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Knowledge about systemic lupus erythematosus (SLE) outcomes among US Asian patients is lacking. The present study was undertaken to examine SLE disease activity, severity, and damage among Asian patients of primarily Chinese and Filipino descent in a multiethnic cohort.California Lupus Epidemiology Study (n = 328) data were analyzed. Data were collected in English, Cantonese, Mandarin, or Spanish using validated instruments for disease activity (Systemic Lupus Erythematosus Disease Activity Index), disease severity (Lupus Severity Index [LSI]), and disease damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). We assessed differences in SLE outcomes among racial/ethnic groups using multivariable linear regression including interaction terms for age at diagnosis and race/ethnicity.Asian was the largest racial/ethnic group (38% [Chinese = 22%; Filipino = 9%; Other = 7%]). Average age at diagnosis was younger among Asian patients (27.9 years), particularly Filipino patients (22.2 years), compared with White (29.4 years) and Black patients (34.0 years). After adjustment, disease activity and damage were not significantly different across groups. Disease severity among Asian patients was significantly higher than among White patients (LSI score 7.1 versus 6.5; P 0.05) but similar among Black and Hispanic patients. Early age at diagnosis was associated with greater organ damage among Asian, Black, and Hispanic patients, but not White patients.SLE was more severe among US Asian patients compared to White patients. Filipinos were affected at strikingly young ages. Asian patients and non-White groups with younger age at diagnosis had greater organ damage than White patients. Such racial/ethnic distinctions suggest the need for heightened clinical awareness to improve health outcomes among Asian patients with SLE. Further study of SLE outcomes across a range of US Asian subgroups is important.

PURPOSE Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices. METHODS A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints. RESULTS Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2; P = .022) higher in patients allocated to AAP + SOC. Global-QOL was higher for patients allocated to AAP + SOC over the first year (+5.7 points, 95% CI, +3.0 to +8.5; P < .001), particularly at 12 (+7.0 points, 95% CI, +3.0 to +11.0; P = .001) and 24 weeks (+8.3 points, 95% CI, +4.0 to +12.6; P < .001). CONCLUSION Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment.

Background: Tumor biobanks are a common research infrastructure. As a collection of biospecimens and annotated data collected to support a multitude of research projects, biobanks facilitate access...

Introduction /Objectives: The objectives were to conduct a survey of cardiologists on their recent experiences with cats that have dilated cardiomyopathy (DCM), and to retrospectively review individual cases of feline DCM. Animals, Materials and Methods Part One: A survey was distributed to cardiologists with questions regarding caseload and clinical management of cats with DCM diagnosed over the past two years. Part Two: Cardiologists completing the survey were invited to submit data from cats recently diagnosed with DCM. Data on signalment, clinical signs, diet, echocardiographic measurements, and outcome were recorded. Results Part One: From 52 completed surveys, many cardiologists responded that measuring and supplementing taurine and recommending a diet change in cats with DCM are common practices. Few (15%) cardiologists reported an increase in number of feline DCM cases over the past two years, although some had cases that improved even if taurine deficiency was not present. Part Two: Twenty of 37 (54%) cats ate low pea/lentil (low PL) diets and 14/37 (38%) ate high pea/lentil (high PL) diets at the time of diagnosis; three had incomplete diet information. Two of 13 cats (15%) in which taurine was measured had levels below the reference range. After adjusting for other variables, cats eating high PL diets that changed diets post-diagnosis had a significantly longer survival time compared to cats eating high PL diets that did not change diets post-diagnosis (P=0.025). Conclusions Additional research is warranted to determine whether there could be a possible association between diet and DCM in cats.

Ryan B Rush,1– 4 Sloan W Rush2,3 1Instituto de la Visión– Hospital La Carlota, Montemorelos, Nuevo León, 67530, México; 2Panhandle Eye Group, Amarillo, TX, 79106, USA; 3Department of Surgery, Texas Tech University Health Science Center, Amarillo, TX, 79106, USA; 4Southwest Retina Specialists, Amarillo, TX, 79106, USACorrespondence: Ryan B RushSouthwest Retina Specialists, 7411 Wallace Blvd, Amarillo, TX, 79106, USATel +1 806 351-1870Email ryan.rush.md@gmail.comPurpose: To report the outcomes in subjects undergoing pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling for the management of treatment-naïve diabetic macular edema (DME).Methods: Ten treatment-naïve subjects with non-proliferative diabetic retinopathy prospectively underwent PPV with ILM peeling for the treatment of DME at a single university-affiliated institution. The preoperative features, intraoperative details and postoperative outcomes were collected and analyzed.Results: All 10 subjects underwent PPV with ILM peeling without significant intraoperative or postoperative complications at 6 months follow-up. Visual acuity improved from a baseline of 0.74 (95% CI: 0.48– 1.0) logMAR (Snellen 20/110) to 0.46 (95% CI: 0.3– 0.62) logMAR (Snellen 20/58) at 6 months follow-up (p=0.045). Optical coherence tomography central macular thickness reduced from a baseline of 456 (95% CI: 394.7– 516.4) microns to 316.8 (95% CI: 275.9– 357.7) microns at 6 months follow-up (p < 0.001).Conclusion: This pilot study suggests that PPV with ILM peeling may be a viable treatment option for the management of treatment naïve DME in subjects with non-proliferative diabetic retinopathy. Development of a randomized controlled trial may be justified to validate the results of this study.Clinicaltrials.gov Identifier #: NCT03660345.Keywords: vitrectomy, internal limiting membrane peeling, diabetic macular edema

PURPOSE To evaluate the benefits of internal limiting membrane peeling in proliferative diabetic retinopathy subjects undergoing pars plana vitrectomy for the treatment of vitreous hemorrhage. METHODS Two hundred and fifty-eight proliferative diabetic retinopathy subjects undergoing pars plana vitrectomy for vitreous hemorrhage were enrolled into the trial. Patients were randomized into one of two cohorts: Group A patients underwent internal limiting membrane peeling, whereas Group B patients did not undergo internal limiting membrane peeling. The main outcome was best-corrected visual acuity at 6 months. Secondary outcomes were optical coherence tomography central macular thickness at 6 months, incidence of diabetic macular edema treatment during the postoperative trial period, and incidence of epiretinal membrane at 6 months. RESULTS Two hundred and seven patients were randomized and completed 6 months follow-up. Group A had better best-corrected visual acuity at 6 months than Group B (P < 0.01). Group A had a lower incidence of diabetic macular edema treatment during the postoperative trial period and a lower incidence of epiretinal membrane at 6 months than Group B (P = 0.02 and P < 0.001, respectively). There was a trend toward lower central macular thickness on optical coherence tomography in Group A than Group B (P = 0.09). There were no significant differences in baseline details or complications intraoperatively or postoperatively between cohorts. CONCLUSION This trial demonstrated better vision, fewer postoperative diabetic macular edema treatments, and a lower incidence of epiretinal membrane at 6 months when internal limiting membrane peeling was performed. Internal limiting membrane peeling may be considered a vital maneuver to perform in proliferative diabetic retinopathy subjects undergoing pars plana vitrectomy for vitreous hemorrhage.

Sloan W Rush,1,2 Ryan B Rush1– 3 1Panhandle Eye Group, Amarillo, TX, 79106, USA; 2Department of Surgery, Texas Tech University Health Science Center, Amarillo, TX, 79106, USA; 3Southwest Retina Specialists, Amarillo, TX, 79106, USACorrespondence: Ryan B RushSouthwest Retina Specialists, 7411 Wallace Blvd, Amarillo, TX, 79106, USATel +1 806 351-1870Email ryan.rush.md@gmail.comPurpose: To report the outcomes of laser in situ keratomileusis (LASIK) in patients with previous microkeratome LASIK using a femtosecond laser platform to create a de novo flap.Methods: The charts of 17 patients that underwent femtosecond-assisted LASIK with de novo flap creation for consecutive refractive error following previous microkeratome LASIK were retrospectively reviewed at a single private practice institution. The baseline characteristics, intraoperative findings and postoperative outcomes were analyzed.Results: All 17 eyes underwent femtosecond-assisted LASIK with de novo flap creation without significant intraoperative or postoperative complications. Uncorrected visual acuity improved postoperatively (p< 0.0001) and remained stable at 6 months follow-up. None of the subjects lost any lines of best spectacle corrected visual acuity or developed epithelial ingrowth during the postoperative period.Conclusion: The femtosecond laser technique described in this report can provide a safe and effective method to deliver LASIK following previous microkeratome LASIK. Future investigations are required to further validate the findings in this study.Keywords: LASIK, cornea, optical coherence tomography

As of January 2021, there are more than 3.8 million women in the United States with a history of breast cancer. The current standard of care for breast cancer involves surgical resection, radiation therapy, adjuvant endocrine therapy, and/or adjuvant chemotherapy. Aromatase inhibitors (AIs) are the gold standard for endocrine therapy in postmenopausal women. Dermatologic adverse events (dAEs) associated with AIs are rare but have been reported in the literature. Commonly reported dAEs include unspecified rash, pruritus, alopecia, vulvovaginal atrophy, vasculitis, and autoimmune/connective tissue disorders. Appropriate preventative strategies and careful management considerations have the potential to optimize the comprehensive care of patients with cancer and improve quality of life. Furthermore, prevention of dAEs can lead to a reduction in cancer treatment interruptions and discontinuations. Herein, we characterize dAEs of AIs and discuss preventative management to reduce the incidence of AI therapy interruption.

