Emergence of zoonotic sporotrichosis in Brazil: a genomic epidemiology study.

BACKGROUND: Zoonotic sporotrichosis is a neglected fungal disease, whereby outbreaks are primarily driven by Sporothrix brasiliensis and linked to cat-to-human transmission. To understand the emergence and spread of sporotrichosis in Brazil, the epicentre of the current epidemic in South America, we aimed to conduct whole-genome sequencing (WGS) to describe the genomic epidemiology. METHODS: In this genomic epidemiology study, we included Sporothrix spp isolates from sporotrichosis cases from Brazil, Colombia, and the USA. We conducted WGS using Illumina NovaSeq on isolates collected by three laboratories in Brazil from humans and cats with sporotrichosis between 2013 and 2022. All isolates that were confirmed to be Sporothrix genus by internal transcribed spacer or beta-tubulin PCR sequencing were included in this study. We downloaded eight Sporothrix genome sequences from the National Center for Biotechnology Information (six from Brazil, two from Colombia). Three Sporothrix spp genome sequences from the USA were generated by the US Centers for Disease Control and Prevention as part of this study. We did phylogenetic analyses and correlated geographical and temporal case distribution with genotypic features of Sporothrix spp isolates. FINDINGS: 72 Sporothrix spp isolates from 55 human and 17 animal sporotrichosis cases were included: 67 (93%) were from Brazil, two (3%) from Colombia, and three (4%) from the USA. Cases spanned from 1999 to 2022. Most (61 [85%]) isolates were S brasiliensis, and all were reported from Brazil. Ten (14%) were Sporothrix schenckii and were reported from Brazil, USA, and Colombia. For S schenckii isolates, two distinct clades were observed wherein isolates clustered by geography. For S brasiliensis isolates, five clades separated by more than 100 000 single-nucleotide polymorphisms were observed. Among the five S brasiliensis clades, clades A and C contained isolates from both human and cat cases, and clade A contained isolates from six different states in Brazil. Compared with S brasiliensis isolates, larger genetic diversity was observed among S schenckii isolates from animal and human cases within a clade. INTERPRETATION: Our results suggest that the ongoing epidemic driven by S brasiliensis in Brazil represents several, independent emergence events followed by animal-to-animal and animal-to human transmission within and between Brazilian states. These results describe how S brasiliensis can emerge and spread within a country. FUNDING: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil; the São Paulo Research Foundation; Productivity in Research fellowships by the National Council for Scientific and Technological Development, and Ministry of Science and Technology of Brazil.

Impaired Interleukin-15 Signaling via BMPR2 Loss Drives Natural Killer Cell Deficiency and Pulmonary Hypertension.

BACKGROUND: Natural killer (NK) cell impairment is a feature of pulmonary arterial hypertension (PAH) and contributes to vascular remodeling in animal models of disease. Although mutations in BMPR2, the gene encoding the BMP (bone morphogenetic protein) type-II receptor, are strongly associated with PAH, the contribution of BMPR2 loss to NK cell impairment remains unknown. We explored the impairment of IL (interleukin)-15 signaling, a central mediator of NK cell homeostasis, as both a downstream target of BMPR2 loss and a contributor to the pathogenesis of PAH. METHODS: The expression, trafficking, and secretion of IL-15 and IL-15Rα (interleukin 15 α-type receptor) were assessed in human pulmonary artery endothelial cells, with or without BMPR2 silencing. NK cell development and IL-15/IL-15Rα levels were quantified in mice bearing a heterozygous knock-in of the R899X-BMPR2 mutation (bmpr2+/R899X). NK-deficient Il15-/- rats were exposed to the Sugen/hypoxia and monocrotaline models of PAH to assess the impact of impaired IL-15 signaling on disease severity. RESULTS: BMPR2 loss reduced IL-15Rα surface presentation and secretion in human pulmonary artery endothelial cells via impaired trafficking through the trans-Golgi network. bmpr2+/R899X mice exhibited a decrease in NK cells, which was not attributable to impaired hematopoietic development but was instead associated with reduced IL-15/IL-15Rα levels in these animals. Il15-/- rats of both sexes exhibited enhanced disease severity in the Sugen/hypoxia model, with only male Il15-/- rats developing more severe PAH in response to monocrotaline. CONCLUSIONS: This work identifies the loss of IL-15 signaling as a novel BMPR2-dependent contributor to NK cell impairment and pulmonary vascular disease.

