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Background: The British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) is a validated global measure of treatment response in systemic lupus erythematosus (SLE) clinical trials but does not include patient-reported outcomes. To evaluate the clinical meaningfulness of a BICLA response from the patient perspective, we aimed to analyse patient-reported outcomes by BICLA responses with anifrolumab or placebo in patients with moderate to severe SLE., Methods: We did a post-hoc analysis of pooled data from the phase 3 TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) trials of anifrolumab, which assessed health-related quality of life using the Short Form 36 Health Survey (SF-36; version 2) and Lupus Quality of Life, fatigue using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), pain using the Numerical Rating Scale, and disease activity using Patient Global Assessment. Changes from baseline and proportions of patients reporting improvements in patient-reported outcomes greater than or equal to the minimum clinically important differences and scores greater than or equal to the normative values were compared in BICLA responders and non-responders and by treatment group (intravenous anifrolumab 300 mg or placebo)., Findings: 726 patients were included in the TULIP trials, of whom 366 received placebo (184 patients in TULIP-1 and 182 in TULIP-2) and 360 received anifrolumab 300 mg (180 patients in each trial). The mean patient age was 41·8 years (SD 11·9). 674 (93%) patients were female, 52 (7%) were male, and 479 (66%) were White; 283 (39%) were BICLA responders and 443 (61%) were BICLA non-responders. Compared with non-responders, BICLA responders reported greater mean improvements from baseline at week 52 in Patient Global Assessment, SF-36, Lupus Quality of Life, FACIT-F, and pain Numerical Rating Scale scores (all nominal p<0·0053). Compared with non-responders, a greater proportion of BICLA responders reported improvements greater than or equal to the minimum clinically important difference across all SF-36 domains; eg, Physical Component Summary (165 [60%] of 277 for responders vs 63 [15%] of 416 for non-responders), Mental Component Summary (140 [51%] of 276 vs 59 [15%] of 416), and role physical (184 [70%] of 264 vs 76 [19%] of 398); Lupus Quality of Life domains; eg, physical health (151 [58%] of 262 vs 60 [15%] of 396), and intimate relationships (77 [41%] of 187 vs 33 [11%] of 286), and FACIT-F (155 [56%] of 276 vs 66 [15%] of 439). Similarly, a greater proportion of BICLA responders had scores equal to or greater than the normative values across all SF-36 domains and FACIT-F compared with BICLA non-responders at week 52. Patients who received anifrolumab reported greater numerical improvements in Patient Global Assessment, SF-36, Lupus Quality of Life, FACIT-F, and pain Numerical Rating Scale scores than those who received placebo., Interpretation: BICLA responders reported significant and clinically meaningful improvements in Patient Global Assessment, health-related quality of life, fatigue, and pain compared with BICLA non-responders. More patients with moderate to severe SLE who received anifrolumab were BICLA responders and had improved health-related quality of life, fatigue, and pain than those who received placebo., Funding: AstraZeneca., Competing Interests: Declaration of interests VS reports consulting fees from AbbVie, Amgen, Arena, AstraZeneca, Bayer, Bioventus, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Corrona, Crescendo/Myriad, Eli Lilly, EMD Serono, Equillium, Flexion, Genentech/Roche, Glenmark, GlaxoSmithKline, Horizon, Inmedix, Janssen, Kypha, Merck, Novartis, Pfizer, Regeneron, Samsung, Samumed, Sandoz, Sanofi, Servier, Setpoint, twoXAR, and UCB. RAF reports grants or research support and consulting fees from AstraZeneca. EFM reports grants from, was a consultant for, and was a speaker at a speaker bureau for AstraZeneca; grants and consulting fees from Bristol Myers Squibb, Eli Lilly, EMD Serono, GlaxoSmithKline, and Janssen; and consulting fees from Amgen, Biogen, Genentech, Servier, UCB, and Wolf Biotherapeutics. KCK reports consulting fees from AstraZeneca, Amgen, Biogen, Bristol Myers Squibb, Chemocentrix, Eli Lilly, Equillium, Genetech/Roche, Gilead, GlaxoSmithKline, Janssen, Kezar, Kirin, Pfizer, and Viela Bio. SO’Q, EGS, GA, and RT are employees of AstraZeneca., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Human Papillomavirus is one of the most well-known pathogens having potential to cause both benign and malignant illnesses. The current controversy focuses on its continuity in non-epithelial tissues and the environment, and its ability to cause infection in these settings. This review addresses the virology aspects that contribute to its presence and resistance in humans and the environment.