The possibility of utilization of inactive fly ash in road concrete compositions by bringing of ash into a non-equilibrium condition with increased reactivity by mechanical activation in a vibration eraser is investigated. It was revealed that the optimal content of binder and fly ash in samples of soil concrete was 8 and 10 wt. %, respectively. It is shown that, due to mechanical activation, the specific surface area of fly ash increases by 2 times, dehydration and carbonization occur and silicon is replaced by aluminum in silicon-oxygen tetrahedra. It has been established that an increase of the content of crystalline carbonate phases is the reason for an increase in the strength of ground concrete. It is determined that the introduction of mechanoactivated fly ash into the composition of soil concretes contributes to increasing their physical and mechanical characteristics to the maximum strength grade M100. This indicates the competitiveness of ground concrete and the possibility of direct use of inactive fly ash in road construction.

Diagnostics tests used to identify the cause of infection using proteomics and genomics have revolutionised microbiology laboratories in recent times. However, approaches to build the capacity of clinical microbiology services in the rural tropics by simply transplanting these approaches have proven difficult to sustain. Tropical fever in the remote tropics is, by definition, a clinical diagnosis where the aetiology of fever is not known, treatment is empirical, guided by clinical suspicion with treatment failure often attributed to incorrect diagnosis or antimicrobial resistance. Tuberculosis (TB) in rural Papua New Guinea (PNG) is mostly diagnosed clinically, perhaps supported by microscopy. In fact, a ‘tuberculosis patient’ in rural PNG is included in the TB register upon commencement of TB treatment with or without any laboratory-based evidence of infection. The roll-out of GeneXpert is continuing to transform TB diagnostic certainty in TB endemic communities. Melioidosis is endemic in tropical regions and is increasingly reported to mimic TB. Isolation and identification of the causative agent Burkholderia pseudomallei remains the gold standard. Here, we discuss the increasing divide between rural and urban approaches to laboratory-based infection diagnosis using these two enigmatic tropical infectious diseases, in rural PNG, as examples.

Summary Background Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, have been proposed as a promising therapeutic option for people with multiple sclerosis on the basis of their immunomodulatory and neuroprotective properties. The MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study was devised to evaluate the safety, tolerability, and activity of autologous MSCs derived from bone marrow and infused intravenously in patients with active multiple sclerosis. Methods MESEMS is a randomised phase 2 trial done at 15 sites in nine countries. Patients (aged 18–50 years) with active relapsing-remitting or progressive multiple sclerosis were included if they had a disease duration of 2–15 years since onset of multiple sclerosis and an Expanded Disability Status Scale score of 2·5–6·5. Patients were randomly assigned (1:1), according to a crossover design, to receive a single intravenous dose of autologous bone marrow-derived MSCs followed by placebo at week 24, or to receive placebo followed by autologous MSCs at week 24, with a follow-up visit at week 48. Primary objectives were to test safety and activity of MSC treatment. The primary safety endpoint was to assess the number and severity of adverse events within each treatment arm. The primary efficacy endpoint was the number of gadolinium-enhancing lesions (GELs) counted over week 4, 12, and 24 compared between treatment groups. The primary efficacy endpoint was assessed in the full analyis set, after all participants completed the week 24 visit. Efficacy endpoints were evaluated using a predefined statistical testing procedure. Safety was monitored throughout the study by recording vital signs and adverse events at each visit. Findings From July 16, 2012, until July 31, 2019, 144 patients were randomly assigned to first receive early intravenous infusion of autologous bone marrow-derived MSCs (n=69) or placebo (n=75). MSC treatment did not meet the primary endpoint of efficacy on the total number of GELs accumulated from baseline to week 24 (rate ratio [RR] 0·94, 95% CI 0·58–1·50; p=0·78). 213 adverse events were recorded, similarly distributed between groups (93 cases recorded in 35 [51%] of 69 patients treated first with MSCs vs 120 cases in 42 [56%] of 75 patients infused first with placebo). The most frequent adverse events reported were infection and infestations, with a total of 54 (25%) of 213 adverse events (18 [19%] of 93 in the early-MSC group and 36 [30%] of 120 in the delayed-MSC group). Nine serious adverse events were reported in seven patients treated with placebo versus none in the MSC group. All serious adverse events were considered to be unrelated to the treatment infusion. No deaths were reported during the study. Interpretation Bone marrow-derived MSC treatment was safe and well tolerated but did not show an effect on GELs, an MRI surrogate marker of acute inflammation, in patients with active forms of multiple sclerosis, at week 24. Thus, this study does not support the use of bone marrow-derived MSCs to treat active multiple sclerosis. Further studies should address the effect of MSCs on parameters related to tissue repair. Funding Fondazione Italiana Sclerosi Multipla (FISM), the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), and the Multiple Sclerosis International Federation (MSIF) for centralised activities. Individual trials participating in the MESEMS network are funded by the following agencies: FISM and Compagnia di San Paolo (Italy); The Danish Multiple Sclerosis Society, The Toyota Foundation, and Danish Blood Donors’ Research Foundation (Denmark); the Spanish Health Research Institute Carlos 3 and the Andalusian Public Foundation Progreso y Salud (Spain); the Royan Institute for Stem Cell Biology and Technology (Iran); the Spinal Cord Injury and Tissue Regeneration Centre Salzburg, Paracelsus Medical University, and Salzburg (Austria); the Fondation pour l’aide a la recherche sur la sclerose en plaques (ARSEP), French Muscular Dystrophy Association (AFM)-Telethon (France); the UK Multiple Sclerosis Society and the UK Stem Cell Foundation (UK); and the Multiple Sclerosis Society of Canada and The Multiple Sclerosis Scientific Research Foundation and Research Manitoba (Canada).

Introduction Kawasaki disease (KD) with coronary artery aneurysms (complex KD) presents relentless challenges for families. Psychosocial experiences and needs were explored. Method A descriptive, exploratory study of adolescents and parents using a needs survey and psychosocial instruments (anxiety, depression, and functional impairment). Results Fifty-one parents and 38 adolescents participated. Predominant interests were for information sheets, newsletters, Web sites, and phone applications. Gaps in disease-specific knowledge and awareness of coronary artery aneurysms between parents and adolescents were identified. Psychosocial concerns for adolescents included symptoms of anxiety (22%), depression (13%), and functional impairment (22%). Multivariable analyses indicated higher depression scores associated with longer travel distance from specialists (p = .04). Parent-reported social concerns for their adolescent were associated with higher anxiety (p = .005) and functional impairment (p = .005). Written commentary complemented the findings. Discussion Care protocols require psychosocial assessment/referral and the use of virtual platforms. The groundwork was laid for developing patient and family-centered strategies.

