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BACKGROUND OBJECTIVES: Human milk (HM) is better tolerated than formula in preterm infants. Insulin, which is naturally present in HM but not in formula, has been suggested as a key factor for feeding tolerance, as it appears to stimulate intestinal maturation. Its precise concentrations during the early postnatal period, however, remains unknown. The objective of this study was to assess the natural timecourse of the HM insulin concentration during the first ten days postpartum. The effect of preterm delivery, maternal obesity, and diurnal rhythm were also assessed. METHOD: HM was collected from 31 non-diabetic mothers (21 preterm [gestational age (GA)

BACKGROUND Rheumatology is considered a low-risk specialty, but studies have shown a prevalence of burnout between 42% and 51%. OBJECTIVES The aim was to determine the prevalence of burnout in rheumatologists in Latin America and the factors associated with it. METHODS Cross-sectional study based on a survey completed through Google Forms platform that was sent by the national rheumatology associations of Latin America. Burnout was assessed with the Maslach Burnout Inventory. Data were analyzed using the statistical program SPSS v.22. RESULTS Two hundred ninety-seven rheumatologists from 15 countries were included, mainly Argentina (28.3%), Brazil (26.3%), and Mexico (12.8%). The majority were women 62%, 42.4% worked in public hospitals with an average of 40.1 ± 14.2 hours per week; 31.3% did research, 13.1% clinical trials, 56.6% teaching, and 42.8% administrative work; 36% received an annual income less than $25,000; 56.6% had burnout in at least 1 dimension. Only 20.2% thought they had burnout, 9.1% were currently receiving professional help, and 15.8% had sought help in the past; 72.1% said they were willing to participate in a program to reduce burnout. The rheumatologists with burnout were younger than those without burnout (46.5 vs 49.9 years, p = 0.015). CONCLUSIONS Burnout affects near half of rheumatologists in Latin America and was associated with younger age, long working hours, low satisfaction, less happiness, higher Patient Health Questionnaire-9, suicidal thoughts, anxiety, income, presence of comorbidities, and low self-esteem.

Feeding preterm infants with mother’s own milk is associated with a reduction in postnatal complications and an improved neurocognitive outcome. Therefore, the bioactive factor composition of human milk has been used as a tool for the development of nutritional supplements with a potential prophylactic or therapeutic effect. The aim of this systematic review was to provide an overview on bioactive factors which have been studied as supplement to enteral nutrition in randomized controlled trials, and to provide an overview of ongoing trials. MEDLINE, EMBASE, CENTRAL, and clinical trial registers were searched. Studies on the antimicrobial protein lactoferrin were excluded as these were summarized very recently in three separate systematic reviews. Studies on vitamins D, K and iron were also excluded as they are already incorporated in most international guidelines. We identified 17 different bioactive factors, which were investigated in 26 studies. Despite the encouraging potential effects of several bioactive factors, more high-quality studies with a sufficient number of preterm infants are required before a certain factor may be implemented into clinical practice. Three large trials (n > 500) that investigate the effects of either enteral insulin or vitamin A are currently ongoing and could provide more definite answers on these specific supplements.

Introduction Disability in RA is associated with loss of workdays, greater use of health resources and a higher prevalence of depression. The purpose of this study was to determine the prevalence of functional disability and the factors associated with it. Methods A cross-sectional study was carried out during January-June 2019 at a rheumatology clinic in the city of Guayaquil. Patients with pre-established RA were included. Functional disability was measured using the HAQ-DI. Data were analyzed using the statistical program SPSS v22. We compared characteristics between patients with and without disability using Student's t-test and chi-square. A multiple logistic regression model for functional disability was made. Results We included 395 patients, 87.8% female and 12.2% male with a mean age of 51.4±12 years and mean duration of disease 13.8±7 years. Most patients had extra-articular manifestations (80.8%) and comorbidities (81.3%). The mean HAQ-DI was 0.8±0.9, with a prevalence of disability of 26.6%. We found a statistically significant relationship between disability and female sex (p=0.018), age (p=0.020), presence of extra-articular manifestations (p=0.008), myalgia (p

International audience; Pandemics are difficult times for the mental health of healthcare professionals, who are more likely to present with PTSD-like symptoms. In the context of a highly contagious communicable disease, telemedicine is a useful alternative to usual care, and should be considered as a means to support healthcare professionals’ mental health. This is a multicenter (n = 19), cross-sectional study, based on a 27-item questionnaire, aiming to investigate the acceptability to healthcare workers of a telepsychiatry service as a means of providing mental health support during the COVID-19 pandemic. Between October and December 2020, 321 responses were received, showing that women, caregiving staff, and those directly involved in the care of COVID-19 patients are less favorable to the idea of receiving remote support. In our population, barriers were related to the clinical setting or ethics, and most of the respondents would not accept a drug prescription by telepsychiatry. Although telepsychiatry should be a part of the armamentarium of mental health management, it is not suitable as a stand-alone approach, and should be combined with conventional face-to-face consultations.

In the development of cancer therapeutics, no suitable replacements for the use of animals that are capable of modeling such complex disease processes are currently available. In orthotopic models, surgery is often required to access the target organ for tumor cell inoculation. Historically analgesics have been withheld in such models in light of potential effects on tumor development. The current study evaluated the effect of the opioid buprenorphine on tumor growth of a human ovarian cancer cell line (OVCAR5 OT luc2 mCherry). Female CB17 SCID mice (n = 150) underwent surgery for orthotopic inoculation and were assigned to 1 of 3 treatment groups: vehicle control, 1 dose of buprenorphine, or 2 doses of buprenorphine administered perioperatively. Bioluminescence imaging revealed no significant difference on tumor engraftment rate or growth between control and analgesia-treated groups. These data demonstrate that acute, perioperative analgesia with buprenorphine did not alter tumor growth. Although further research is needed to evaluate potential effects of buprenorphine in other cell lines and mouse strains, the justification for withholding analgesia and the potential influence of pain and stress due to insufficient analgesia in these models should be considered thoroughly.

Summary Background Few large projects have evaluated the factors that influence the HIV RNA concentrations (viral load) in cerebrospinal fluid (CSF) during antiretroviral therapy (ART) over time. We aimed to determine the correlates of HIV RNA in CSF in a large cohort. Methods We analysed longitudinal data from adults living with HIV in the US CHARTER cohort. Participants in the CHARTER study were recruited from six US academic medical centres—in Baltimore (MD), Galveston (TX), New York (NY), St Louis (MO), San Diego (C92A), and Seattle (WA). Participants in this study had been assessed at least three times between Sept 4, 2003, and Sept 14, 2010, and were taking ART and underwent venous and lumbar puncture with measurement of HIV RNA concentration at all assessments. The lower limit of quantification of the HIV RNA assays was 50 copies per mL. Data were analysed with longitudinal mixed effects logistic regression to identify correlates of HIV RNA concentration (as a binary [detectable or not] and as a continuous variable) in CSF over time. We tested demographic characteristics, plasma HIV RNA, nadir and current CD4 cell count in blood, current CD8 cell count in blood, estimated duration of HIV infection, AIDS diagnosis, duration of ART, adherence to ART, ART characteristics, and CSF characteristics as potential correlates. Findings At the time of analysis, 2207 assessments from 401 participants met the criteria for inclusion in this study. Mean duration of observation was 33·7 months (range 12–84). HIV RNA concentrations in 710 (32·2%) plasma specimens and in 255 (11·6%) CSF specimens were greater than the lower limit of quantification. The best multivariate model of HIV RNA concentration in CSF greater than the lower limit of quantification over time included increased plasma HIV RNA concentration (odds ratio 18·0 per 1 log10 copy per mL, 95% CI 11·3 to 28·8; p Interpretation The identified correlates of HIV RNA concentration in CSF during ART could strengthen clinical prediction of risk for failure to achieve or maintain HIV RNA suppression in CSF. Because most participants in this analysis were ART-experienced and were taking a three-drug regimen that did not include an integrase inhibitor, future research should focus on participants who are taking their first ART regimens or regimens that include integrase inhibitors or two drugs. Funding The work was supported by the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.