Background: Down syndrome is a chromosomal disorder with considerable neurodevelopmental impact and neurodegenerative morbidity. In a pilot trial in young adults with Down syndrome, memantine (a drug approved for Alzheimer's disease) showed a significant effect on a secondary measure of episodic memory. We aimed to test whether memantine would improve episodic memory in adolescents and young adults with Down syndrome., Methods: We did a randomised, double-blind, placebo-controlled phase 2 trial with a parallel design, stratified by age and sex. Participants (aged 15-32 years) with either trisomy 21 or complete unbalanced translocation of chromosome 21 and in general good health were recruited from the community at one site in Brazil and another in the USA. Participants were randomly assigned (1:1) to receive either memantine (20 mg/day orally) or placebo for 16 weeks. Computer-generated randomisation tables for both sites (allocating a placebo or drug label to each member of a unique pair of participants) were centrally produced by an independent statistician and were shared only with investigational pharmacists at participating sites until unblinding of the study. Participants and investigators were masked to treatment assignments. Neuropsychological assessments were done at baseline (T1) and week 16 (T2). The primary outcome measure was change from baseline to week 16 in the California Verbal Learning Test-second edition short-form (CVLT-II-sf) total free recall score, assessed in the per-protocol population (ie, participants who completed 16 weeks of treatment and had neuropsychological assessments at T1 and T2). Linear mixed effect models were fit to data from the per-protocol population. Safety and tolerability were monitored and analysed in all participants who started treatment. Steady-state concentrations in plasma of memantine were measured at the end of the trial. This study is registered at ClinicalTrials.gov, number NCT02304302., Findings: From May 13, 2015, to July 22, 2020, 185 participants with Down syndrome were assessed for eligibility and 160 (86%) were randomly assigned either memantine (n=81) or placebo (n=79). All participants received their allocated treatment. Linear mixed effect models were fit to data from 149 (81%) participants, 73 in the memantine group and 76 in the placebo group, after 11 people (eight in the memantine group and three in the placebo group) discontinued due to COVID-19 restrictions, illness of their caregiver, adverse events, or low compliance. The primary outcome measure did not differ between groups (CVLT-II-sf total free recall score, change from baseline 0·34 points [95% CI -0·98 to 1·67], p=0·61). Memantine was well tolerated, with infrequent mild-to-moderate adverse events, the most common being viral upper respiratory infection (nine [11%] participants in the memantine group and 12 [15%] in the placebo group) and transient dizziness (eight [10%] in the memantine group and six [8%] in the placebo group). No serious adverse events were observed. Amounts of memantine in plasma were substantially lower than those considered therapeutic for Alzheimer's disease., Interpretation: Memantine was well tolerated, but cognition-enhancing effects were not recorded with a 20 mg/day dose in adolescents and young adults with Down syndrome. Exploratory analyses point to a need for future work., Funding: Alana Foundation., Translation: For the Portuguese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: This study retrospectively evaluated the medium- and long-term results of patients submitted to double-bundle (DB) anterior cruciate ligament (ACL) reconstruction., Methods: A retrospective study of case series at a single center. Cases submitted to isolated ACL reconstruction with at least five years of follow-up were included. The following data were collected: demographic data; practice of competitive sport before the injury; previous surgery; injury/surgery in the contralateral knee; return to the practices of sports and level; re-injury (postoperative time; mechanism; need for surgery); and symptoms at the last clinical follow-up visit. Descriptive and sub-group analyses were performed., Results: Sixty-nine patients were included; 52 men (75%), 49 athletes (71%), 47 (68%) with primary injury, mean age of 30 years (SD 10). The patients were followed up for an average of 8.7 years (minimum 5, maximum 11.8) after surgery. After the reconstruction, 67 (97%) returned to the sport; 75% at the same level as before the injury. Ten patients (14%) suffered re-injury after an average of 32 months (between 9 and 50 months). Regarding the outcome of re-injury, no statistically significant differences were