INTRODUCTION Per-oral endoscopic myotomy (POEM) has been widely adopted for the treatment of achalasia as it provides a precise, tailored myotomy in a minimally invasive endoscopic procedure. Several short-term studies and a few long-term studies have confirmed that POEM is a safe and effective treatment for achalasia. However, the long-term outcome of POEM performed by trainees is unknown. MATERIALS AND METHODS We conducted a retrospective study of all patients who underwent POEM for achalasia at our tertiary care center during December 2012 and January 2019. All procedures performed with trainees were included. The primary outcome was the clinical response to POEM, defined as an Eckardt score of

First responders encounter many hazards in the execution of their duties, and exposure to hazardous materials such as opioids is a primary safety concern. The ongoing opioid crisis in the United States continues to be a major public health issue, with overdose deaths from opioids reaching epidemic levels. Although responders frequently encounter opioids, available data on safety and risk are not always well-communicated, and we identified a need for refresher and just-in-time training products on this topic. In response, we created a training video series that is informative, concise, and visually appealing. The video series, available on YouTube, was tested with a small initial population, with findings suggesting key questions for a larger study focused on integration of the refresher training with existing programs to optimize retention and adoption of safety practices.

Dilated cardiomyopathy (DCM) is a disease of the heart muscle that affects both humans and dogs. Certain canine diets have been associated with DCM, but the diet-disease link is unexplained, and novel methods are needed to elucidate mechanisms. We conducted metabolomic profiling of 9 diets associated with canine DCM, containing ≥ 3 pulses, potatoes, or sweet potatoes as main ingredients, and in the top 16 dog diet brands most frequently associated with canine DCM cases reported to the FDA (3P/FDA diets), and 9 non-3P/FDA diets. We identified 88 named biochemical compounds that were higher in 3P/FDA diets and 23 named compounds that were lower in 3P/FDA diets. Amino acids, amino acid-derived compounds, and xenobiotics/plant compounds were the largest categories of biochemicals that were higher in 3P/FDA diets. Random forest analyses identified the top 30 compounds that distinguished the two diet groups with 100% predictive accuracy. Four diet ingredients distinguished the two diet groups (peas, lentils, chicken/turkey, and rice). Of these ingredients, peas showed the greatest association with higher concentrations of compounds in 3P/FDA diets. Moreover, the current foodomics analyses highlight relationships between diet and DCM in dogs that can identify possible etiologies for understanding diet-disease relationships in dogs and humans.

Background Colony-stimulating factor-1 receptor (CSF1R)-related leukoencephalopathy is a rapidly progressive neurodegenerative disease for which there is currently no cure. Hematopoietic stem cell transplantation (HSCT) has been proposed as a disease-modifying treatment. Objective The objective of this study was to determine the effect of HSCT on disease progression. Methods We collected all available clinical data from a cohort of 7 patients with CSF1R-related leukoencephalopathy who underwent HSCT at our institutions. Clinical data included detailed neurological examination by a board-certified neurologist, serial cognitive screens, formal neuropsychological evaluations, and serial brain magnetic resonance imaging (MRI). Results Our patients had an average disease duration of 27.6 months at the time of transplant, and we have 87 months of total posttransplant follow-up time (median, 11; range, 2-27). One patient died in the periprocedural period. The remaining patients showed a variable response to treatment, with 6 of 7 patients trending toward stabilization on motor examination, cognitive scores, and/or MRI abnormalities, especially with white matter lesion burden. Conclusions This is the largest series of patients with CSF1R-related leukoencephalopathy receiving HSCT. We conclude that HSCT can stabilize the disease in some patients. Variability in patient responsiveness suggests that measures of disease heterogeneity and severity need to be considered when evaluating a patient's candidacy for transplant. HSCT appears to be the first disease-modifying therapy for CSF1R-related leukoencephalopathy. This milestone may serve as a foothold toward better understanding the disease's pathomechanism, thus providing new opportunities for better disease-specific therapies. © 2021 International Parkinson and Movement Disorder Society.

There is a need to identify brain connectivity alterations predictive of transdiagnostic processes that may confer vulnerability for affective symptomology. Here, we tested whether amygdala resting-state functional connectivity (rsFC) mediated the relationship between catastrophizing (negative threat appraisals and predicting poorer functioning) and altered threat-safety discrimination learning (critical to flexibly adapt to new and changing environments) in adolescents with persistent pain. We examined amygdala rsFC in 46 youth with chronic pain and 29 healthy peers (age M = 15.8, SD = 2.9; 64 females) and its relationship with catastrophizing and threat-safety learning. We used a developmentally appropriate threat-safety learning paradigm and performed amygdala seed-based rsFC and whole-brain mediation analyses. Patients exhibited enhanced connectivity between the left amygdala and right supramarginal gyrus (SMG) (cluster-level P-FDR < 0.05), whereas right amygdala rsFC showed no group differences. Only in patients, elevated catastrophizing was associated with facilitated threat-safety learning (CS+>CS-; rp = 0.49, P = 0.001). Furthermore, in patients, elevated catastrophizing was associated with reduced left amygdala connectivity with SMG / parietal operculum, and increased left amygdala connectivity with hippocampus, dorsal striatum, paracingulate, and motor regions (P < 0.001). In addition, blunted left amygdala rsFC with right SMG/parietal operculum mediated the association between catastrophizing and threat-safety learning (P < 0.001). To conclude, rsFC between the left amygdala (a core emotion hub) and inferior parietal lobe (involved in appraisal and integration of bodily signals and attentional reorienting) explains associations between daily-life relevant catastrophizing and threat-safety learning. Findings provide a putative model for understanding pathophysiology involved in core psychological processes that cut across diagnoses, including disabling pain, and are relevant for their etiology.

Sodium chloride (NaCl) 23.4% solution has been shown to reduce intracranial pressure (ICP) and reverse transtentorial herniation. A limitation of 23.4% NaCl is its high osmolarity (8008 mOsm/l) and the concern for tissue injury or necrosis following extravasation when administered via peripheral venous access. The use of this agent is therefore often limited to central venous or intraosseous routes of administration. Our objective was to evaluate the safety and efficacy of administration of 23.4% NaCl via peripheral venous access compared with administration via central venous access. We reviewed pharmacy records to identify all administrations of 23.4% NaCl at our institution between December 2017 and February 2020. Medical records were then reviewed to identify complications, such as extravasation, soft tissue injury or necrosis, hypotension (mean arterial pressure less than 65 mm Hg), pulmonary edema, hemolysis, and osmotic demyelination. We also compared the change in physiological variables, such as ICP, mean arterial pressure, cerebral perfusion pressure, and heart rate, as well as laboratory values, such as sodium, chloride, bicarbonate, creatinine, and hemoglobin, following administration of 23.4% NaCl via the peripheral and central venous routes. We identified 299 administrations of 23.4% NaCl (242 central and 57 peripheral) in 141 patients during the study period. There was no documented occurrence of soft tissue injury or necrosis in any patient. One patient developed hypotension following central administration. Among the 38 patients with ICP monitoring at the time of drug administration, there was no significant difference in median ICP reduction (− 13 mm Hg [central] vs. − 24 mm Hg [peripheral], p = 0.21) or cerebral perfusion pressure augmentation (16 mm Hg [central] vs. 15 mm Hg [peripheral], p = 0.87) based on route of administration. Peripheral venous administration of 23.4% NaCl is safe and achieves a reduction in ICP equivalent to that achieved by administration via central venous access.

BACKGROUND: Indoor environments contain a broad diversity of non-pathogenic Basidiomycota yeasts, but their role in exacerbating adverse health effects has remained unclear. OBJECTIVE: To understand the role of Vishniacozyma victoriae exposure and its impact on human health. METHODS: A qPCR assay was developed to detect and quantify an abundant indoor yeast species, Vishniacozyma victoriae (syn. Cryptococcus victoriae), from homes participating in the New York City Neighborhood Asthma and Allergy Study (NAAS). We evaluated the associations between V. victoriae, housing characteristics, and asthma relevant health endpoints. RESULTS: V. victoriae was quantified in 236 of the 256 bedroom floor dust samples ranging from less than 300 to 45,918 cell equivalents/mg of dust. Higher concentrations of V. victoriae were significantly associated with carpeted bedroom floors (P=0.044), mean specific humidity (P=0.004), winter (P