Is positron emission tomography/magnetic resonance imaging a reliable tool for detecting vascular activity in treated childhood-onset Takayasu's arteritis? A multicentre study.

OBJECTIVES: Toassess whether 18F-fluordeoxiglucose (18F-FDG) PET/MRI) with angiographic sequences can contribute to detecting vessel wall inflammation in patients with childhood-onset Takayasu's arteritis (c-TA) under immunosuppressive therapy. METHODS: A three-centre cross-sectional study was conducted. 18F-FDG PET/MRI scans were performed in c-TA patients and in oncologic patients, who served as the control group. Clinical and laboratory characteristics were also analysed. RESULTS: Seventeen c-TA patients (65% females) between the ages of 6 and 21 years with a mean disease duration of 9.4 years were recruited. Only one patient presented clinical disease activity and six (35.6%) had increased ESR and/or CRP levels. The most frequent magnetic resonance angiography (MRA) findings were stenosis and thickening, observed in 82.4 and 70.6% of c-TA patients, respectively. 18F-FDG PET revealed 18F-FDG uptake greater than the liver in at least one arterial segment in 15 (88.2%) patients in a qualitative analysis and a median maximum standardized uptake value (SUVmax) of 3.22 (interquartile range 2.76-3.69) in a semi-quantitative analysis. c-TA patients presented significantly higher SUVmax values than oncologic patients (P < 0.001). A positive correlation between SUVmax and CRP levels (ρ = 0.528, P = 0.029) was seen. CONCLUSION: A state-of-the-art imaging modality was used in c-TA patients and revealed a strong arterial FDG uptake even in patients in apparent remission. We suppose that this finding may represent silent activity in the vessel wall; however, we cannot exclude the possibility of arterial remodelling. Importantly, a negative imaging scan may help in immunosuppression withdrawal in daily clinical practice.

Endothelial BMPR2 Loss Drives a Proliferative Response to BMP (Bone Morphogenetic Protein) 9 via Prolonged Canonical Signaling.

OBJECTIVE: Pulmonary arterial hypertension is a disease of proliferative vascular occlusion that is strongly linked to mutations in BMPR2-the gene encoding the BMPR-II (BMP [bone morphogenetic protein] type II receptor). The endothelial-selective BMPR-II ligand, BMP9, reverses disease in animal models of pulmonary arterial hypertension and suppresses the proliferation of healthy endothelial cells. However, the impact of BMPR2 loss on the antiproliferative actions of BMP9 has yet to be assessed. Approach and Results: BMP9 suppressed proliferation in blood outgrowth endothelial cells from healthy control subjects but increased proliferation in blood outgrowth endothelial cells from pulmonary arterial hypertension patients with BMPR2 mutations. This shift from growth suppression to enhanced proliferation was recapitulated in control human pulmonary artery endothelial cells following siRNA-mediated BMPR2 silencing, as well as in mouse pulmonary endothelial cells isolated from endothelial-conditional Bmpr2 knockout mice (Bmpr2EC-/-). BMP9-induced proliferation was not attributable to altered metabolic activity or elevated TGFß (transforming growth factor beta) signaling but was linked to the prolonged induction of the canonical BMP target ID1 in the context of BMPR2 loss. In vivo, daily BMP9 administration to neonatal mice impaired both retinal and lung vascular patterning in control mice (Bmpr2EC+/+) but had no measurable effect on mice bearing a heterozygous endothelial Bmpr2 deletion (Bmpr2EC+/-) and caused excessive angiogenesis in both vascular beds for Bmpr2EC-/- mice. CONCLUSIONS: BMPR2 loss reverses the endothelial response to BMP9, causing enhanced proliferation. This finding has potential implications for the proposed translation of BMP9 as a treatment for pulmonary arterial hypertension and suggests the need for focused patient selection in clinical trials.

Laparoscopic sleeve gastrectomy versus laparoscopic Roux-en-Y gastric bypass in the pediatric population: a MBSAQIP analysis.