Airborne pollen monitoring is of global socio-economic importance as it provides information on presence and prevalence of allergenic pollen in ambient air. Traditionally, this task has been performed by microscopic investigation, but novel techniques are being developed to automate this process. Among these, DNA metabarcoding has the highest potential of increasing the taxonomic resolution, but uncertainty exists about whether the results can be used to quantify pollen abundance. In this study, it is shown that DNA metabarcoding using trnL and nrITS2 provides highly improved taxonomic resolution for pollen from aerobiological samples from the Netherlands. A total of 168 species from 143 genera and 56 plant families were detected, while using a microscope only 23 genera and 22 plant families were identified. NrITS2 produced almost double the number of OTUs and a much higher percentage of identifications to species level (80.1%) than trnL (27.6%). Furthermore, regressing relative read abundances against the relative abundances of microscopically obtained pollen concentrations showed a better correlation for nrITS2 (R2 = 0.821) than for trnL (R2 = 0.620). Using three target taxa commonly encountered in early spring and fall in the Netherlands (Alnus sp., Cupressaceae/Taxaceae and Urticaceae) the nrITS2 results showed that all three taxa were dominated by one or two species (Alnus glutinosa/incana, Taxus baccata and Urtica dioica). Highly allergenic as well as artificial hybrid species were found using nrITS2 that could not be identified using trnL or microscopic investigation (Alnus × spaethii, Cupressus arizonica, Parietaria spp.). Furthermore, perMANOVA analysis indicated spatiotemporal patterns in airborne pollen trends that could be more clearly distinguished for all taxa using nrITS2 rather than trnL. All results indicate that nrITS2 should be the preferred marker of choice for molecular airborne pollen monitoring., Graphical abstract Unlabelled Image, Highlights • DNA successfully extracted from microscopic pollen slides and Burkard-collected tapes. • nrITS2 and trnL DNA metabarcoding improves taxonomic resolution of airborne pollen. • Relative read abundance nrITS2 shows higher correlation with pollen counts than trnL. • Finer scale spatiotemporal patterns in pollen trends detected using nrITS2. • Detection of artificial hybrid (Alnus × spaethii) that significantly prolongs hay fever season

Objectives Drugs with anticholinergic properties are associated with an increased prevalence of delirium, especially in older persons. The aim of this study was to evaluate the association between the use of this class of drugs in nursing home (NH) patients and prevalence of delirium, particularly in people with dementia. Design Cross-sectional multicenter study. Setting and participants 3924 nursing home patients of 57 nursing homes in 7 European countries participating in the Services and Health for Elderly in Long TERmcare (SHELTER) project. Methods Descriptive statistics, calculation of percentage, and multivariable logistic analysis were applied to describe the relationship between anticholinergic drug use and prevalence of delirium in NH patients. The Anticholinergic Risk Scale (ARS) and the Anticholinergic Burden Scale (ACB) were used to calculate the anticholinergic load. Results 54% of patients with dementia and 60% without dementia received at least 1 anticholinergic drug according to the ACB. The prevalence of delirium was higher in the dementia group (21%) compared with the nondementia group (11%). Overall, anticholinergic burden according to the ACB and ARS was associated with delirium both in patients with and without dementia, with odds ratios ranging from 1.07 [95% confidence interval (CI) 0.94-1.21] to 1.26 (95% CI 1.11-1.44). These associations reached statistical significance only in the group of patients with dementia. Among patients with dementia, delirium prevalence increased only modestly with increasing anticholinergic burden according to the ACB, from 20% (with none or minimal anticholinergic burden) to 25% (with moderate burden) and 27% delirium (with strong burden scores). Conclusions and Implications The ACB scale is relatively capable to detect anticholinergic side effects, which are positively associated with prevalence of delirium in NH patients. Given the modest nature of this association, strong recommendations are currently not warranted, and more longitudinal studies are needed.

It is my great pleasure to introduce this comic. Our project originated from an honest conversation with my friend and colleague Prof Chris Murray: how to communicate complex issues surrounding the issue of organ donation? Over the last seven years I have had the honour of being an ambassador for the Organ Donation campaign by telling my son, Andrew’s, story. Through my role as an Organ Donation ambassador I meet courageous and selfless people. Some are in desperate need of hope, some are in the position to provide hope, and those who, through their professionalism and dedication, transform lives. Our sincere thanks for the support of the following organisations: University of Dundee; the NHS Blood and Transplant Specialist Nurses in Organ Donation; Dundee Comics Creative Space; Good Life, Good Death, Good Grief, and the Organ Donation Comics team. it is only through their support that this project came to fruition. In the following pages we share heartfelt stories and life experiences related to organ donation. By doing so we hope to bring awareness to a wider audience and prompt honest conversations about organ donation. Finally, I would like thank my sons Andrew and Stuart for warming my heart. Through tears and laughter we present to you… The Gift.452

Delirium is a common serious complication in dementia that is associated with poor prognosis and a high burden on caregivers and healthcare professionals. Appropriate care is therefore important at an early stage for patients with delirium superimposed on dementia To gain insight into the care of six patients with delirium superimposed on dementia, 19 semi-structured interviews were conducted focused on the experiences of caregivers and professionals. The interviews revealed four themes that appeared to play a role: 1. experiences with and views on behavioral problems of these patients, 2. recognition and diagnosis of delirium in dementia, 3. views on good care and 4. organizational aspects. Knowledge gaps about delirium in dementia, as well as ethical considerations, play an important role in organizing timely and adequate care for patients with delirium superimposed on dementia.