Background Hypophosphatasia (HPP), a rare metabolic disease, can be inherited in an autosomal recessive (biallelic) or an autosomal dominant (monoallelic) manner. Most of the severe, early-onset, frequently lethal HPP in infants is acquired through recessive inheritance; less severe, later-onset, typically nonlethal HPP phenotypes are acquired through either dominant or recessive inheritance. HPP's variable clinical presentation arises from >400 identified ALPL pathogenic variants with likely variable penetrance, especially with autosomal dominant inheritance. This post hoc analysis investigated the relationship between ALPL variant state (biallelic and monoallelic) and clinical outcomes with asfotase alfa in HPP. Methods Data were pooled from two phase 2, randomized, open-label studies in adolescents and adults with HPP; one study evaluated the efficacy and safety of different doses of asfotase alfa (n = 25), and the other assessed the pharmacodynamics and safety of asfotase alfa (n = 19). Patients were grouped by ALPL variant state (biallelic or monoallelic). Available data from both studies included ALPL pathogenic variant state, Baseline characteristics, HPP-specific medical history, and Baseline TNSALP substrate levels (inorganic pyrophosphate [PPi] and pyridoxal 5′-phosphate [PLP]) concentrations). Clinical outcomes over 5 years of treatment were available from only the efficacy and safety study. Results In total, 44 patients with known variant status were included in the pooled analysis (biallelic, n = 30; monoallelic, n = 14). The most common pathogenic variant was c.571G > A (p.Glu191Lys) in biallelic patients (allele frequency: 19/60) and c.1133A > T (p.Asp378Val) in monoallelic patients (allele frequency: 7/28). Median (min, max) Baseline PPi concentrations were significantly higher in patients with a biallelic vs monoallelic variant state (5.3 [2.2, 12.1] vs 4.3 [3.5, 7.4] μM; P = 0.0113), as were Baseline PLP concentrations (221.4 [62.4, 1590.0] vs 75.1 [28.8, 577.0] ng/mL; P = 0.0022). HPP-specific medical history was generally similar between biallelic and monoallelic patients in terms of incidence and type of manifestations; notable exceptions included fractures, which were more common among monoallelic patients, and delayed walking and bone deformities such as abnormally shaped chest and head and bowing of arms or legs, which were more common among biallelic patients. Data from the efficacy and safety study (n = 19) showed that median PPi and PLP concentrations were normalized over 5 years of treatment in patients with both variant states. Median % predicted distance walked on the 6-Minute Walk Test remained within the normal range for monoallelic patients over 4 years of treatment, and improved from below normal ( Conclusions Although patients with biallelic variants had significantly higher Baseline PPi and PLP levels than monoallelic variants, both groups generally showed similar pretreatment Baseline clinical characteristics. Treatment with asfotase alfa for up to 5 years normalized TNSALP substrate concentrations and improved functional outcomes, with no clear differences between biallelic and monoallelic variant states. This study suggests that patients with HPP have significant disease burden, regardless of ALPL variant state.

Background: Whether advances in identification and management of atrial fibrillation and atrial flutter (collectively, AF) have led to improved outcomes is unclear. We sought to study trends in clinical outcomes selected as quality indicators for nonvalvular AF in Canada. Methods: We identified hospitalized patients with a first diagnosis of nonvalvular AF between April 2006 and March 2015, in all of Canada except Quebec. We assessed trends in 1-year incidence of stroke/systemic embolism (SSE), major bleeding, and initial heart failure (HF) hospitalization. Results: The cohort included 466,476 patients. The median age was 77 years (interquartile range, 68-84 years), 46% were female, and 68% had a Congestive Heart Failure, Hypertension, Age (≥75 years), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 years), Sex (Female) (CHA2DS2-VASc) score > 3. Within 1 year of discharge, 3.5% were hospitalized for stroke or SSE, 1.6% for major bleeding, and 8.6% for new HF. Over the study period, the crude rate of SSE declined from 3.6% to 3.3% (P = 0.002), whereas the rates of hospitalization for new HF and for major bleeding did not significantly change. After adjustment for CHA2DS2-VASc score, the yearly rates of incident SSE (risk ratio, 0.99; 95% confidence interval [CI], 0.98-0.99; P = 0.002) and HF (risk ratio, 0.99; 95% CI, 0.99-1.00; P = 0.001) declined ≤ 1% absolute, whereas major bleeding remained unchanged (risk ratio, 1.00; 95% CI, 0.99-1.00; P = 0.28). Conclusions: Among hospitalized patients with nonvalvular AF in Canada, the rate of SSE and new HF decreased modestly over a 10-year period, with no significant change in major bleeding. Efforts to study process-based quality indicators, with increased focus on HF prevention, are needed. Résumé: Contexte: On ne sait pas si les avancées en matière de détection et de prise en charge de la fibrillation auriculaire et du flutter auriculaire (collectivement appelés « FA » ci-après) ont permis d’améliorer les résultats pour les patients. Nous avons donc étudié les tendances à l’égard de résultats cliniques particuliers pris comme indicateurs de qualité relatifs à la FA non valvulaire au Canada. Méthodologie: Nous avons recensé les patients hospitalisés au Canada (sauf au Québec) entre avril 2006 et mars 2015 en raison d’une FA non valvulaire nouvellement diagnostiquée. Nous avons évalué les tendances quant à la survenue d’un accident vasculaire cérébral ou d’une embolie systémique (AVC/ES), d’une hémorragie majeure et d’une première hospitalisation pour insuffisance cardiaque. Résultats: La cohorte comprenait 466 476 patients, dont l’âge médian était de 77 ans (intervalle interquartile : 68 à 84 ans); 46 % des patients étaient des femmes, et 68 % avaient un score CHA2DS2-VASc (Congestive Heart Failure [insuffisance cardiaque congestive], hypertension, âge [≥ 75 ans], diabète, Stroke/Transient Ischemic Attack [AVC/accident ischémique transitoire] – maladie vasculaire, âge [65-74 ans], sexe [femmes]) supérieur à 3. Dans l’année suivant la sortie de l’hôpital, 3,5 % des patients ont été hospitalisés en raison d’un AVC ou d’un AVC/ES, 1,6 %, en raison d’une hémorragie majeure et 8,6 %, en raison d’une nouvelle insuffisance cardiaque. Au cours de la période étudiée, le taux brut d’AVC/ES est passé de 3,6 % à 3,3 % (p = 0,002), tandis que les taux d’hospitalisation en raison d’une nouvelle insuffisance cardiaque ou d’une hémorragie majeure n’ont pas changé de manière significative. Après correction pour tenir compte du score CHA2DS2-VASc, les taux annuels de survenue d’un AVC/ES (rapport des risques de 0,99; intervalle de confiance [IC] à 95 % : de 0,98 à 0,99; p = 0,002) et d’une insuffisance cardiaque (rapport des risques de 0,99; IC à 95 % : de 0,99 à 1,00; p = 0,001) ont diminué de ≤ 1 % en valeur absolue, tandis que le taux de survenue d’une hémorragie majeure n’a pas changé (rapport des risques : 1,00; IC à 95 % : de 0,99 à 1,00; p = 0,28). Conclusions: Parmi les patients hospitalisés au Canada en raison d’une FA non valvulaire, les taux d’AVC/ES et de nouvelle insuffisance cardiaque ont affiché une réduction modeste sur une période de 10 ans, tandis que le taux d’hémorragie majeure n’a pas changé de manière significative. D’autres études évaluant les indicateurs de qualité fondés sur les procédés, notamment en matière de prévention de l’insuffisance cardiaque, s’imposent.

Atrial fibrillation (AF) is the most common arrhythmia in the world. Despite the increasing prevalence, there remains a limited understanding of how the pre-diagnosis symptom experience varies by gender. The purpose of this study was to retrospectively explore gender differences/similarities in the pre-diagnosis period of AF. Twenty-six adults (13 men and 13 women) were interviewed guided by the Symptom Experience in AF (SEAF). Data were analyzed using a two-step approach to thematic analysis. Women had greater challenges receiving a timely diagnosis, with 10 women (77%) experiencing symptoms ≥1 year prior to their diagnosis, in comparison to only three (23%) of the men. Women also reported more severe symptoms, less AF-related knowledge, viewed themselves as low risk for cardiovascular disease, and described how their comorbid conditions confused AF symptom evaluation. This study provides a foundational understanding of differences/similarities in the AF symptom experience by gender.