BACKGROUND: The growing prevalence of childhood obesity has resulted in an increased number of children and adolescents who undergo bariatric surgery. The safety of laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB) remains controversial in the pediatric population. OBJECTIVE: To assess the safety of LSG compared with LRYGB in patients aged ≤21 years. SETTING: A retrospective analysis of the 2016 to 2017 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database. METHODS: Patients aged ≤21 years who underwent LSG or LRYGB were identified in the 2016 to 2017 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database. A logistic regression model was used to create a 1:1 propensity-score matched cohort adjusting for age, sex, body mass index, and obesity-related co-morbidities. Unmatched and propensity-score matched analyses were performed to compare baseline characteristics and outcome data between LSG and LRYGB procedure groups. Primary outcomes of interest included 30-day major complications, such as death, reoperation, and anastomotic leak. RESULTS: Of 3571 patients included in our study, 2911 (81.52%) underwent LSG and 660 (18.48%) underwent LRYGB. Patients who underwent LRYGB had an increased body mass index and a higher rate of obesity-related co-morbidities. The LRYGB group had a significantly increased rate of major complications within the first 30 days in both the unmatched cohort (4.55% versus 1.34%, P < .001) and the propensity-score matched cohort (4.57% versus .91%, P < .001). CONCLUSIONS: LSG and LRYGB are both relatively safe to perform in the pediatric population with acceptable complication rates and low mortality. However, LSG demonstrated a significantly decreased rate of major complications in the first 30 days compared with LRYGB.

Variations in Nationwide Readmission Patterns after Umbilical Hernia Repair.

Up to one in three readmissions occur at a different hospital and are thus missed by current quality metrics. There are no national studies examining 30-day readmission, including to different hospitals, after umbilical hernia repair (UHR). We tested the hypothesis that a large proportion were readmitted to a different hospital, that risk factors for readmission to a different hospital are unique, and that readmission costs differed between the index and different hospitals. The 2013 to 2014 Nationwide Readmissions Database was queried for patients admitted for UHR, and cost was calculated. Multivariate logistic regression identified risk factors for 30-day readmission at index and different hospitals. There were 102,650 admissions for UHR and 8.9 per cent readmissions, of which 15.8 per cent readmissions were to a different hospital. The most common reason for readmission was infection (25.8%). Risk factors for 30-day readmission to any hospital include bowel resection, index admission at a for-profit hospital, Medicare, Medicaid, and Charlson Comorbidity Index ≥ 2. Risk factors for 30-day readmission to a different hospital include elective operation, drug abuse, discharge to a skilled nursing facility, and leaving against medical advice. The median cost of initial admission was higher in those who were readmitted ($16,560 [$10,805-$29,014] vs $11,752 [$8151-$17,724], P < 0.01). The median cost of readmission was also higher among those readmitted to a different hospital ($9826 [$5497-$19,139] vs $9227 [$5211-$16,817], P = 0.02). After UHR, one in six readmissions occur at a different hospital, have unique risk factors, and are costlier. Current hospital benchmarks fail to capture this subpopulation and, therefore, likely underestimate UHR readmissions.

Safety and Feasibility of a Lower-Cost Stapler in Bariatric Surgery.

BACKGROUND: Laparoscopic staplers are integral to bariatric surgery. Their pricing significantly impacts the overall cost of procedures. An independent device company has designed a stapler handle and single-use reloads for cross-compatibility and equivalency with existing manufacturers, at a lower cost. OBJECTIVES: We aim to demonstrate non-inferior function and cross-compatibility of a newly introduced stapler handle and reloads compared to our institution's current stapling system in a large animal survival study. SETTING: University-affiliated animal research facility, USA. METHODS: Matched small bowel anastomoses were created in four pigs, one with each stapler (a total of two per animal). After 14 days, investigators blinded to stapler type evaluated the anastomoses grossly and microscopically. Each anastomosis was scored on multiple measures of healing. Individual parameters were added for a global "healing score." RESULTS: Clinical stapler function and gross quality of anastomoses were similar between stapler groups. Individual scores for anastomotic ulceration, reepithelialization, granulation tissue, mural healing, eosinophilic infiltration, serosal inflammation, and microscopic adherences were also statistically similar. The mean "healing scores" were equal. While this study was underpowered for subtle differences, safe and reliable performance in large animals still supports the feasibility of introducing new devices into human use. CONCLUSIONS: The new stapler system delivers a similar technical performance and is cross-compatible with currently marketed stapling devices. An equivalent quality device at a lower price point should enable case cost reduction, helping to maintain hospital case margin and procedure value in the face of potentially declining reimbursement. This device may provide a safe and functional alternative to currently used laparoscopic surgical staplers.