Objectives To determine whether ultrasound (US) imaging of obese pregnant women in early gestation improves fetal cardiac visualization. Methods We report a prospective longitudinal trial comparing late first- and early second-trimester US to traditional second-trimester US for fetal cardiac screening in maternal obesity. All study participants received US for fetal cardiac screening at a gestational age of 13 weeks to 15 weeks 6 days using a transvaginal or transabdominal approach (UST1). All patients also underwent a traditional transabdominal examination at 20 to 22 weeks (UST2). If UST2 failed to complete the cardiac visualization, a follow up examination (second UST2) was performed 2 to 4 weeks later. Imaging was considered complete if the visceral situs, 4 chambers, outflow tracts, and 3 vessels were visualized. The completion rates between UST1 and UST2 were the primary outcomes. A power analysis (85%) and sample size calculation (n = 145) were performed. Results A total of 152 pregnancies met study criteria. Completion rates of cardiac screening were 77% for UST1 and 70% for UST2 (P = .143). This comparison reached statistical significance in patients with a body mass index of greater than 40 kg/m2 (UST1 [69%] versus UST2 [38%]; P = .001). Sixty-two percent of patients with a body mass index of greater than 40 kg/m2 required second UST2. The highest fetal cardiac screening completion rate was achieved when UST1 was combined with UST2 (96.1%). In 1 fetus, congenital heart disease was detected at UST1 and later confirmed. Conclusions This study represents the largest prospective trial assessing early-gestation US for fetal cardiac screening in the setting of maternal obesity. In obese pregnancies, the addition of early-gestation US to the 20- to 22-week US substantially improves the visualization of fetal cardiac anatomy.

Background: Chagas disease is a major neglected vector-borne disease. In this study, we investigated the safety and efficacy of three oral E1224 (a water-soluble ravuconazole prodrug) regimens and benznidazole versus placebo in adult chronic indeterminate Chagas disease. Method: In this proof-of-concept, double-blind, randomised phase 2 clinical trial, we recruited adults (18–50 years) with confirmed diagnosis of Trypanosoma cruzi infection from two outpatient units in Bolivia. Patients were randomised with a computer-generated randomisation list, which was stratified by centre and used a block size of ten. Patients were randomly assigned (1:1:1:1:1) to five oral treatment groups: high-dose E1224 (duration 8 weeks, total dose 4000 mg), low-dose E1224 (8 weeks, 2000 mg), short-dose E1224 (4 weeks + 4 weeks placebo, 2400 mg), benznidazole (60 days, 5 mg/kg per day), or placebo (8 weeks, E1224-matched tablets). Double-blinding was limited to the E1224 and placebo arms, and assessors were masked to all treatment allocations. The primary efficacy endpoint was parasitological response to E1224 at the end of treatment, assessed by PCR. The secondary efficacy endpoints were parasitological response to benznidazole at end of treatment, assessed by PCR; sustainability of parasitological response until 12 months; parasite clearance and changes in parasite load; incidence of conversion to negative response in conventional and non-conventional (antigen trypomastigote chemiluminescent ELISA [AT CL-ELISA]) serological response; changes in levels of biomarkers; and complete response. The primary analysis population consisted of all randomised patients by their assigned treatment arms. This trial is registered with ClinicalTrials.gov, number NCT01489228. Findings: Between July 19, 2011, and July 26, 2012, we screened 560 participants with confirmed Chagas disease, of whom 231 were enrolled and assigned to high-dose E1224 (n=45), low-dose E1224 (n=48), short-dose E1224 (n=46), benznidazole (n=45), or placebo (n=47). Parasite clearance was observed with E1224 during the treatment phase, but no sustained response was seen with low-dose and short-dose regimens, whereas 13 patients (29%, 95% CI 16·4–44·3) had sustained response with the high-dose regimen compared with four (9%, 2·4–20·4) in the placebo group (p

Oxygen-related Thermal Donors in n-type Czochralski silicon (Cz-Si) wafers have been investigated using hyperspectral photoluminescence imaging and OxyMap. Thermal Donors give rise to two photoluminescence emissions, one narrow peak at 0.767 eV, and one broad band with centre peak at 0.72 eV that is also measurable at room temperature. The spectral imaging was first carried out on the sample cooled to 90 K, then repeated at room temperature (300 K). The possibility to delimitate at room temperature defects-rich zones with hyperspectral photoluminescence imaging is evidenced.

Objectives The 2012 Eunice Kennedy Shriver National Institute of Child Health fetal imaging consensus suggested that fetal anatomy ultrasound in obese pregnancies be performed at 20 to 22 weeks, with follow-up in 2 to 4 weeks if anatomy is incomplete. It was postulated that imaging in early gestation may improve visualization, although no prospective trials had been done to date. Methods We performed a prospective longitudinal blinded trial comparing an early gestation ultrasound (13 + 0 to 15 + 6 weeks) with the traditional second-trimester ultrasound for completion of the fetal anatomy survey in obese patients. Inclusion criteria included singleton gestation, body mass index (BMI) more than 30, less than 16 + 0 weeks' gestation, and no karyotype abnormality; exclusion criteria included age younger than 18 years, more than 16 weeks' gestation at time of consent, and BMI less than 30. Participants received a transvaginal and/or transabdominal sonogram for fetal anatomic survey at 13 + 0 to 15 + 6 weeks' gestation (US1). Images from US1 were blinded to physicians and sonographers performing subsequent examinations. All participants underwent the traditional transabdominal sonogram at 18 to 24 weeks (US2). If US2 failed to complete the anatomic survey, a repeat transabdominal sonogram (2-US2) was performed 2 to 4 weeks later. Results A total of 152 pregnancies met the criteria. Anatomy completion rate was 57.2% for US1 and 62.5% for US2, which was not statistically significant, even when stratified by BMI. Excluding the philtrum, the US1 performed better than US2 for class III obesity (65.5% versus 45.5% [P = .035]). Combination of US1 + US2 yielded a higher completion rate than US2 + 2-US2 (94.1% versus 83.6% [P = .0023]). Conclusions In the setting of maternal obesity, the addition of an ultrasound in early gestation may be of highest benefit for patients with class III obesity (BMI > 40 kg/m2).

Latin America has scarce information related to rheumatologist's education, working conditions, productivity, and job satisfaction. The purpose of this survey was to describe the training and clinical practice characteristics of the rheumatology community in Latin America.This is a cross-sectional study. A digital survey was created, approved, and endorsed by the scientific committee of the Pan-American League of Associations for Rheumatology (PANLAR) and later sent to the rheumatology associations of the region. The data was analyzed in the statistical program SPSS v.22.We included 600 surveys of rheumatologists from 19 Latin American countries. The majority were females (53%) and mestizos (58%). The mean age was 46.8 ± 11.7 years. The most frequent workplace was public/government hospitals 33.5% followed by private practice 28.8%, private hospital 20.8%, and university hospital 15.5%. The average number of weekly working hours was 37.8 ± 17.7. 87.5% worked in adult rheumatology, 12.7% pediatric rheumatology, and 23.5% internal medicine. Average satisfaction with practice as a rheumatologist was 5.3/7, career options 4.3/7, location 4.7/7, income 3.5/7, job security 3.7/7, and colleagues and co-workers 4.5/7. Finally, 69.7% had an annual compensation of 50,000 US dollars.The majority of the rheumatologists in the region who responded were women, worked in public hospitals, and were satisfied with their clinical practice. There was a low level of income for the region. Key Points • This is the first study that showed the demographic and clinical practice characteristics of rheumatologists in Latin America. • The challenges faced by Latin rheumatologists are like those faced by the region: ethnic diversity, gender differences, migration, difficult access to education, limited research, and low income. • Due to the high prevalence of rheumatic diseases and the shortage of professionals in this area, it is essential to analyze the current workforce and the projections of supply and demand in rheumatology that are expected in the future.