found between subgroups of athletes vs non-athletes or primary injury vs revision surgery, despite a significant tendency towards increased re-injury levels in athletes. However, this tendency was not statistically significant., Conclusion: In our series of patients operated on with the double-bundle technique and with a long follow-up time, 14% presented re-injury, with no differences between primary and revision cases, and with a trend towards higher re-injury levels among the athletes in relation to the non-athletes. The rate of return to sport was satisfactory, with 97%, of which 75% were playing at the same level as before the injury., Competing Interests: Declarations of interest: Wagner Castropil is a paid consultant for DePuy Synthes; All other authors declare no potential conflict of interest

Objective: The British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) is a validated global measure of treatment response in systemic lupus erythematosus (SLE) clinical trials. To understand the relevance of BICLA in clinical practice, we investigated relationships between BICLA response and routine SLE assessments, patient-reported outcomes (PROs), and medical resource utilization., Methods: This was a post hoc analysis of pooled data from the phase III, randomized, placebo-controlled, 52-week TULIP-1 (ClinicalTrials.gov identifier: NCT02446912; n = 457) and TULIP-2 (ClinicalTrials.gov identifier: NCT02446899; n = 362) trials of intravenous anifrolumab (150/300 mg once every 4 weeks) in patients with moderate-to-severe SLE. Changes from baseline to week 52 in clinical assessments, PROs, and medical resource use were compared in BICLA responders versus nonresponders, regardless of treatment assignment., Results: BICLA responders (n = 318) achieved significantly improved outcomes compared with nonresponders (n = 501), including lower flare rates, higher rates of attainment of sustained oral glucocorticoid taper to ≤7.5 mg/day, greater improvements in PROs (Functional Assessment of Chronic Illness Therapy-Fatigue, Short Form 36 Health Survey), and fewer SLE-related hospitalizations/emergency department visits (all nominal P < 0.001). Compared with nonresponders, BICLA responders had greater improvements in global and organ-specific disease activity (Physician's Global Assessment, SLE Disease Activity Index 2000, Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity, and joint counts; all nominal P < 0.001). BICLA responders had fewer lupus-related serious adverse events than nonresponders., Conclusion: BICLA response is associated with clinical benefit in SLE assessments, PROs, and medical resource utilization, confirming its value as a clinical trial end point that is associated with measures important to patient care., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Systemic lupus erythematosus (SLE) management objectives include preventing disease flares while minimizing glucocorticoid exposure. Pooled data from the phase 3 TULIP-1 and TULIP-2 trials in patients with moderate to severe SLE were analyzed to determine anifrolumab's effect on flares, including those arising with glucocorticoid taper., Methods: TULIP-1 and TULIP-2 were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks for 48 weeks). For patients receiving baseline glucocorticoid ≥10 mg/day, attempted taper to ≤7.5 mg/day prednisone or equivalent from Weeks 8-40 was required and defined as sustained reduction when maintained through Week 52. Flares were defined as ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B scores versus the previous visit. Flare assessments were compared for patients receiving anifrolumab versus placebo., Results: Compared with placebo (n = 366), anifrolumab (n = 360) was associated with lower annualized flare rates (rate ratio 0.75, 95% confidence interval [CI] 0.60-0.95), prolonged time to first flare (hazard ratio 0.70, 95% CI 0.55-0.89), and fewer patients with ≥1 flare (difference -9.3%, 95% CI -16.3 to -2.3), as well as flares in organ domains commonly active at baseline (musculoskeletal, mucocutaneous). Fewer BILAG-based Composite Lupus Assessment responders had ≥1 flare with anifrolumab (21.1%, 36/171) versus placebo (30.4%, 34/112). Of patients who achieved sustained glucocorticoid reductions from ≥10 mg/day at baseline, more remained flare free with anifrolumab (40.0%, 76/190) versus placebo (17.3%, 32/185)., Conclusions: Analyses of pooled TULIP-1 and TULIP-2 data support that anifrolumab reduces flares while permitting glucocorticoid taper in patients with SLE. ClinicalTrials.gov identifiers TULIP-1 NCT02446912 (clinicaltrials.gov/ct2/show/NCT02446912);TULIP-2 NCT02446899 (clinicaltrials.gov/ct2/show/NCT02446899).