Background Associations of diet with dilated cardiomyopathy are under investigation. Objectives That cardiac assessment would show abnormalities in healthy dogs eating grain‐free (GF) diets or diets with Food and Drug Administration (FDA)‐listed ingredients of concern (peas, lentils, or potatoes) as top 10 ingredients (FDA‐PLP), but not in dogs eating grain‐inclusive (GI) diets or diets without FDA‐listed ingredients of concern (PLP) in the top 10 ingredients (NoFDA‐PLP). Animals One hundred eighty‐eight healthy Doberman Pinschers, Golden Retrievers, Miniature Schnauzers, and Whippets. Methods This study was an observational cross‐sectional study. Echocardiograms, cardiac biomarkers, and blood and plasma taurine concentrations were compared between dogs eating GF (n = 26) and GI (n = 162) diets, and between FDA‐PLP (n = 39) and NoFDA‐PLP (n = 149) diets, controlling for age and breed. Demographic characteristics, murmurs, genetic status, and ventricular premature complexes (VPCs) during examination were compared between dogs eating different diet types. Results No differences in echocardiographic variables, N‐terminal pro‐B‐type natriuretic peptide or whole blood taurine were noted between dogs eating different diet types. Dogs eating GF diets had higher median high‐sensitivity cardiac troponin I (hs‐cTnI) (GF 0.076 ng/mL [Interquartile range (IQR), 0.028‐0.156] vs. GI 0.048 [IQR, 0.0026‐0.080]; P

Using pre-treatment biomarkers to guide patients to the preferred antidepressant medication treatment could be a promising approach to enhance its current modest response and remission rates. This open-label prospective study assessed the feasibility of using such pre-treatment biomarkers, by using previously identified EEG features (paroxysmal activity; alpha peak frequency; frontal alpha asymmetry) to inform the clinician in selecting among three different antidepressants (ADs; escitalopram, sertraline, venlafaxine) as compared to Treatment As Usual (TAU). EEG data were obtained from 195 outpatients with major depressive disorder prior to eight weeks of AD treatment. Primary outcome measure was the percentage change between before and after treatment on the Beck Depression Inventory-II (BDI-II). We compared TAU and EEG-informed prescription through AN(C)OVAs. Recruitment started with patients receiving TAU to establish baseline effectiveness, after which we recruited patients receiving EEG-informed prescription. 108 patients received EEG-informed prescription and 87 patients received TAU. Clinicians and patients were satisfied with the protocol. Overall, 70 (65%) of the EEG-informed clinicians followed recommendations (compared to 52 (60%) following prescriptions in the TAU group), establishing feasibility. We here confirm that treatment allocation informed by EEG variables previously reported in correlational studies, was feasible.

Nager syndrome epitomizes the acrofacial dysostoses, which are characterized by craniofacial and limb defects. The craniofacial defects include midfacial retrusion, downslanting palpebral fissures, prominent nasal bridge, and micrognathia. Limb malformations typically include hypoplasia or aplasia of radial elements including the thumb. Nager syndrome is caused by haploinsufficiency of SF3B4, encoding a spliceosomal protein called SAP49. Here, we report a patient with a loss of function variant in SF3B4 without acrofacial dysostosis or limb defects, whose reason for referral was developmental and growth delay. This patient is evidence of a broader phenotypic spectrum associated with SF3B4 variants than previously appreciated.

Background: The benefits of pimobendan in the treatment of congestive heart failure (CHF) in cats with hypertrophic cardiomyopathy (HCM) have not been evaluated prospectively. Hypothesis/objectives: To investigate the effects of pimobendan in cats with HCM and recent CHF and to identify possible endpoints for a pivotal study. We hypothesized that pimobendan would be well-tolerated and associated with improved outcome. Animals: Eighty-three cats with HCM and recently controlled CHF: 30 with and 53 without left ventricular outflow tract obstruction. Methods: Prospective randomized placebo-controlled double-blind multicenter nonpivotal field study. Cats received either pimobendan (0.30 mg/kg q12h, n = 43), placebo (n = 39), or no medication (n = 1) together with furosemide (

About half of pediatric blunt trauma patients undergo an abdominopelvic computed tomographic (CT) scan, while few of these require intervention for an intraabdominal injury. We evaluated the effectiveness of an evidence-based guideline for blunt abdominal trauma at a Level I pediatric trauma center.Pediatric blunt trauma patients (n = 998) age 0-15 years who presented from the injury scene were evaluated over a 10 year period. After five years, we implemented our guideline in which the decision for CT was standardized based on mental status, abdominal examination, and laboratory results (alanine aminotransferase, aspartate aminotransferase, hemoglobin, urinalysis).There were no differences in age, GCS, SIPA or ISS scores between the patients before or after guideline implementation. Nearly half of the patients (48.3%) underwent CT scan before guideline implementation compared to 36.7% after (p 0.0002). There was no difference in ISS (p = 0.44) between CT scanned patients in either group. No statistical differences were found in rate of intervention (p = 0.20), length of stay (p = 0.65), or readmission rate (0.2%) before versus after guideline implementation. There were no missed injuries.Implementation of an evidence-based clinical guideline for pediatric patients with blunt abdominal trauma decreases the rate of CT utilization while accurately identifying significant injuries.III.

Low reward responsiveness (RR) is associated with poor psychological well-being, psychiatric disorder risk, and psychotropic treatment resistance. Functional MRI studies have reported decreased activity within the brain's reward network in individuals with RR deficits, however the neurochemistry underlying network hypofunction in those with low RR remains unclear. This study employed ultra-high field glutamate chemical exchange saturation transfer (GluCEST) imaging to investigate the hypothesis that glutamatergic deficits within the reward network contribute to low RR. GluCEST images were acquired at 7.0 T from 45 participants (ages 15-29, 30 females) including 15 healthy individuals, 11 with depression, and 19 with psychosis spectrum symptoms. The GluCEST contrast, a measure sensitive to local glutamate concentration, was quantified in a meta-analytically defined reward network comprised of cortical, subcortical, and brainstem regions. Associations between brain GluCEST contrast and Behavioral Activation System Scale RR scores were assessed using multiple linear regressions. Analyses revealed that reward network GluCEST contrast was positively and selectively associated with RR, but not other clinical features. Follow-up investigations identified that this association was driven by the subcortical reward network and network areas that encode the salience of valenced stimuli. We observed no association between RR and the GluCEST contrast within non-reward cortex. This study thus provides new evidence that reward network glutamate levels contribute to individual differences in RR. Decreased reward network excitatory neurotransmission or metabolism may be mechanisms driving reward network hypofunction and RR deficits. These findings provide a framework for understanding the efficacy of glutamate-modulating psychotropics such as ketamine for treating anhedonia.

The present work aims to morphologically and molecularly characterize an Eimeria sp. recovered from an adult, captive barred owl Strix varia in Mississippi, USA. While the owl was shedding oocysts, no clinical signs of coccidiosis were observed. Oocysts collected from a barred owl, S. varia were isolated from feces by fecal flotation and characterized by light microscopy. The oocysts were allowed to sporulate in K2Cr2O7 for 7 days and measured for comparison with previously described Eimeria species. Genomic DNA was extracted from measured oocysts and the cytochrome c oxidase subunit 1 mitochondrial gene was amplified and sequenced for comparison and phylogenetic analyses with publicly available sequence data. Oocysts collected from S. varia were morphologically and molecularly consistent with all previous accounts of Eimeria megabubonis from the great horned owl Bubo virginianus and morphologically consistent with the only account of Eimeria varia from S. varia. Phylogenetic analyses grouped the E. megabubonis sequence from the present study with previously reported sequences from E. megabubonis. Morphological and molecular data from oocysts collected in this study reveal S. varia is a host for E. megabubonis. Agreement between current data, morphological and molecular data of E. megabubonis, and morphological data from the original description of E. varia indicates E. varia is a junior synonym of E. megabubonis.