Background Premenstrual dysphoric disorder (PMDD) is an understudied, debilitating disorder of women. Given evidence for prefrontal cortical and limbic dysfunction in PMDD, we compared intrinsic connectivity of the executive control network (ECN), default mode network (DMN), and amygdala in women with PMDD vs. controls. Methods Thirty-six women (18 PMDD, 18 control) participated in fMRI during the follicular and luteal phases of the menstrual cycle. At each time, resting-state functional connectivity was evaluated both before and after participants performed an emotion regulation task. The ECN was identified using independent components analysis, and connectivity of left and right amygdala seeds was also evaluated. Results Nonparametric permutation testing identified a cluster in the left middle temporal gyrus (MTG) with significantly stronger connectivity to the left ECN in women with PMDD vs. controls in all four fMRI sessions. Women with PMDD exhibited no difference in functional connectivity between menstrual cycle phases. Amygdala connectivity did not differ between the groups but differed significantly with menstrual phase, with left amygdala connectivity to cingulate cortex being significantly stronger during the follicular vs. luteal phase. Right amygdala connectivity to the middle frontal gyrus was also stronger during the follicular vs. luteal phase, with no group differences. These findings suggest that women with PMDD have different intrinsic network dynamics in the left executive control network compared to healthy controls.

Objective This study aims to compare completion rates and reproducibility of myocardial performance index (MPI) using conventional spectral Doppler versus tissue Doppler in an unselected high-risk third trimester population.Study Design This was a prospective cross-sectional study of high-risk pregnancies at ≥28 + 0 weeks’ gestation. Conventional spectral and tissue Doppler MPI of the left ventricle (LV) and right ventricle (RV) was attempted on all patients.Results Seventy-nine pregnancies were evaluated. LV tissue Doppler MPI was completed more frequently than LV conventional spectral Doppler MPI (63/79, 79.7% vs. 45/79, 55.7%), p-value Conclusion Tissue Doppler had statistically higher completion rates than conventional spectral Doppler, including the obese subgroup, with evidence of strong reproducibility in the third trimester.

Background The aim of this retrospective study was to examine the longitudinal association between disease activity and radiographic damage in a cohort of patients with early RA (symptom onset Methods Baseline to 3-year follow-up data were used from patients included in the DREAM remission induction cohort. Patients received protocolized T2T treatment, aimed at 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR) remission. Disease activity (DAS28-ESR and C-reactive protein, CRP) were assessed at least every 3 months; X-rays of the hand and feet at inclusion, 6 months, and 1, 2, and 3 years were scored using modified Sharp/van der Heijde scoring (SHS). Between and within-person associations between time-integrated disease activity and radiographic progression over time were examined. Results A subset of 229 out of 534 included patients were available for analysis. At the between-patient level, time-integrated DAS28-ESR scores were not significantly correlated with progression at the 6 month and 2-year follow-up and only weakly at the 1-year (Pearson’s correlation coefficient r = 0.17, P r = 0.21, P r between 0.39 and 0.59; P values Conclusions In early RA patients treated according to T2T, radiographic progression appears to be an individually determined disease process, driven by factors other than consistent high disease activity. For individual patients, the intra-patient relation between disease activity and cumulative radiographic damage during the first 6 months is a good indicator for this relation in later years. Trial registration Netherlands Trial Register NTR578, 12 January 2006.

Background: Objectives: To know the availability of treatment for rheumatologic and autoimmune conditions in Latin America, according to rheumatologists in the region. Methods: A digital survey was created using Google Forms, it was approved and endorsed by the scientific committee of PANLAR, and later sent to the different Rheumatology associations of the region. The data was analyzed in the statistical program SPSS v.23. Results: 456 surveys were filled by rheumatologists from 23 countries. The majority were females (54%). The mean age was 47.18 ± 11.79 [25-78] years. 91% reported access to DMARDs, methotrexate 95%, azathioprine 94%, cyclophosphamide 92%, hydroxychloroquine 92%, leflunomide 90%, mycophenolate mofetil 90%, sulfazalasin 88%, cyclosporine 80%, tacrolimus 64%, chloroquine 60%. 85% have access to biological therapy: adalimumab (78%), etarnercept (83%), rituximab (81%), infliximab (74%), tocilizumab (73%), abatacept (67%), golimumab (63%), certolizumab (59%), secukinumab (55%), ustekinumab (44%), certolizumab (59%), belimumab (47%), canakinumab (22%), sarilumab (15%), ixekizumab (12%), anakinra (10%) and rilonacept (3%). 58% have access to biosimilar drugs: rituximab (27%), infliximab (24%), etanercept (18%) and adalimumab (4%). 61% have access to small molecules such as: tofacitinib 62%, baricitinib 18% and ruxolutinib 1%. Regarding the survey by each country 95% reported access to DMARDs: between 80-100% (Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Cuba, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, Paraguay, Peru, Puerto Rico, Dominican Republic). 70% of the countries reported access to biological therapy between 80-100% (Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Ecuador, El Salvador, Guatemala, Honduras, Panama, Paraguay, Puerto Rico, Uruguay.) 15% did not have access to biosimilar therapy (Cuba, Honduras and Uruguay). 30% have access to therapy with small molecules between 80 -100% (Argentina, Guatemala, Honduras, Panama, Paraguay and Dominican Republic), 25% did not have access to small molecules (Cuba, Uruguay and Venezuela). Conclusion: It is evident that most Latin American countries have access to drugs focused on rheumatic diseases, however, there are substantial differences in countries that do not have access to all therapies. In addition, newer treatment as small molecules are less accessible to the region. Disclosure of Interests: None declared

Background: Currently, Latin America does not have detailed information of rheumatologists in the region based on: education, working conditions, productivity, distribution of time between work activities and job satisfaction. Objectives: The purpose of this survey was to provide more information on the rheumatology community in Latin America Methods: A digital survey was created using the Google Forms platform, it was approved and endorsed by the scientific committee of PANLAR and later sent to the different rheumatology associations of the region. The data was analyzed in the statistical programSPSS v.23: Results: 456 surveys of rheumatologists from 23 countries were received. The majority were females (54%). The mean age was 47.18 ± 11.79 [25-78] years, with a majority of mixed race 58%. 63% are married, 23% are single, 8% are divorced, 5% in free union and 2% are widowed. The mean number of children was 2 [0-7]. Birthplaces included Argentina (27%), Brazil (18%). The setting of the professional practice after obtaining the title of specialists was: public hospital (35%), private (25%), private/teaching in a university hospital (12%), public/teaching in a university hospital (14%), and industry (1%). The main place of work was in public/government hospitals by 30% followed by private practice 31%, private hospital 23%, university hospital 15% and nonprofit organizations 1%. The average of weekly working hours was 39.12 ± 27.53. 89% of the sample practices adult rheumatology, 17% pediatric rheumatology, 2% immunology and 3% another specialty. 30% had an early arthritis care center at their workplace, 71% had an infusion unit, 17% had ultrasound, 23% had a densitometer, 17% had a resonator and 9% had X-rays, however, most work in collaboration. 30% have training in ultrasound and 9% are in training period, 75% have training in reading densitometry and 2% in training period, 54% have training in resonance reading and 11% in training period. The average satisfaction with practice as a rheumatologist was 5/7, career options/professional growth 4/7, geographic location 5/7, income 4/7, job security 4/7, colleagues and co-workers 5/7. 33% had an annual compensation of Conclusion: The majority of rheumatologists in the region who responded were female and feel satisfied with their clinical practice. This survey shows a low level of income for the region, however, more data should be obtained. This is the first study of its kind in Latin America, being an initiative for similar projects. Disclosure of Interests: None declared