Objective: To investigate long-term safety and tolerability of anifrolumab, a human monoclonal antibody to the type I interferon (IFN) receptor subunit 1, in patients with moderate-to-severe systemic lupus erythematosus (SLE)., Methods: This 3-year, multinational, open-label extension study included adult patients who completed treatment (48 weeks of anifrolumab or placebo; 12-week follow-up) in the MUSE phase IIb randomized controlled trial (RCT). Patients initially received 1,000 mg of anifrolumab intravenously every 4 weeks, which was reduced to 300 mg every 4 weeks based on the benefit/risk profile established in the MUSE trial. Adverse events (AEs) were assessed monthly. Exploratory end points included the SLE Disease Activity Index 2000 (SLEDAI-2K), Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), pharmacodynamics, and health-related quality of life (HRQoL)., Results: Of the 246 patients who completed the RCT, 218 (88.6%) enrolled in the open-label extension study, of which 139 (63.8%) completed 3 years of treatment. Approximately 69.7% of patients reported ≥1 AE during the first year of open-label extension treatment. Frequency and patterns of serious AEs and AEs of special interest over 3 years were consistent with those reported for 1 year of treatment in the RCT. Few patients (6.9%) discontinued treatment due to AEs. No new safety signals were identified. Improvement in the SLEDAI-2K was sustained over 3 years. SDI and Short Form 36 health survey scores remained stable. Neutralization of type I IFN gene signatures was maintained in the IFN-high population, and C3, C4, and anti-double-stranded DNA showed trends toward sustained improvement., Conclusion: Long-term anifrolumab treatment demonstrates an acceptable safety profile with sustained improvement in SLE disease activity, HRQoL, and serologic measures., (© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: 300 mg of intravenous anifrolumab every 4 weeks added to standard-of-care treatment for patients with systemic lupus erythematosus (SLE) reduced disease activity and glucocorticoid requirement in a previous phase 3 trial. Because patients might find subcutaneous administration more convenient than intravenous delivery, we aimed to evaluate the pharmacokinetics, pharmacodynamics, safety, and efficacy of subcutaneous anifrolumab in patients with SLE, active skin disease, and a high type I interferon gene signature., Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 2 study was done at 12 hospitals and outpatient clinics in Hungary, South Korea, Poland, and the USA. Eligible patients were aged 18-70 years, and had SLE with high type I interferon gene signature and an activity score on the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) of at least 10. Enrolled participants were randomly assigned (3:1:3:1) by use of a voice-web response system to receive either 150 mg of subcutaneous anifrolumab or corresponding placebo, or 300 mg of subcutaneous anifrolumab or corresponding placebo in addition to stable standard-of-care treatment. The study was double-blinded with respect to intervention but not dose, until 12 weeks. Doses of oral glucocorticoids were tapered after week 12. The primary pharmacokinetic endpoint was the serum concentration of anifrolumab based on the maximum concentration after the first dose and the minimum (trough) concentration before subsequent doses and was measured in all patients who received anifrolumab and had at least one quantifiable serum pharmacokinetics observation following the first dose. The primary pharmacodynamic endpoint was neutralisation of the type I interferon pharmacodynamic signature at week 12 and was assessed in all patients with a high type I interferon pharmacodynamics signature at baseline based on a 21-gene test. Safety was evaluated in the full analysis set, which included all patients who received at least one dose of anifrolumab. This trial is completed and is registered at ClinicalTrials.gov, NCT02962960., Findings: Between March 14, 2017, and Oct 26, 2017, 36 patients were randomly assigned to receive 150 mg of anifrolumab (n=14), 300 mg of anifrolumab (n=13), or placebo (n=9). Two patients in the anifrolumab 150 mg group were excluded from the pharmacodynamic analysis set (n=34). Ten (71%) of 14 patients in the anifrolumab 150 mg group, ten (77%) of 13 patients in the anifrolumab 300 mg group, and nine (100%) of the nine patients in the placebo group completed 52 weeks of treatment. At week 12, pre-dose mean trough serum concentrations of anifrolumab were more than dose proportional between the anifrolumab 150 mg group (19·82 μg/mL [SD 15·01]) and the anifrolumab 