Fang Liu-Walsh,1 Neena K Tierney,1 James Hauschild,2 Allison K Rush,1 John Masucci,3 Gregory C Leo,3 Kimberly A Capone1 1Johnson & Johnson Consumer Inc., Skillman, NJ, USA; 2Johnson & Johnson Microbiological Quality & Sterility Assurance, Johnson & Johnson Inc., Raritan, NJ, USA; 3Janssen R&D Companies of Johnson & Johnson, Springhouse, PA, USACorrespondence: Fang Liu-Walsh; Kimberly A CaponeJohnson & Johnson Consumer Inc., 199 Grandview Road, Skillman, NJ 08558-9418, USAEmail fliuwals@ITS.JNJ.com; KCapone@its.jnj.comBackground: Multiple skin conditions have been associated with alterations in the diversity and composition of the skin microbiome, including dry skin and atopic dermatitis. In these conditions, a number of commensal skin bacteria have been implicated in supporting a healthy skin barrier, including Staphylococcus epidermidis. Recent clinical studies in patients with mild-to-moderate atopic dermatitis and dry/itchy skin have shown significantly improved skin barrier function and microbial diversity upon treatment with moisturizers containing 1% colloidal oat. We hypothesized that direct use of colloidal oat by skin microbes contributes to these therapeutic benefits.Methods: Skin bacterial growth was assessed using the BacT/ALERT system. Staphylococcus aureus and S. epidermidis growth rates and metabolism were compared in an in vitro competition assay. The effect of a 1% colloidal oat–containing moisturizer on lactic acid content of the stratum corneum was clinically assessed in subjects with moderate-to-severe dry skin. S. epidermidis gene expression was evaluated by next-generation mRNA sequencing. Short-chain fatty acids were quantified in bacterial culture supernatants.Results: In vitro, colloidal oat increased the growth rate of S. epidermidis vs S. aureus, as well as the metabolism of S. epidermidis. Colloidal oat also significantly increased lactic acid concentrations in supernatants of both strains and decreased pH, consistent with clinical findings that 6-week use of a 1% colloidal oat–containing lotion significantly increased lactic acid on dry skin. Further analyses suggest that colloidal oat alters the gene expression profile of S. epidermidis.Conclusion: Colloidal oat directly affects the growth, metabolism, lactic acid production, and gene expression of skin commensal bacteria, as shown via in vitro studies. The increased production of lactic acid reflects clinical observations with colloidal oat–containing skin moisturizers. Our findings suggest a new mechanism for colloidal oat as a skin prebiotic, which may contribute to improvements in skin and microbiome diversity in various skin conditions, including dry/itchy skin and atopic dermatitis.Keywords: atopic dermatitis, dry skin, colloidal oat, skin barrier function, skin microbiome, skin moisturizer, S. epidermidis

Custom 3D printed total talus implants have been used successfully as a functional alternative to arthrodesis or amputation in cases of severe talar destruction or loss. However, the ideal material and construct still remains to be elucidated. Current models have been made from aluminum ceramic, cobalt chrome, stainless steel, titanium, or metal combinations. The implants may be constrained (subtalar arthrodesis) or unconstrained (press fit within mortise). They may also be combined with a tibial prosthesis or used in isolation. The majority of currently published case studies examine unconstrained and isolated implants. This case study presents satisfactory 1-y outcomes in 3 cobalt chrome constrained total talar implants used in combination with a tibial prosthesis, and a literature review of total talus replacements.

Heterogeneity in the clinical presentation of major depressive disorder and response to antidepressants limits clinicians’ ability to accurately predict a specific patient’s eventual response to therapy. Validated depressive symptom profiles may be an important tool for identifying poor outcomes early in the course of treatment. To derive these symptom profiles, we first examined data from 947 depressed subjects treated with selective serotonin reuptake inhibitors (SSRIs) to delineate the heterogeneity of antidepressant response using probabilistic graphical models (PGMs). We then used unsupervised machine learning to identify specific depressive symptoms and thresholds of improvement that were predictive of antidepressant response by 4 weeks for a patient to achieve remission, response, or nonresponse by 8 weeks. Four depressive symptoms (depressed mood, guilt feelings and delusion, work and activities and psychic anxiety) and specific thresholds of change in each at 4 weeks predicted eventual outcome at 8 weeks to SSRI therapy with an average accuracy of 77% (p = 5.5E-08). The same four symptoms and prognostic thresholds derived from patients treated with SSRIs correctly predicted outcomes in 72% (p = 1.25E-05) of 1996 patients treated with other antidepressants in both inpatient and outpatient settings in independent publicly-available datasets. These predictive accuracies were higher than the accuracy of 53% for predicting SSRI response achieved using approaches that (i) incorporated only baseline clinical and sociodemographic factors, or (ii) used 4-week nonresponse status to predict likely outcomes at 8 weeks. The present findings suggest that PGMs providing interpretable predictions have the potential to enhance clinical treatment of depression and reduce the time burden associated with trials of ineffective antidepressants. Prospective trials examining this approach are forthcoming.

The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway upregulates key cellular defenses. Clinical trials are utilizing pharmacologic Nrf2 inducers such as bardoxolone methyl to treat chronic kidney disease, but Nrf2 activation has been linked to a paradoxical increase in proteinuria. To understand this effect, we examined genetically engineered mice with elevated Nrf2 signaling due to reduced expression of the Nrf2 inhibitor, Kelch-like ECH-associated protein 1 (Keap1). These Keap1FA/FA mice lacked baseline proteinuria but exhibited increased proteinuria in experimental models evoked by adriamycin, angiotensin II, or protein overload. After injury, Keap1FA/FA mice had increased glomerulosclerosis, nephrin disruption and shedding, podocyte injury, foot process effacement, and interstitial fibrosis. Keap1FA/FA mice also had higher daytime blood pressures and lower heart rates measured by radiotelemetry. Conversely, Nrf2 knockout mice were protected from proteinuria. We also examined the pharmacologic Nrf2 inducer CDDO-Im. Compared to angiotensin II alone, the combination of angiotensin II and CDDO-Im significantly increased proteinuria, a phenomenon not observed in Nrf2 knockout mice. This effect was not accompanied by additional increases in blood pressure. Finally, Nrf2 was found to be upregulated in the glomeruli of patients with focal segmental glomerulosclerosis, diabetic nephropathy, fibrillary glomerulonephritis, and membranous nephropathy. Thus, our studies demonstrate that Nrf2 induction in mice may exacerbate proteinuria in chronic kidney disease.

Purpose The Vagus Nerve Stimulation (VNS) Therapy System has been studied for more than 20 years in patients with severe, treatment-resistant, chronic mood disorder, i.e., difficult-to-treat depression (DTD). This review distills some of the implications of this research for future therapeutic trials in this population. Methods A narrative review is provided on VNS in DTD. Protocols for a new, large, sham-controlled trial and a global, longitudinal observational study are described. Results Following encouraging results in open studies, a randomized, masked, sham-controlled trial of VNS for DTD failed to demonstrate an effect on the primary outcome. The negative results may have been partly due to inadequate treatment duration (10 weeks). In long-term observational studies, adjunctive VNS, combined with treatment-as-usual (VNS+TAU), was administered to more than 1100 DTD patients and compared with TAU alone in more than 400 patients. VNS+TAU had superior antidepressant effects, but maximal symptom reduction was often observed after 12 months or longer of stimulation. VNS+TAU had also marked superiority in durability of benefit. Sustained levels of symptom reduction below the traditional cutoff for response (i.e. < 50%) were associated with improved quality of life. Limitations Most comparisons of VNS+TAU and TAU were derived from observational, open label studies. Conclusion The history of VNS in DTD has implications for interventional studies in this population, and perhaps other chronic medical disorders. The slow onset of benefit with VNS necessitates considerably longer controlled observation periods to establish efficacy. Durability of benefit should be routinely incorporated in efficacy assessment. New outcome metrics are needed to both categorically identify clinically meaningful benefit and to integrate information on symptom burden over time.

Cardiac hemangiosarcoma, especially primary, is infrequently reported in the horse and remains a diagnostic challenge because of vague clinical signs and difficulty to reach an antemortem diagnosis. A 17-year-old American Quarter Horse gelding was presented with a history of tongue swelling and secondary aspiration pneumonia. Initial assessment indicated dehydration, and thoracic ultrasound revealed an abnormal structure within the myocardium alongside the previously suspected aspiration pneumonia. A subsequent, complete echocardiogram identified a large, heterogeneous, ill-defined mass invading and replacing the normal myocardium of the right ventricular free wall. Because of lack of improvement the horse was euthanized, and postmortem examination confirmed primary cardiac hemangiosarcoma with no further masses identified in other organs. This case is an unusual presentation of primary cardiac hemangiosarcoma for which echocardiography played a significant role in identifying a cardiac mass.