Background:Rheumatology is considered a low-risk specialty, but studies have shown a prevalence of burnout between 42% to 51%1,2. Factors associated with it include the use of electronic medical records, administrative tasks and prolonged working hours. This has several repercussions such as higher prevalence of depression/anxiety and less productivity.Objectives:To determine the prevalence of burnout in rheumatologists in Latin America and the factors associated with it.Methods:Cross-sectional study based on a survey completed through Google Forms platform that was sent by the national rheumatology associations of Latin America. Burnout was assessed with the Maslach Burnout Inventory (MBI) with cut off values of ≥27 for emotional exhaustion (EE), ≥10 for depersonalization (DP), and ≤33 for personal accomplishment (PA). Other variables were studied such as demographics, working conditions, satisfaction, comorbidities, depression using PHQ-9 and happiness using the Subjective Happiness Scale. Data was analyzed using the statistical program SPSS v.22.Results:297 rheumatologists from 15 countries were included, mainly Argentina (28.3%), Brazil (26.3%) and Mexico (12.8%). The majority were women 62%, 42.4% worked in public hospitals with an average of 40.1 ± 14.2 hours per week. 31.3% did research, 13.1% clinical trials, 56.6% teaching, and 42.8% administrative work. 36% received an annual income less than 25K.56.6% had burnout in at least 1 dimension. According to the dimensions, 35.7% had burnout in EE, 25.6% in PA and 26.6% in DP. 32.3% had burnout in only 1 dimension, 17.2% in two and 7.1% in all three dimensions. Only 20.2% thought they had burnout, 9.1% were currently with professional help and 15.8% had sought help in the past. 72.1% said they were willing to participate in a program to reduce burnout.The rheumatologists with burnout were younger than those without burnout (46.5 vs 49.9 years, p = 0.015), mentioned more frequently that they would like to decrease the number of working hours (56.5% vs 36.4%, p = 0.002) and had lower practice satisfaction (5.2 vs 6.2, p Conclusion:Burnout affects near half of rheumatologists in Latin America and was associated to younger age, long working hours, low satisfaction, less happiness, higher PHQ-9, suicidal thoughts, anxiety, income, presence of comorbidities and low self-esteem. Most of the rheumatologists were willing to participate in programs to reduce burnout which represents an opportunity for interventions to reduce this syndrome.References:[1]Martin K. Medscape Rheumatologist Lifestyle, Happiness & Burnout Report 2020. 2020; Available at: https://www.medscape.com/slideshow/2020-lifestyle-rheumatologist-6012480#4. Accessed July 10, 2020.[2]Tiwari V, Kavanaugh A, Martin G, Bergman M. High impact of burnout on rheumatology practitioners. Journal of rheumatology 2020:jrheum.191110.Disclosure of Interests:None declared

Summary The clinical importance of anterior foregut endoderm (AFE) derivatives, such as thyrocytes, has led to intense research efforts for their derivation through directed differentiation of pluripotent stem cells (PSCs). Here, we identify transient overexpression of the transcription factor (TF) NKX2-1 as a powerful inductive signal for the robust derivation of thyrocyte-like cells from mouse PSC-derived AFE. This effect is highly developmental stage specific and dependent on FOXA2 expression levels and precise modulation of BMP and FGF signaling. The majority of the resulting cells express thyroid TFs (Nkx2-1, Pax8, Foxe1, Hhex) and thyroid hormone synthesis-related genes (Tg, Tpo, Nis, Iyd) at levels similar to adult mouse thyroid and give rise to functional follicle-like epithelial structures in Matrigel culture. Our findings demonstrate that NKX2-1 overexpression converts AFE to thyroid epithelium in a developmental time-sensitive manner and suggest a general methodology for manipulation of cell-fate decisions of developmental intermediates., Graphical Abstract, Highlights • Transient Nkx2-1 overexpression robustly converts foregut endoderm to thyroid lineage • The effect is highly developmental stage specific and dependent on BMP/FGF signals • The progeny self-organizes to 3D structures reminiscent of follicular thyroid tissue • Mature cultures produce T4 hormone at levels comparable with mouse thyroid tissue, Ikonomou and colleagues found that pluripotent stem cell-derived anterior foregut endoderm can be robustly converted to thyroid progenitors through transient expression of the transcription factor Nkx2-1. This inductive effect is highly stage specific and relies on thyroid specification signals. The thyrocyte-like progeny self-organize into follicle structures in 3D culture and express mature thyroid proteins indicative of functionality (TG, NIS, T4).

With aging of HIV populations, there is concern that Alzheimer’s disease (AD) may become prevalent and difficult to distinguish from HIV-associated neurocognitive disorders. To date, there are no reports documenting histologically verified Alzheimer’s neuropathology in individuals with HIV and dementia. Herein, we report two antiretroviral-treated, virally suppressed, HIV-infected individuals autopsied by the Manhattan HIV Brain Bank. Subject A presented to study at 52 years, already dependent in instrumental activities of daily living (ADLs), with severe cognitive impairment inclusive of learning and memory dysfunction. Her history was significant for educational disability and head trauma. She had rapid cognitive decline and, by death at age 59 years, was bed-bound, incontinent, and non-communicative. At autopsy, she exhibited severe AD neuropathologic change (NIA-AA score A3B3C3) and age-related tau astrogliopathy (ARTAG). She was homozygous for APOE e3/e3. No HIV DNA was detected in frontal lobe by nested polymerase chain reaction. Subject B was a community dwelling 81-year-old woman who experienced sudden death by pulmonary embolus. Prior to death, she was fully functional, living independently, and managing all ADLs. At autopsy, she displayed moderate amyloid and severe tau AD neuropathologic changes (A2B3C2), ARTAG, and cerebral congophilic angiopathy. She was an APOE e3/e4 heterozygote, and HIV DNA, but not RNA, was detected in frontal lobe, despite 20 years of therapy-induced viral suppression. We conclude that in the setting of HIV, AD neuropathology may occur with or without symptomatic cognitive dysfunction; as with seronegative individuals, there are likely to be complex factors in the generation of clinically relevant impairments.