300 mg group (60·28 μg/mL [43·66]), and the pharmacokinetics were non-linear. At week 12, the median percentage neutralisation of the type I interferon gene signature was higher with 150 mg (88·0% [median absolute deviation 7·4]) and 300 mg (90·7% [3·3]) of anifrolumab than with placebo (18·5% [8·1]), and more patients in the anifrolumab 150 mg group and the anifrolumab 300 mg group than in the placebo group had neutralisation of 75% or more (eight [67%] of 12 vs ten [77%] of 13 vs one [11%] of nine). At least one adverse event was reported by 23 (85%) of 27 patients in the anifrolumab groups and by seven (78%) of nine patients in the placebo group; most adverse events were of mild-to-moderate severity. Serious adverse events were reported in six (22%) of 27 patients in the anifrolumab groups (four patients in the 150 mg group and two in the 300 mg group). No serious adverse events were reported in the placebo group. Herpes zoster infection was reported by three (11%) of 27 patients in the anifrolumab groups and by one (11%) of nine patients in the placebo group. There were no treatment-related deaths., Interpretation: Anifrolumab, administered subcutaneously every 2 weeks to patients with SLE and moderate-to-severe skin manifestations, had non-linear pharmacokinetics that were more than dose proportional, and neutralised the type I interferon gene signature in a dose-dependent manner. The safety profile was consistent with previous studies of intravenous anifrolumab, supporting the continued development of anifrolumab as a subcutaneously administered therapy for patients with SLE., Funding: AstraZeneca., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: In phase II and III trials, anifrolumab, a human monoclonal antibody that binds type I interferon receptor subunit 1, has shown efficacy in adults with moderate to severe SLE. We evaluated the safety and tolerability of anifrolumab using data pooled from these trials to more precisely estimate the rate and severity of adverse events (AEs)., Methods: Data were pooled from patients receiving monthly intravenous anifrolumab 300 mg or placebo in MUSE, TULIP-1 and TULIP-2. Key safety endpoints included percentages and exposure-adjusted incidence rates (EAIRs) of patients who experienced AEs, serious AEs (SAEs), AEs leading to discontinuation and AEs of special interest., Results: During treatment, 86.9% of patients receiving anifrolumab 300 mg (n=459) experienced AEs (≥1) versus 79.4% receiving placebo (n=466), and 4.1% versus 5.2% experienced an AE leading to discontinuation of investigational product. SAEs (≥1) were experienced by 11.8% and 16.7% of patients receiving anifrolumab and placebo, respectively (EAIR risk difference (95% CI) -7.2 (-12.5 to -1.9)), including lupus exacerbations classified as SAEs (1.5% and 3%, respectively). Infections occurred in 69.7% and 55.4% of patients receiving anifrolumab and placebo, respectively; difference in reported rates was driven by herpes zoster (HZ) and mild and moderate respiratory (excluding pneumonia) infections. The risk of HZ was increased with anifrolumab versus placebo (6.1% vs 1.3%, respectively; EAIR risk difference (95% CI) 5.4 (2.8 to 8.4)); most HZ events were mild or moderate, cutaneous and resolved without treatment discontinuation. Serious infections occurred in 4.8% and 5.6% of patients receiving anifrolumab and placebo, respectively., Conclusions: In this pooled analysis of 925 patients with moderate to severe SLE, monthly intravenous anifrolumab 300 mg was generally well tolerated over 52 weeks with an acceptable safety profile. Anifrolumab was associated with an increased incidence of HZ and respiratory tract infections and lower reported rate of SLE worsening as SAEs., Competing Interests: Competing interests: RT, GA, LP, MAM and RNK are employees of AstraZeneca. RAF has received grant/research support and consulting fees from AstraZeneca. EM has received grant support from, was a consultant for and was a speaker at a speaker bureau for AstraZeneca; received grant support and consulting fees from AbbVie, BMS, Eli Lilly, GSK, Janssen, Merck Serono and UCB; received grant support from BMS; and received consulting fees from Amgen, Biogen, CSL Inc, Neovacs and Wolf Biotherapeutics., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Carbapenem resistance rates increased exponentially between 2014 and 2017 in Portugal (~80%), especially in Klebsiella pneumoniae . We characterized the population of carbapanemase-producing Enterobacterales (CPE) infecting or colonizing hospitalized patients (2017-2018) in a central hospital from northern Portugal, where KPC-3-producing K. pneumoniae