NHS Diabetes guideline for the perioperative management of the adult patient with diabetes.

These Joint British Diabetes Societies guidelines, commissioned by NHS Diabetes, for the perioperative management of the adult patient undergoing surgery are available in full in the Supporting Information. This document goes through the seven stages of the patient journey when having surgery. These are: primary care referral; surgical outpatients; preoperative assessment; hospital admission; surgery; post-operative care; discharge. Each stage is given its own considerations, outlining the roles and responsibilities of each group of healthcare professionals. The evidence base for the recommendations made at each stage, discussion of controversial areas and references are provided in the report. This document has two key recommendations. Firstly, that the management of the elective adult surgery patients should be with modification to their usual diabetes treatment if the fasting is minimized because the routine use of a variable rate intravenous insulin infusion is not recommended. Secondly, that poor preoperative glycaemic control leads to post-outcomes and thus, where appropriate, needs to be addressed prior to referral for surgery.

Joint British Diabetes Societies guideline for the management of diabetic ketoacidosis.

The Joint British Diabetes Societies guidelines for the management of diabetic ketoacidosis (these do not cover Hyperosmolar Hyperglycaemic Syndrome) are available in full at: (i) http://www.diabetes.org.uk/About_us/Our_Views/Care_recommendations/The-Management-of-Diabetic-Ketoacidosis-in-Adults; (ii) http://www.diabetes.nhs.uk/publications_and_resources/reports_and_guidance; (iii) http://www.diabetologists-abcd.org.uk/JBDS_DKA_Management.pdf. This article summarizes the main changes from previous guidelines and discusses the rationale for the new recommendations. The key points are: Monitoring of the response to treatment (i) The method of choice for monitoring the response to treatment is bedside measurement of capillary blood ketones using a ketone meter. (ii) If blood ketone measurement is not available, venous pH and bicarbonate should be used in conjunction with bedside blood glucose monitoring to assess treatment response. (iii) Venous blood should be used rather than arterial (unless respiratory problems dictate otherwise) in blood gas analysers. (iv) Intermittent laboratory confirmation of pH, bicarbonate and electrolytes only. Insulin administration (i) Insulin should be infused intravenously at a weight-based fixed rate until the ketosis has resolved. (ii) When the blood glucose falls below 14 mmol/l, 10% glucose should be added to allow the fixed-rate insulin to be continued. (iii) If already taking, long-acting insulin analogues such as insulin glargine (Lantus(®), Sanofi Aventis, Guildford, Surry, UK) or insulin detemir (Levemir(®), Novo Nordisk, Crawley, West Sussex, UK.) should be continued in usual doses. Delivery of care (i) The diabetes specialist team should be involved as soon as possible. (ii) Patients should be nursed in areas where staff are experienced in the management of ketoacidosis.

Systems biology of the neurospora biological clock.

A major challenge of systems biology is explaining complex traits, such as the biological clock, in terms of the kinetics of macromolecules. The clock poses at least four challenges for systems biology: (i) identifying the genetic network to explain the clock mechanism quantitatively; (ii) specifying the clock's functional connection to a thousand or more genes and their products in the genome; (iii) explaining the clock's response to light and other environmental cues; and (iv) explaining how the clock's genetic network evolves. Here, the authors illustrate an approach to these problems by fitting an ensemble of genetic networks to microarray data derived from oligonucleotide arrays with approximately all 11 000 Neurospora crassa genes represented. A promising genetic network for the clock mechanism is identified.

Low energy availability, not exercise stress, suppresses the diurnal rhythm of leptin in healthy young women.