Background The United States Food and Drug Administration is investigating possible diet‐associated dilated cardiomyopathy (DCM) in dogs and cats. Objectives To retrospectively review DCM cases for signalment, diet information, echocardiographic changes, and survival. Animals Client‐owned dogs (n = 71). Methods Medical records of dogs diagnosed with DCM between January 1, 2014 and September 30, 2018 were reviewed. Dogs were grouped into “traditional” or “nontraditional” diet categories and whether or not diet was changed after diagnosis. Results For dogs eating nontraditional diets, those that had their diets changed had a larger percentage decrease in normalized systolic left ventricular internal dimension (P = .03) and left atrial:aorta ratio (P

Rare genetic diseases preponderantly affect the nervous system causing neurodegeneration to neurodevelopmental disorders. This is the case for both Menkes and Wilson disease, arising from mutations in ATP7A and ATP7B, respectively. The ATP7A and ATP7B proteins localize to the Golgi and regulate copper homeostasis. We demonstrate genetic and biochemical interactions between ATP7 paralogs with the conserved oligomeric Golgi (COG) complex, a Golgi apparatus vesicular tether. Disruption ofDrosophilacopper homeostasis by ATP7 tissue-specific transgenic expression caused alterations in epidermis, aminergic, sensory, and motor neurons. Prominent among neuronal phenotypes was a decreased mitochondrial content at synapses, a phenotype that paralleled with alterations of synaptic morphology, transmission, and plasticity. These neuronal and synaptic phenotypes caused by transgenic expression of ATP7 were rescued by downregulation of COG complex subunits. We conclude that the integrity of Golgi-dependent copper homeostasis mechanisms, requiring ATP7 and COG, are necessary to maintain mitochondria functional integrity and localization to synapses.SIGNIFICANCE STATEMENTMenkes and Wilson disease affect copper homeostasis and characteristically afflict the nervous system. However, their molecular neuropathology mechanisms remain mostly unexplored. We demonstrate that copper homeostasis in neurons is maintained by two factors that localize to the Golgi apparatus, ATP7 and the conserved oligomeric Golgi (COG) complex. Disruption of these mechanisms affect mitochondrial function and localization to synapses as well as neurotransmission and synaptic plasticity. These findings suggest communication between the Golgi apparatus and mitochondria through homeostatically controlled cellular copper levels and copper-dependent enzymatic activities in both organelles.

Background Given increasing incidence of cognitive impairment and dementia, further understanding of modifiable factors contributing to increased healthspan is crucial. Extensive literature provides evidence that physical activity (PA) delays the onset of cognitive impairment; however, it is unclear whether engaging in PA in older adulthood is sufficient to influence progression through cognitive status categories. Method Applying a coordinated analysis approach, this project independently analyzed 14 longitudinal studies (NTotal = 52 039; mean baseline age across studies = 69.9–81.73) from North America and Europe using multistate survival models to estimate the impact of engaging in PA on cognitive status transitions (nonimpaired, mildly impaired, severely impaired) and death. Multinomial regression models were fit to estimate life expectancy (LE) based on American PA recommendations. Meta-analyses provided the pooled effect sizes for the role of PA on each transition and estimated LEs. Results Controlling for baseline age, sex, education, and chronic conditions, analyses revealed that more PA is significantly associated with decreased risk of transitioning from nonimpaired to mildly impaired cognitive functioning and death, as well as substantially longer LE. Results also provided evidence for a protective effect of PA after onset of cognitive impairment (eg, decreased risk of transitioning from mild-to-severe cognitive impairment; increased likelihood of transitioning backward from severe-to-mild cognitive impairment), though between-study heterogeneity suggests a less robust association. Conclusions These results yield evidence for the importance of engaging in PA in older adulthood for cognitive health, and a rationale for motivating older adults to engage consistently in PA.

Improving long‐term kidney transplant outcomes requires novel treatment strategies, including delayed calcineurin inhibitor (CNI) substitution, tested using informative trial designs. An alternative approach to the usual superiority‐based trial is a noninferiority trial design that tests whether an investigational agent is not unacceptably worse than standard of care. An informative noninferiority design, with biopsy‐proven acute rejection (BPAR) as the endpoint, requires determination of a prespecified, evidence‐based noninferiority margin for BPAR. No such information is available for delayed CNI substitution in kidney transplantation. Herein we analyzed data from recent kidney transplant trials of CNI withdrawal and “real world” CNI‐ based standard of care, containing subjects with well‐documented evidence of immune quiescence at 6 months posttransplant—ideal candidates for delayed CNI substitution. Our analysis indicates an evidence‐based noninferiority margin of 13.8% for the United States Food and Drug Administration's composite definition of BPAR between 6 and 24 months posttransplant. Sample size estimation determined that ~225 randomized subjects would be required to evaluate noninferiority for this primary clinical efficacy endpoint, and superiority for a renal function safety endpoint. Our findings provide the basis for future delayed CNI substitution noninferiority trials, thereby increasing the likelihood they will provide clinically implementable results and achieve regulatory approval., This meta‐analysis defines a noninferiority margin to use in the design of a phase II/III delayed calcineurin inhibitor substitution trial in kidney transplantation.

Therapeutic targeting of immune checkpoints has garnered significant attention in the area of cancer immunotherapy, in which efforts have focused in particular on cytotoxic T lymphocyte antigen 4 (CTLA4) and PD1, both of which are members of the CD28 family. In autoimmunity, these same pathways can be targeted to opposite effect: to curb the over-exuberant immune response. The CTLA4 checkpoint serves as an exemplar, whereby CTLA4 activity is blocked by antibodies in cancer immunotherapy and augmented by the provision of soluble CTLA4 in autoimmunity. Here, we review the targeting of co-stimulatory molecules in autoimmune diseases, focusing in particular on agents directed at members of the CD28 or tumour necrosis factor receptor families. We present the state of the art in co-stimulatory blockade approaches, including rational combinations of immune inhibitory agents, and discuss the future opportunities and challenges in this field. Immune activating antibodies that target co-stimulatory molecules have altered the cancer therapy landscape. Here, Walker and colleagues discuss therapies — particularly those that target molecules in the same families as CTLA4 and PD1 or TNF receptor — that inhibit the immune system and are being investigated for the treatment of autoimmune diseases. They describe the future opportunities and challenges for the field, including combination approaches.

BackgroundAtrial fibrillation is a complex condition associated with a broad spectrum of symptoms, coupled with variability in the frequency, duration and severity of symptoms. Early treatment seeking is important to reduce the risk of stroke, heart failure and dementia. Despite the increasing prevalence, there remains a limited understanding of the symptom experience prior to an atrial fibrillation diagnosis, and how these experiences influence treatment-related decisions and time frames.AimsThis qualitative study aimed to explore the symptom experiences of patients receiving an early diagnosis of less than 48 hours and a late diagnosis of 48 hours or more after symptom awareness.MethodsTwenty-six adults were interviewed guided by the symptom experience model. The symptom checklist was used to probe patient’s symptoms further. Data were analysed using a two-step approach to thematic analysis utilising concepts from the symptom experience model.ResultsThe two groups differed in their perception, evaluation and response to symptoms. The early diagnosis group (n = 6) experienced traumatic, severe and persistent symptoms, evoking concern and urgent treatment seeking. Conversely, the late diagnosis group (n = 20) reported more vague, paroxysmal symptoms that were readily ignored, self-theorised as non-illness related, and engaged in non-treatment strategies. Healthy self-perceptions, past experiences, atrial fibrillation knowledge and healthcare provider interactions influenced early or late treatment seeking.ConclusionFor many, the atrial fibrillation pre-diagnosis was a tumultuous period, requiring prolonged periods to recognise symptoms and formulate treatment-seeking responses. This study may promote future research and strategies aimed at facilitating the early identification and response to symptoms among atrial fibrillation patients.