capsular type K64 has caused an initial outbreak. We gathered phenotypic (susceptibility data), molecular (population structure, carbapenemase, capsular type) and biochemical (FT-IR) data, together with patients' clinical and epidemiological information. A high diversity of Enterobacterales species, clones (including E. coli ST131) and carbapenemases (mainly KPC-3 but also OXA-48 and VIM) was identified three years after the onset of carbapenemases spread in the hospital studied. ST147-K64 K. pneumoniae , the initial outbreak clone, is still predominant though other high-risk clones have emerged (e.g., ST307, ST392, ST22), some of them with pandrug resistance profiles. Rectal carriage, previous hospitalization or antibiotherapy were presumptively identified as risk factors for subsequent infection. In addition, our previously described Fourier Transform infrared (FT-IR) spectroscopy method typed 94% of K. pneumoniae isolates with high accuracy (98%), and allowed to identify previously circulating clones. This work highlights an increasing diversity of CPE infecting or colonizing patients in Portugal, despite the infection control measures applied, and the need to improve the accuracy and speed of bacterial strain typing, a goal that can be met by simple and cost-effective FT-IR based typing.

The COVID-19 pandemic has called attention to the contribution of comorbidities, including cancer and brought additional challenges to previously existing programs for cancer treatment and control. The COVID-19 pandemic in Cuba was addressed through an integrated all-society action plan that to date has been largely successful with a low incidence of COVID-19 and mortality rates several-fold lower than worldwide averages. Despite downsizing many other health components all oncology services were maintained. Between March 11, when the first case was detected, until July 23, Cuba reported 2,449 cases of COVID-19 that included 28 (1.14%) with a diagnosis of cancer. Distribution among cancer diagnoses did not deviate from that expected according to cancer epidemiology in Cuba. However, although the probability of getting infected with the coronavirus for a cancer patient (0.012%), was not higher than that of the general population (0.020%), 9 of the 28 (32.1%) died, a lethality higher than that of COVID-19 patients without cancer (3.5%) a difference that is statistically significant (P< .001). We argue that going forward scientific research on the relationship of aging, inflammation and cancer, including identification of biomarkers and the development of novel therapeutic interventions, should become one of the priorities in the post-COVID agenda of both oncologists and infectious disease scientists., Competing Interests: Conflicts of interest Authors do not have any commercial or financial conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

Background: Wild capuchin monkeys (Sapajus libidinosus) usually are found in conserved forests near the zoo and the urban areas of Brasília city, Brazil. In this study, some capuchin monkeys were captured using traps, followed by safe biological procedures for their overall health analysis, based on specific haematological and biochemical tests of blood samples., Methods: Blood was collected from a total of 17 monkeys for the determination of parameters, namely packed cell volume (PCV), leucocytes, erythrocytes, platelets and triglycerides. Statistical analyses for average values, median, standard deviation and range were performed., Results: These parameters were set based on the minimum and maximum values obtained from the blood tests. Data are presented in tabulated form., Conclusions: Capture procedures were based on animal safety analysis for free-living animals and would help future studies on wild animals. The collected samples used in this study suggested the animals to be apparently healthy in their habitat., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Fructans, such as inulin and fructooligosaccharides (FOS), have several effects on human health owing to their prebiotic character, including anti-microbial and anti-cancer effects, and to their influence on the absorption of minerals, which is very important in childhood and adolescence., Objective: Our aim was to review the role of some fructans in the absorption of vitamins and minerals in children and adolescents., Methods: We conducted a narrative review of the absorption of nutrients with fructans. We collected quantitative data for our thematic analysis, which was performed using the electronic databases Medline, Lilacs, Web of Science, and Scopus from January 2000 and January 2019. This