Because the effect of exercise on leptin was not established, we controlled energy intake (I) and exercise energy expenditure (E) to distinguish the independent effects of energy availability (A = I - E) and exercise stress (everything associated with exercise except its energy cost) on the diurnal leptin rhythm in healthy young women. In random order, we set A = 45 and 10 kcal. kg lean body mass(-1) (LBM) x day(-1) for 4 days during the early follicular phase of separate menstrual cycles in sedentary (S, n = 7) and exercising (X, n = 9: E = 30 kcal x kg LBM(-1) x day(-1)) women. Low energy availability suppressed the 24-h mean (P < 10(-6)) and amplitude (P < 10(-5)), whereas exercise stress did not (both P > 0.2). Suppressions of the 24-h mean (-72 +/- 3 vs. -53 +/- 3%, P < 0.001) and amplitude (-85 +/- 3 vs. -58 +/- 6%, P < 0.001) were more extreme in S vs. X than previously reported effects on luteinizing hormone pulsatility and carbohydrate availability. Thus the diurnal rhythm of leptin depends on energy, or carbohydrate, availability, not intake, and exercise has no suppressive effect on the diurnal rhythm of leptin beyond the impact of its energy cost on energy availability.

The Robert Tiffany Lectureship. Vital signs at the millennium: becoming more than we are.

Presenting this lecture named for my colleague, the late Robert Tiffany, is an honor. He was part of the first International Conference on Cancer Nursing 20 years ago, which was my first international meeting. It was part of what expanded our Texas--only cancer prevention and detection program for nurses into an international effort. Lessons acquired through this work in the past include learning to respect and honor cultural differences, adapting control programs to the resources at hand, accepting a role as a leader and being an agent for change, and passing on what has been learned to others. The challenges of today include the worldwide death and disability toll of lung cancer, the threat of breast cancer and the promise of regular screening to lower its morbidity and mortality, and the hope that a willingness to adapt screening for cervical cancer in developing countries will lower its mortality rate. Twenty years in the future we can expect nurses to remain educators, exemplars, and agents of change; cancer prevention and early detection to rise in the hierarchy of care; continued collaborative care between physicians and nurses; enhanced patient care through information access; and a larger role for cancer genetics in nursing practice.

Outcomes study of a course in breast-cancer screening.

BACKGROUND: The Breast Cancer Screening Module is a professional training course within the Professional Education for Prevention and Early Detection (PEPED) program at the University of Texas M. D. Anderson Cancer Center. An outcomes study was done to determine the module's ability to improve screening practices crucial to breast-cancer control. METHODS: The five-day course combines 17 hours of class work with 20 hours of hands-on clinical training. Subjects were followed for one year post-training. Six outcome areas were evaluated: 1) knowledge about breast-cancer prevention; 2) clinical skills; 3) changes in routine practice; 4) numbers of patients screened, referred, and diagnosed; 5) trainee satisfaction with the course; and 6) barriers to implementing screening in routine practice. The study population was 63 subjects (all nurse professionals). RESULTS: Outcomes were positive in all six evaluation areas-significant gains in general and clinical knowledge tests (p < or = 0.05); a significant increase from 54.2% pre-training to 70.5% post-training in risk counseling (p < or = 0.05); a sustained increase in screening practices (4.3 times and 2.8 times greater at 6 and 12 months post-training, respectively); 72% rate of high course satisfaction; and barriers to improved screening practices, such as time limitations among 60.4% of subjects and 57.6% of their employers, were identified. CONCLUSIONS: This unique training enhances breast-cancer prevention and screening practices and early detection.

Screening rural and suburban children with the Preschool Language Scale.

A population of 528 Nebraska 4- and 5-year-old boys and girls, 214 rural children and 214 suburban children residing in the same school district in the rural-suburban interface west of metropolitan Omaha, were administered the Preschool Language Scale (PLS) to help determine future eligibility for kindergarten placement and possible remedial services. Rural and suburban cultures led to significantly different performance profiles on the PLS. Language ability was overestimated as both groups scored above age level using the age equivalency tables and performance quotients published for the Preschool Language Scale. Also, a significantly higher percentage of rural children failed a wide age range of Verbal Ability and Auditory Comprehension items. Differences were disproportionately due to Verbal Ability test items requiring the rural child to use responsive verbalized language. The PLS did not consistently satisfy criteria for culturally nonbiased, ecologically valid assessment.