BACKGROUND Racial and ethnic disparities are a barrier in delivery of healthcare across the USA. Care for minority patients tends to be clustered into a small number of providers at minority hospitals, which has been associated with worse clinical outcomes in several conditions. However, the outcomes of treatment in patients with end-stage liver disease (ESLD) at predominately minority hospitals are unknown. We investigated the burden of the problem. METHODS We utilized the nationwide in-patient sample (NIS) to conduct a retrospective nationwide cohort analysis. All patients >18 years of age admitted with ESLD were included in the analysis. A multivariate logistic regression model was used to study the mortality rate among patients with ESLD treated at minority hospitals compared to nonminority hospitals. RESULTS A total of 53 281 467 hospitalizations from the 2008 to 2014 NIS were analyzed. There were 163 470 patients with ESLD that met inclusion criteria. In-hospital mortality rates for all races were 8.0 and 8.1% in black and Hispanic minority hospitals, respectively, compared to 7.3% in nonminority hospitals (P

Tuberculosis (TB)-type 2 diabetes mellitus (T2D) comorbidity is re-emerging as a global public health problem. T2D is a major risk factor for increased susceptibility to TB infection and reactivation leading to higher morbidity and mortality. The pathophysiological mechanisms of T2D contributing to TB susceptibility are not fully understood, but likely involve dysregulated immune responses. In this study, a diet-induced murine model that reflects the cardinal features of human T2D was used to assess the immune responses following an intravenous Mycobacterium tuberculosis (Mtb) infection. In this study, T2D significantly increased mortality, organ bacillary burden and inflammatory lesions compared to non-diabetic controls. Organ-specific pro-inflammatory cytokine responses were dysregulated as early as one day post-infection in T2D mice. Macrophages derived from T2D mice showed reduced bacterial internalization and killing capacity. An early impairment of antimycobacterial functions of macrophages in diabetes is a key mechanism that leads to increased susceptibility of T2D.

Background Patients with a history of opioid use disorder (OUD) tend to have more complications, higher readmission rates, and increased costs following orthopaedic procedures. This study evaluated patients undergoing hallux valgus correction for their odds of increased (1) readmission rates, (2) emergency room (ER) visits, and (3) costs. Methods Patients undergoing hallux valgus corrections with OUD history were identified using a national Medicare administrative claims database of approximately 24 million orthopaedic surgery patients. OUD patients were matched to non–opioid use disorder (NUD) patients in a 1:4 ratio by age, sex, Elixhauser-Comorbidity Index (ECI), diabetes mellitus, hyperlipidemia, hypertension, and tobacco use. The query yielded 6318 patients (OUD = 1276; NUD = 5042) who underwent a hallux valgus correction. Primary outcomes analyzed included odds of 90-day readmission rates, 30-day ER visits, and 90-day episode-of-care costs. Demographics, odds ratios (ORs), ECI, and cost were assessed as appropriate using a Pearson χ2 test, logistic regression, and a t test. A P value Results There were no significant differences in demographics between OUD and NUD patients. OUD patients had higher incidence and odds of 90-day readmission (9.56% vs 6.04%; OR = 1.55; P < .001) and 30-day ER visits (0.86% vs 0.35%; OR = 2.42; P = .021) and incurred greater 90-day episode-of-care costs ($7208.28 vs $6134.75; P < .001) compared with NUD patient controls. Conclusion The study demonstrates the possible influence of OUD on higher odds of readmission, ER visits, and costs following a hallux valgus correction. Levels of Evidence Level III: Retrospective cohort study

To describe changes in hemodynamics, respiratory support, and growth associated with transcatheter PDA closure (TCPC) in ELBW infants, stratified by postnatal age at treatment. This is an observational study of ELBW infants who underwent TCPC at ≤4 weeks (Group-1; n = 34), 4–8 weeks (Group-2; n = 33), and >8 weeks of age (Group-3; n = 33). Hemodynamic assessment was performed during TCPC. Multivariate Cox-proportionate-hazard modeling was used to identify factors associated with respiratory severity score (RSS) > 2 for >30 days following TCPC. In comparison with Group-1, Group-3 infants had higher pulmonary vascular resistance (PVRi = 3.3 vs. 1.6 WU*m2; P = 0.01), less weight gain between 4 and 8 weeks of age (16 vs. 25 g/day) and took longer to achieve RSS 2 for >30 days was associated with TCPC > 8 weeks (OR = 3.2, 95% CI: 1.75–5.8; p = 0.03) and PVRi ≥ 3 (OR = 4.5, 95% CI: 2.7–8.9; p

PURPOSE To evaluate outcome data of patients undergoing DeJour sulcus-deepening trochleoplasty with medial patellofemoral ligament reconstruction (MPFLR) for high-grade trochlear dysplasia at a single institution in the United States. METHODS A total of 67 patients (76 knees) with severe trochlear dysplasia and recurrent patellar instability were prospectively enrolled and underwent DeJour sulcus-deepening trochleoplasty with MPFLR from 2011 to 2019. Inclusion criteria included recurrent lateral patellar instability following failure of conservative treatment with radiographic evidence of severe trochlear dysplasia (DeJour types B or D). Patients with less than 2-year follow-up were excluded. Radiographic analysis, physical examination, clinical follow-up, patient demographics, and patient-reported outcome measures were obtained for all patients at each visit. RESULTS Forty patients (44 knees) had complete 2-year or longer follow-up and were included. The majority of patients were female (81.8%) with a mean age of 19.2 years (standard deviation [SD] 6.7; range 13.2-47.0). Follow-up ranged from 2.0 years to 6.8 years (mean 3.6 years, SD 1.35). In total, 45.5% had failed previous surgery for patellar instability. Eight knees developed arthrofibrosis and the overall reoperation rate was 27.3%. No patients had fixation failure and no further surgery was required for instability. The mean preoperative International Knee Documentation Committee score of 50.8 improved to 79.1 (P < .001), and the mean preoperative Kujala score of 56.4 improved to 86.5 (P < .001). Patients reported high satisfaction rates (mean 9.1 of 10). When applicable, 100% of patients returned to work, whereas 84.8% returned to sport. There was no significant radiographic progression of patellofemoral arthritis at a mean of 2.4 years after surgery (SD 1.7). CONCLUSIONS DeJour sulcus-deepening trochleoplasty combined with MPFLR and used with tibial tubercle osteotomy and lateral release is a reliable and effective treatment for recurrent patellar instability due to severe trochlear dysplasia, even in this group with many revisions of previous procedures. LEVEL OF EVIDENCE IV, case series.

Acute kidney injury (AKI) is a risk factor for the development of chronic kidney disease (CKD). One mechanism for this phenomenon is renal microvascular rarefaction and subsequent chronic impairment in perfusion. However, diagnostic tools to monitor the renal microvasculature in a noninvasive and quantitative manner are still lacking. Ultrasound super-resolution imaging is an emerging technology that can identify microvessels with unprecedented resolution. Here, we applied this imaging technique to identify microvessels in the unilateral ischemia-reperfusion injury mouse model of AKI-to-CKD progression in vivo. Kidneys from 21 and 42 day post- ischemia-reperfusion injury, the contralateral uninjured kidneys, and kidneys from sham-operated mice were examined by ultrasound super-resolution and histology. Renal microvessels were successfully identified by this imaging modality with a resolution down to 32 μm. Renal fibrosis was observed in all kidneys with ischemia-reperfusion injury and was associated with a significant reduction in kidney size, cortical thickness, relative blood volume, and microvascular density as assessed by this imaging. Tortuosity of the cortical microvasculature was also significantly increased at 42 days compared to sham. These vessel density measurements correlated significantly with CD31 immunohistochemistry (R(2)=0.77). Thus, ultrasound super-resolution imaging provides unprecedented resolution and is capable of noninvasive quantification of renal vasculature changes associated with AKI-to-CKD progression in mice. Hence, this technique could be a promising diagnostic tool for monitoring progressive kidney disease.

OBJECTIVES: Children with medical complexity (CMC) have an increased risk of adverse events after hospital discharge. Authors of previous studies have evaluated discharge communication practices with primary care providers (PCPs) in adults and general pediatric patients. There is a lack of evidence surrounding hospitalist communication practices at discharge for CMC. In this study, we explore hospitalist-to-PCP communication for CMC at hospital discharge. METHODS: A retrospective chart review was performed at a single tertiary care children’s hospital. The population included patients with ≥1 complex chronic condition who were discharged from the pediatric hospitalist team. The presence, type, and quality of discharge communication were collected. A descriptive analysis in which we used χ2, t test, Wilcoxon rank testing, and odds ratios was conducted to identify differences in communication practices in CMC. RESULTS: We identified 368 eligible patients and reviewed their electronic medical records. Discharge communication was documented for 59% of patient encounters. Communication was less likely to occur for patients with technology dependence (P = .01), older patients (P = .02), and those who were admitted to a teaching service (P = .04). The quality of discharge summaries did not change for patients with technology dependence compared with patients without technology dependence. CONCLUSIONS: Communication with the PCP at discharge was less likely to be documented in children with technology dependence. Hospitalists may encounter barriers in completion of appropriate and timely discharge communication with PCPs for CMC. Consistent handoff processes could be used to improve care for our patients with enhanced coordination needs.