review comprises a total of 10 articles., Results: Few studies were found regarding the use of prebiotics and nutrient absorption in children. Studies on calcium, iron, magnesium, and vitamin D were the most prevalent. Some studies reported that FOS appears to increase calcium uptake in the gut and stimulates the growth of bifidobacterium in the colon, reducing iron intake by enteric pathogens, and increasing the absorption of these minerals. Others reported an improvement in the absorption of vitamin D and E with inulin., Conclusion: Consumption of fructans improves the health of the microbiota, altering the absorption of some nutrients., (Copyright © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Aim: Magnetic resonance imaging (MRI) is increasingly being used to evaluate brown adipose tissue (BAT) function. Reports on the extent and direction of cold-induced changes in MRI fat fraction and estimated BAT volume vary between studies. Here, we aimed to explore the effect of different fat fraction threshold ranges on outcomes measured by MRI. Moreover, we aimed to investigate the effect of cold exposure on estimated BAT mass and energy content. Methods: The effects of cold exposure at different fat fraction thresholding levels were analyzed in the supraclavicular adipose depot of nine adult males. MRI data were reconstructed, co-registered and analyzed in two ways. First, we analyzed cold-induced changes in fat fraction, T2* relaxation time, volume, mass, and energy of the entire supraclavicular adipose depot at different fat fraction threshold levels. As a control, we assessed fat fraction differences of deltoid subcutaneous adipose tissue (SAT). Second, a local analysis was performed to study changes in fat fraction and T2* on a voxel-level. Thermoneutral and post-cooling data were compared using paired-sample t -tests ( p < 0.05). Results: Global analysis unveiled that the largest cold-induced change in fat fraction occurred within a thermoneutral fat fraction range of 30-100% (-3.5 ± 1.9%), without changing the estimated BAT volume. However, the largest cold-induced changes in estimated BAT volume were observed when applying a thermoneutral fat fraction range of 70-100% (-3.8 ± 2.6%). No changes were observed for the deltoid SAT fat fractions. Tissue energy content was reduced from 126 ± 33 to 121 ± 30 kcal, when using a 30-100% fat fraction range, and also depended on different fat fraction thresholds. Voxel-wise analysis showed that while cold exposure changed the fat fraction across nearly all thermoneutral fat fractions, decreases were most pronounced at high thermoneutral fat fractions. Conclusion: Cold-induced changes in fat fraction occurred over the entire range of thermoneutral fat fractions, and were especially found in lipid-rich regions of the supraclavicular adipose depot. Due to the variability in response between lipid-rich and lipid-poor regions, care should be taken when applying fat fraction thresholds for MRI BAT analysis., (Copyright © 2020 Abreu-Vieira, Sardjoe Mishre, Burakiewicz, Janssen, Nahon, van der Eijk, Riem, Boon, Dzyubachyk, Webb, Rensen and Kan.)

WHO's 2015 End Tuberculosis Strategy can succeed only through universal health coverage, social protection, poverty alleviation and effective multisector actions to tackle social determinants in general. The pediatric age group is particularly vulnerable to tuberculosis and historically neglected worldwide. However, this group is a priority within Cuba's National Tuberculosis Control Pro-gram that has functioned since 1970, and Cuba is considered a low-incidence country with rates < 7 per 100,000 population since 2011. Tuberculosis incidence in children aged <15 years is <1 per 100,000, similar to that reported in high-income countries and rep-resenting less than 2% of total cases in Cuba. Since 1999, no deaths from tuberculosis, coinfection with HIV or resistance to the two first-line TB drugs have been reported in affected children, and most diagnosed cases correspond to early, primary forms of the disease. These results place Cuba among the countries on track to eliminate TB by 2050. This article reviews the pillars and components of the 2015 End TB Strategy and the strategies devel-oped by the National Tuberculosis Control Program that enabled Cuba to bring incidence below the 2035 targets of WHO's End TB strategy. The article also proposes other actions Cuba can take, despite limited resources, to eliminate TB, particularly in the pedi-atric age group.KEYWORDS Tuberculosis, communicable disease control, disease control programs, preventive health services, child health, World Health Organization, Cuba.