Item does not contain fulltext IMPORTANCE: Infections and necrotizing enterocolitis, major causes of mortality and morbidity in preterm infants, are reduced in infants fed their own mother's milk when compared with formula. When own mother's milk is not available, human donor milk is considered a good alternative, albeit an expensive one. However, most infants at modern neonatal intensive care units are predominantly fed with own mother's milk. The benefits of add-on donor milk over formula are not clear. OBJECTIVE: To determine whether providing donor milk instead of formula as supplemental feeding whenever own mother's milk is insufficiently available during the first 10 days of life reduces the incidence of serious infection, necrotizing enterocolitis, and mortality. DESIGN, SETTINGS, AND PARTICIPANTS: The Early Nutrition Study was a multicenter, double-blind randomized clinical trial in very low-birth-weight infants (birth weight

Objectives To investigate changes in the cardiac axis (CAx) within the cardiac cycle of normal fetuses and fetuses with congenital heart defects (CHD). Methods This was a retrospective case–control study in which stored videoclips of four-chamber views from 527 prenatal ultrasound examinations performed at 18 + 0 to 36 + 6 weeks of gestation were reviewed. Among the ultrasound scans included, 287 were of normal fetuses (controls) and 240 were of fetuses with CHD. In each case, the CAx was measured at end systole (just before the atrioventricular (AV) valve opened) and at end diastole (just before the AV valve closed). CAx measurements of fetuses with CHD were compared to those of controls. Results The mean CAx in the control group was 45.9 ± 8.5° at end systole and 38.3 ± 8.4° at end diastole (P

Cystic echinococcosis (CE) is an important helminthic zoonotic disease that commonly affects the liver and lungs. Imaging methods and serology establish the diagnosis in most cases. Chest x-ray can diagnose uncomplicated pulmonary hydatid cysts, whereas superinfection and/or rupture of the hydatid cyst (complicated cysts) may change the radiographic appearance and lead to delayed diagnosis and treatment. We report the case of a patient with hemoptysis and chest pain, where computer tomography scan of the lung suggested a large, ruptured hydatid cyst. However, serological tests with indirect hemagglutination (IHA)for Echinococcus granulosus antibodies were negative, and there was massive growth of Streptococcus pneumoniae in sputum. Based on this, we concluded that the patient had a bacterial lung abscess. The diagnosis of CE was only made after surgical removal of the cyst followed by microscopy and polymerase chain reaction.

Background Early and intensive targeted treatment with disease modifying anti-rheumatic drugs (DMARDs) has been shown to lead to substantial reductions in disease activity and radiograph damage in patients with early rheumatoid arthritis (RA). The aim of this quasi-experimental study was to compare the first-year radiographic progression rates between a treat-to-target (T2 T) strategy with initial combination therapy (strategy II, started in 2012) versus an initial step-up monotherapy (strategy I, started in 2006). Methods A total of 128 patients from strategy II was individually matched with 128 patients from strategy I on sex, age (± 5 yrs.) and baseline disease activity (± 0.5 on the DAS28). Differences in radiographic progression (Sharp/van der Heijde) scores (SHS) and the number of patients experiencing a minimal clinically important difference (MCID; ≥ 5 SHS points) between both strategies were tested with Mann Whitney U and chi-square tests. Next, linear and logistic regression analyses were performed to examine which baseline variables were associated with radiographic progression scores and the probability of experiencing an MCID within 1 year. Results Patients with initial combination therapy had slightly higher baseline disease activity scores and pain scores, but better mental health scores. Patients with initial monotherapy had significantly more, and more frequently clinically relevant, radiographic progression after 1 year. Experiencing a MCID was independently associated with fewer tender joints (p = 0.050) and higher erythrocyte sedimentation rate (p = 0.015) at baseline. Conclusion Treating early RA patients with initial combination therapy results in better radiographic outcomes than initial monotherapy in daily clinical practice. Trial registration Netherlands Trial Register NTR578, 12 January 2006.

BackgroundDifficulties in regulating emotions are linked to the core symptoms of premenstrual dysphoric disorder (PMDD). We therefore investigated the neural substrates of emotion-regulation problems in women with PMDD.MethodsOn the basis of self-evaluations over 2 months on the Daily Record of Severity of Problems, eligible participants were assigned to two groups: PMDD and control (18 per group). Functional magnetic resonance imaging (fMRI) and a well-validated task were used to assess brain function during emotion regulation. Participants were tested twice, once during the follicular (asymptomatic) and once in the late luteal (symptomatic) phase of the menstrual cycle.ResultsWomen with PMDD gave higher ratings of negative affect in the luteal phase than in the follicular phase, and compared with healthy control participants during the luteal phase. A region-of-interest fMRI analysis indicated that during the late luteal phase, women with PMDD had hypoactivation in right dorsolateral prefrontal cortex (dlPFC) during all conditions of the emotion-regulation task, not only in the contrast that isolated emotion regulation. An exploratory whole-brain, voxel-wise analysis showed that women with PMDD had less activation in the precentral gyrus during the luteal phase than the follicular phase, and less activation in the postcentral gyrus compared with control participants.ConclusionsDuring the luteal phase of the menstrual cycle, women with PMDD experience difficulty regulating emotions. Hypoactivation in the right dlPFC may contribute to this problem, but may be related more generally to other affective symptoms of PMDD. Hypofunction in the right pre- and postcentral gyri warrants additional study.

To describe the changes over a 9-year period in the number and rate of diagnostic testing after the introduction of the combined first-trimester screen and subsequent noninvasive prenatal testing.The number of prenatal screening and diagnostic tests was recorded over a 9-year period from billing records. Three time intervals were considered: 1) 20 months before a combined first-trimester screen was offered; 2) 72 months after a combined first-trimester screen was offered; and 3) 16 months after noninvasive prenatal testing introduction. Prenatal testing was compared per year, per time interval, and per 100 morphologic ultrasonograms to account for fluctuations in patient number.A total of 15,418 prenatal tests was recorded during the study period, consisting of 9,780 combined first-trimester screen, 1,265 noninvasive prenatal testing, 608 chorionic villus sampling (CVS), and 3,765 amniocenteses. Combined first-trimester screen peaked at 1,836 in 2009-2010 but declined by 48.1% after noninvasive prenatal testing was introduced. Combined first-trimester screen per 100 morphologic ultrasonograms also significantly decreased (P.05) after noninvasive prenatal testing introduction. Chorionic villus sampling peaked after combined first-trimester screen introduction in 2007-2008 with 100 procedures, representing an 81.8% increase from prefirst-trimester screen. After the introduction of noninvasive prenatal testing, CVS declined by 68.6% during 2012-2013. Chorionic villus sampling per 100 morphologic ultrasonograms followed the same trend. Amniocentesis declined every year of the study period (78.8% overall), including 60.3% after combined first-trimester screen and a further 46.7% after noninvasive prenatal testing. Monthly amniocentesis procedures per 100 morphologic ultrasonograms significantly decreased (P.05) after introduction of a combined first-trimester screen and noninvasive prenatal testing.The introduction of combined first-trimester screen was associated with an increase in CVS and a decrease in amniocentesis testing. Noninvasive prenatal testing was associated with a subsequent decrease in CVS and further decrease in amniocentesis. LEVEL OF EVIEDENCE: III.

