for anxiety and depression were compared with the reference standard of the HADS using dialysis population specific cutoffs (HADS anxiety subscale ≥6 and HADS depression subscale ≥7). Logistic regression was used to create receiver operating characteristics (ROC) curves. Results: We recruited 50 participants with a mean age of 64 (SD = 12.4) years, of whom 52% were male and 96% were on ≥3× weekly hemodialysis. Using the reference standards, 28 (56%) had a diagnosis of anxiety and 27 (54%) had a diagnosis of depression. Areas under the ROC curves were 0.83 for anxiety and 0.81 for depression using ESAS scores of ≥2. Limitations: Sample size and the lack of a reference gold standard. Conclusions: The ESAS single questions for anxiety and depression have reasonable discrimination in a hemodialysis population. The use of more complex and time-consuming screening instruments could be reduced by adopting the ESAS questions for anxiety and depression in hemodialysis.

Background: Nonvalvular atrial fibrillation (NVAF) is an independent risk factor for ischemic stroke and is common in chronic kidney disease (CKD) and dialysis patients. The use of oral anticoagulation to prevent stroke and systemic embolism in the setting of kidney disease is controversial. Novel alternatives to vitamin K antagonists include left atrial appendage occlusion devices (LAAOD) and apixaban. Objective: We sought to elicit Canadian nephrologist views regarding stroke and systemic embolism prevention therapies in CKD and dialysis patients with NVAF. Design: Survey. Setting: Online via https://www.surveymonkey.com . Participants: Canadian Society of Nephrology members actively treating adult dialysis patients with NVAF. Measurements: Management questions were asked with response options consisting of a Likert scale ranging from 1 to 8 (with 1 being definitely would not and 8 being definitely would ). Methods: We randomly allocated each respondent to 2 of 4 cases that varied by stroke and bleeding risks (using varying CHADS2 and HASBLED scores, respectively). Results: There were 91 responses (36.3% response rate) from mostly university (83.5%) and also community with university affiliation (12.1%) and community (4.4%) nephrologists. Warfarin was more likely to be recommended in individuals at high stroke risk and low bleeding risk (mean = 5.47, 95% confidence interval = 4.87-6.07) and less likely to be recommended in individuals at moderate stroke risk and high bleeding risk (mean = 2.89, 95% confidence interval = 2.37-3.41). The likelihood of recommending LAAOD did not vary by stroke or bleeding risks (means ranging from 3.92-4.90). Apixaban was not likely to be recommended in any case (means ranging from 2.60-3.50). However, nephrologists felt there was equipoise regarding anticoagulation strategies allowing participation in appropriate randomized controlled trials (RCTs). Limitations: The survey only involved nephrologists and only 4 cases with dichotomized risk categories were presented instead of complete range of stroke and bleeding risk combinations. As with any survey, there was the potential for responder bias and treatment decisions are not anchored directly to patient management. Conclusions: Nephrologists caring for patients with kidney disease appear willing to include patients in clinical trials examining alternatives to warfarin for stroke and systemic embolism prevention for NVAF in the setting of kidney disease.

This study aimed to describe real-life microbiological testing of adults hospitalised with community-acquired pneumonia (CAP) and to assess concordance with the 2007 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) and 2011 European Respiratory Society (ERS) CAP guidelines. This was a cohort study based on the Global Initiative for Methicillin-resistant Staphylococcus aureus Pneumonia (GLIMP) database, which contains point-prevalence data on adults hospitalised with CAP across 54 countries during 2015. In total, 3702 patients were included. Testing was performed in 3217 patients, and included blood culture (71.1%), sputum culture (61.8%), Legionella urinary antigen test (30.1%), pneumococcal urinary antigen test (30.0%), viral testing (14.9%), acute-phase serology (8.8%), bronchoalveolar lavage culture (8.4%) and pleural fluid culture (3.2%). A pathogen was detected in 1173 (36.5%) patients. Testing attitudes varied significantly according to geography and disease severity. Testing was concordant with IDSA/ATS and ERS guidelines in 16.7% and 23.9% of patients, respectively. IDSA/ATS concordance was higher in Europe than in North America (21.5% versus 9.8%; p

Chronic graft-versus-host disease occurs in 20–50% of allogeneic hematopoietic cell transplant survivors. We surveyed patients about their quality of life, symptoms, health status, comorbid conditions and medications. Instruments included the Short-Form-36 (SF-36), the Patient-Reported Outcomes Measurement Information System (PROMIS) Global and PROMIS-29 scales and the Lee Chronic Graft-versus-Host Disease Symptom Scale. Functional status was measured by self-reported Karnofsky performance status and work status. Of 3027 surveys sent to recipients surviving one or more years after transplantation, 1377 (45%) were returned. Among these, patients reported that their chronic graft-versus-host disease was mild (n=257, 18.7%), moderate (n=110, 8.0%) or severe (n=25, 1.8%). Another 377 (27.4%) had never had chronic graft-versus-host disease and 280 (20.3%) had had chronic graft-versus-host disease but it had resolved. We excluded 328 (23.8%) patients who did not answer the questions about chronic graft-versus-host disease. Patients who reported moderate or severe chronic graft-versus-host disease reported worse quality of life, lower performance status, a higher symptom burden and were more likely to be taking prescription medications for pain, anxiety and depression compared to those with resolved chronic graft-versus-host disease. Self-reported measures were similar between patients with resolved chronic graft-versus-host disease and those who had never had it. Our data suggest that the PROMIS measures may be able to replace the SF-36 in the assessment of chronic graft-versus-host disease. Between 26.7–39.4% of people with active chronic graft-versus-host disease were unable to work due to health reasons, compared with 12.1% whose chronic graft-versus-host disease had resolved and 15.4% who had never had chronic graft-versus-host disease. Mouth, eye and nutritional symptoms persisted after resolution of chronic graft-versus-host disease. These results show that better prevention of and treatment for chronic graft-versus-host disease are needed to improve survivorship after allogeneic transplantation.