Controversy exists as to whether effects of HIV infection can be detected in the cognitive profiles of substance users, with methodological differences in degree of control for confounding factors a major contributor to empirical discrepancies. To address this shortcoming, we conducted a small but well-controlled study aimed at isolating HIV neurocognitive (NC) effects in a group of chronic substance users. Thirty HIV-negative substance users were individually matched to 30 HIV-positive substance users on relevant medical and demographic factors, including reading level and methadone therapy status. Results revealed that reading level, methadone maintenance therapy, and positive urine toxicology each exerted significant influence on NC function, and that HIV status was a significant predictor of learning and speeded processing after these control factors were considered. The HIV-positive group also displayed significantly more neurologically assessed motor impairment (p < .05), which was specifically related to impaired cognition in this group and independent of degree of immunocompromise. These data demonstrate the need for increased attention to clinical/demographic characteristics of groups under study. They also show that with applied methodological rigor, the deleterious effects of HIV on cognition can be parsed from substance use, even in small samples with chronic and active use histories. (JINS, 2013, 19, 1–11)

The use of preclinical models to study tumor biology and response to treatment is central to cancer research. Long-established human cell lines, and many transgenic mouse models, often fail to recapitulate the key aspects of human malignancies. Thus, alternative models that better represent the heterogeneity of patients' tumors and their metastases are being developed. Patient-derived xenograft (PDX) models in which surgically resected tumor samples are engrafted into immunocompromised mice have become an attractive alternative as they can be transplanted through multiple generations,and more efficiently reflect tumor heterogeneity than xenografts derived from human cancer cell lines. A limitation to the use of PDXs is that they are difficult to transfect or transduce to introduce traceable reporters or to manipulate gene expression. The current protocol describes methods to transduce dissociated tumor cells from PDXs with high transduction efficiency, and the use of labeled PDXs for experimental models of breast cancer metastases. The protocol also demonstrates the use of labeled PDXs in experimental metastasis models to study the organ-colonization process of the metastatic cascade. Metastases to different organs can be easily visualized and quantified using bioluminescent imaging in live animals, or GFP expression during dissection and in excised organs. These methods provide a powerful tool to extend the use of multiple types of PDXs to metastasis research.

SummaryTwo populations of Nkx2-1+ progenitors in the developing foregut endoderm give rise to the entire postnatal lung and thyroid epithelium, but little is known about these cells because they are difficult to isolate in a pure form. We demonstrate here the purification and directed differentiation of primordial lung and thyroid progenitors derived from mouse embryonic stem cells (ESCs). Inhibition of TGFβ and BMP signaling, followed by combinatorial stimulation of BMP and FGF signaling, can specify these cells efficiently from definitive endodermal precursors. When derived using Nkx2-1GFP knockin reporter ESCs, these progenitors can be purified for expansion in culture and have a transcriptome that overlaps with developing lung epithelium. Upon induction, they can express a broad repertoire of markers indicative of lung and thyroid lineages and can recellularize a 3D lung tissue scaffold. Thus, we have derived a pure population of progenitors able to recapitulate the developmental milestones of lung/thyroid development.

Premenstrual dysphoric disorder (PMDD) is a psychiatric disorder that causes serious impairments in the functioning and quality of life of affected women. Until recently, research efforts were somewhat hampered by the lack of formal diagnostic criteria, which have now been codified as a category in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Better characterization of deficits in socioemotional functioning caused by PMDD may aid in improving treatment efforts. In this investigation, prospective symptom ratings, based on DSM-5 criteria, were used to measure PMDD symptoms in 36 women (18 with PMDD and 18 healthy controls). Two self-report inventories, the Emotion Regulation Questionnaire and the Difficulties in Emotion Regulation Scale, were used to measure ability to regulate emotions, and socioemotional functioning was measured by inventories of social connectedness, perceived stress, and affect. Potential relationships between ability to regulate emotion and PMDD symptom severity, as well as other measures of socioemotional functioning and affective state, were tested. Women with PMDD reported significantly more behavioral impulsivity and greater difficulties in regulating emotion and in socioemotional functioning. Cognitive or behavioral strategies to improve these problems may benefit women with PMDD and help to alleviate distress caused by this disorder.

Objectives To report changes in the use of the combined first-trimester screen (FTS) in patients classified as high and low risk for fetal aneuploidy, including after introduction of noninvasive prenatal testing (NIPT). Methods A prospectively collected database was reviewed to investigate changes in FTS use before and after American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 77 (Obstet Gynecol 2007; 109:217-227), which recommended that all patients be offered aneuploidy screening, and after NIPT introduction. High-risk patients were classified as 35 years or older at the estimated time of delivery or those with an abnormal prior screen, abnormal ultrasound findings, or family history of aneuploidy. Data were normalized per 100 morphologic ultrasound examinations to account for changes in patient number over time. Statistical significance was defined as P Results A total of 10,125 FTSs were recorded during the 88-month study period, including 2962 in high-risk patients and 7163 in low-risk patients. The total number of FTSs performed per 100 morphologic ultrasound examinations significantly increased after ACOG Practice Bulletin No. 77 and significantly decreased after NIPT introduction. In high-risk patients, the total number of FTSs performed per 100 morphologic ultrasound examinations significantly increased after ACOG Practice Bulletin No. 77 but significantly decreased after NIPT introduction. In contrast, in low-risk patients, the total number of FTSs performed per 100 morphologic ultrasound examinations significantly increased after ACOG Practice Bulletin No.77 but was not statistically different after NIPT introduction. Conclusions American College of Obstetricians and Gynecologists Practice Bulletin No. 77 significantly increased patient use of FTS. The introduction of NIPT significantly decreased FTS use in the high-risk population but not in the low-risk population.

Glucagon has a short plasma t1/2in vivo, with renal extraction playing a major role in its elimination. Glucagon is degraded by neutral endopeptidase (NEP) 24.11 in vitro, but the physiological relevance of NEP 24.11 in glucagon metabolism is unknown. Therefore, the influence of candoxatril, a selective NEP inhibitor, on plasma levels of endogenous and exogenous glucagon was examined in anesthetized pigs. Candoxatril increased endogenous glucagon concentrations, from 6.3 ± 2.5 to 20.7 ± 6.3 pmol/l [COOH-terminal (C)-RIA, P < 0.05]. During glucagon infusion, candoxatril increased the t1/2determined by C-RIA (from 3.0 ± 0.5 to 17.0 ± 2.5 min, P < 0.005) and midregion (M)-RIA (2.8 ± 0.5 to 17.0 ± 3.0 min, P < 0.01) and reduced metabolic clearance rates (MCR; 19.1 ± 3.2 to 9.4 ± 2.0 ml·kg−1·min−1, P < 0.02, C-RIA; 19.2 ± 4.8 to 9.0 ± 2.3 ml·kg−1·min−1, P < 0.05, M-RIA). However, neither t1/2nor MCR determined by NH2-terminal (N)-RIA were significantly affected ( t1/2, 2.7 ± 0.4 to 4.5 ± 1.6 min; MCR, 30.3 ± 6.4 to 28.5 ± 9.0 ml·kg−1·min−1), suggesting that candoxatril had no effect on NH2-terminal degradation but leads to the accumulation of NH2-terminally truncated forms of glucagon. Determination of arteriovenous glucagon concentration differences revealed that renal glucagon extraction was reduced (but not eliminated) by candoxatril (from 40.4 ± 3.8 to 18.6 ± 4.1%, P < 0.02, C-RIA; 29.2 ± 3.1 to 14.7 ± 2.2%, P < 0.02, M-RIA; 26.5 ± 4.0 to 19.7 ± 3.5%, P < 0.06, N-RIA). Femoral extraction was reduced by candoxatril when determined by C-RIA (from 22.7 ± 2.4 to 8.0 ± 5.1%, P < 0.05) but was not changed significantly when determined using M- or N-RIAs (10.0 ± 2.8 to 4.7 ± 3.7%, M-RIA; 10.5 ± 2.5 to 7.8 ± 4.2%, N-RIA). This study provides evidence that NEP 24.11 is an important mediator of the degradation of both endogenous and exogenous glucagon in vivo.

Glucagon metabolism under basal (endogenous) conditions and during intravenous glucagon infusion was studied in anesthetized pigs by use of midregion (M), COOH-terminal (C), and NH2-terminal (N)-RIAs. Arteriovenous concentration differences revealed a negative extraction of endogenous glucagon immunoreactivity across the portal bed (-35.4 ± 11.0, -40.3 ± 9.6, -35.6 ± 16.9%, M-, C-, N-RIA, respectively), reflecting net secretion of pancreatic glucagon and intestinal glicentin and oxyntomodulin, but under exogenous conditions, a net extraction occurred (11.6 ± 3.6 and 18.6 ± 5.7%, C- and N-RIA, respectively). Hindlimb extraction of endogenous (17.4 ± 3.7%, C-RIA) and exogenous (29.1 ± 4.8 and 19.8 ± 5.1%, C- and M-RIA) glucagon was detected, indicating M and C cleavage of the molecule. Renal extraction of glucagon was detected by all assays under endogenous (19.4 ± 6.7, 33.9 ± 7.1, 29.5 ± 6.7%, M-, C-, N-RIA) and exogenous conditions (46.9 ± 4.8, 46.4 ± 6.0, 47.0 ± 7.7%; M-, C-, N-RIA), indicating substantial elimination of the peptide. Hepatic glucagon extraction was undetectable under basal conditions and detected only by M-RIA (10.0 ± 3.8%) during glucagon infusion, indicating limited midregional cleavage of the molecule. The plasma half-life determined by C- and N-RIAs (2.7 ± 0.2 and 2.3 ± 0.2 min) were similar, but both were shorter than when determined by M-RIA (3.2 ± 0.2 min, P < 0.02). Metabolic clearance rates were similar regardless of assay (14.4 ± 1.1, 13.6 ± 1.7, 17.0 ± 1.7 ml·kg-1·min-1, M-, C-, N-RIA). Porcine plasma degraded glucagon, but this was not significantly affected by the dipeptidyl peptidase IV (DPP IV) inhibitor valine-pyrrolidide, and in anesthetized pigs, glucagon's metabolic stability was unchanged by DPP IV inhibition. We conclude that tissue-specific metabolism of glucagon occurs, with the kidney being the main site of removal and the liver playing little, if any, role. Furthermore, valine-pyrrolidide has no effect on glucagon stability, suggesting that DPP IV is unimportant in glucagon metabolism in vivo, in contrast to its significant role in the metabolism of the other proglucagon-derived peptides and glucose-dependent insulinotropic polypeptide.

Background/Aims: Although delirium is generally regarded as a transient syndrome, persistence of delirium in patients with cognitive impairment - even with fatal outcome - has been reported as well. This study aims to describe the clinical features and neuropathological correlates of this type of delirium. Methods: Inclusion criteria for this case series were: (1) severe persistent delirium until death, (2) history of cognitive decline and (3) consent for brain autopsy. Medical records were examined in combination with collected clinical data and neuropathological findings. Result: In 15 patients, all living at home before admission, episodes with delirium lasted for 4.2 months on average. No distinct medical causes of persistent delirium could be identified. Pathological diagnoses included Alzheimer's disease and dementia with Lewy bodies as well as single cases of Creutzfeldt-Jakob disease and progressive supranuclear palsy. Conclusion: Severe, persistent and fatal delirium in patients with cognitive impairment can occur relatively early in the disease trajectory and is associated with diverse neuropathologies.

The Control of Allergic Rhinitis and Asthma Test (CARAT) monitors control of asthma and allergic rhinitis. To determine the CARAT’s minimal clinically important difference (MCID) and to evaluate the psychometric properties of the Dutch CARAT. CARAT was applied in three measurements at 1-month intervals. Patients diagnosed with asthma and/or rhinitis were approached. MCID was evaluated using Global Rating of Change (GRC) and standard error of measurement (s.e.m.). Cronbach’s alpha was used to evaluate internal consistency. Spearman’s correlation coefficients were calculated between CARAT, the Asthma Control Questionnaire (ACQ5) and the Visual Analog Scale (VAS) on airway symptoms to determine construct and longitudinal validity. Test–retest reliability was evaluated with intra-class correlation coefficient (ICC). Changes in pollen counts were compared with delta CARAT and ACQ5 scores. A total of 92 patients were included. The MCID of the CARAT was 3.50 based on GRC scores; the s.e.m. was 2.83. Cronbach’s alpha was 0.82. Correlation coefficients between CARAT and ACQ5 and VAS questions ranged from 0.64 to 0.76 (P

Background. Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) can show variable clinical trajectories. Previous longitudinal studies of HAND typically have been brief, did not use adequate normative standards, or were conducted in the context of a clinical trial, thereby limiting our understanding of incident neurocognitive (NC) decline and recovery. Methods. We investigated the incidence and predictors of NC change over 16–72 (mean, 35) months in 436 HIV-infected participants in the CNS HIV Anti-Retroviral Therapy Effects Research cohort. Comprehensive laboratory, neuromedical, and NC assessments were obtained every 6 months. Published, regression-based norms for NC change were used to generate overall change status (decline vs stable vs improved) at each study visit. Survival analysis was used to examine the predictors of time to NC change. Results. Ninety-nine participants (22.7%) declined, 265 (60.8%) remained stable, and 72 (16.5%) improved. In multivariable analyses, predictors of NC improvements or declines included time-dependent treatment status and indicators of disease severity (current hematocrit, albumin, total protein, aspartate aminotransferase), and baseline demographics and estimated premorbid intelligence quotient, non-HIV-related comorbidities, current depressive symptoms, and lifetime psychiatric diagnoses (overall model P < .0001). Conclusions. NC change is common in HIV infection and appears to be driven by a complex set of risk factors involving HIV disease, its treatment, and comorbid conditions.

Improvements in the diagnosis and treatment of congenital disorders have resulted in a change in surgical practice. Many conditions that formerly required corrective surgery immediately after birth are no longer surgical emergencies. Most babies with congenital anomalies that can be corrected by surgery are now stabilized and optimized before the procedure. This article focused on the more common conditions that require semi-elective or urgent surgery in the neonatal period. Salient features of each of these disorders were described. Factors unique to each of these conditions that can affect the anesthetic course of these children were discussed. Methods and techniques that may aid in the anesthetic management of these children were delineated.