Background: In Latin America, there is scarce information about severe asthma (SA) according to the ERS/ATS 2014 criteria. This study aimed to compare the demographic, socio, clinical characteristics, treatment, and use of healthcare resources between SA and non-severe asthma (NSA) patients in Argentina, Colombia, Chile and Mexico., Methods: A cross-sectional study was conducted including 594 asthma patients from outpatient specialized sites. A descriptive analysis was performed comparing SA patients and NSA. Chi-square and Mann Whitney tests were used to assess associations between asthma severity and outcome variables., Results: Using ERS/ATS 2014 criteria, 31.0% of the patients were identified as SA. SA patients were older at diagnosis (mean age 31.64 years vs 24.71 years, p < 0.001) and had higher proportion of uncontrolled asthma than the NSA patients (64.1% vs 53.2%, p < 0.001). SA patients reported a significantly higher proportion of both hospital admission and emergency room (ER) visits due to asthma in the last year, compared with NSA patients, 8.7% vs. 3.7% (p = 0.011) and 37.0% vs. 21.7% (p < 0.001), respectively., Conclusions: SA patients were older, had greater proportions in some comorbidities and experienced increased healthcare utilization. Also, our results showed that even in patients using the last steps of treatment (GINA step 4 or 5), there was still a higher proportion of uncontrolled disease.

Aims/hypothesis: The aim of this study was to evaluate the effect of sitagliptin on glucose tolerance, plasma lipids, energy expenditure and metabolism of brown adipose tissue (BAT), white adipose tissue (WAT) and skeletal muscle in overweight individuals with prediabetes (impaired glucose tolerance and/or impaired fasting glucose)., Methods: We performed a randomised, double-blinded, placebo-controlled trial in 30 overweight, Europid men (age 45.9 ± 6.2 years; BMI 28.8 ± 2.3 kg/m 2 ) with prediabetes in the Leiden University Medical Center and the Alrijne Hospital between March 2015 and September 2016. Participants were initially randomly allocated to receive sitagliptin (100 mg/day) (n = 15) or placebo (n = 15) for 12 weeks, using a randomisation list that was set up by an unblinded pharmacist. All people involved in the study as well as participants were blinded to group assignment. Two participants withdrew from the study prior to completion (both in the sitagliptin group) and were subsequently replaced with two new participants that were allocated to the same treatment. Before and after treatment, fasting venous blood samples and skeletal muscle biopsies were obtained, OGTT was performed and body composition, resting energy expenditure and [ 18 F] fluorodeoxyglucose ([ 18 F]FDG) uptake by metabolic tissues were assessed. The primary study endpoint was the effect of sitagliptin on BAT volume and activity., Results: One participant from the sitagliptin group was excluded from analysis, due to a distribution error, leaving 29 participants for further analysis. Sitagliptin, but not placebo, lowered glucose excursion (-40%; p < 0.003) during OGTT, accompanied by an improved insulinogenic index (+38%; p < 0.003) and oral disposition index (+44%; p < 0.003). In addition, sitagliptin lowered serum concentrations of triacylglycerol (-29%) and very large (-46%), large (-35%) and medium-sized (-24%) VLDL particles (all p < 0.05). Body weight, body composition and energy expenditure did not change. In skeletal muscle, sitagliptin increased mRNA expression of PGC1β (also known as PPARGC1B) (+117%; p < 0.05), a main controller of mitochondrial oxidative energy metabolism. Although the primary endpoint of change in BAT volume and activity was not met, sitagliptin increased [ 18 F] FDG uptake in subcutaneous WAT (sWAT; +53%; p < 0.05). Reported side effects were mild and transient and not necessarily related to the treatment., Conclusions/interpretation: Twelve weeks of sitagliptin in overweight, Europid men with prediabetes improves glucose tolerance and lipid metabolism, as related to increased [ 18 F] FDG uptake by sWAT, rather than BAT, and upregulation of the mitochondrial gene PGC1β in skeletal muscle. Studies on the effect of sitagliptin on preventing or delaying the progression of prediabetes into type 2 diabetes are warranted., Trial Registration: ClinicalTrials.gov NCT02294084., Funding: This study was funded by Merck Sharp & Dohme Corp, Dutch Heart Foundation, Dutch Diabetes Research Foundation, Ministry of Economic Affairs and the University of Granada.

Background: Spontaneous coronary artery dissection (SCAD) is an unusual cause of acute coronary syndrome (ACS). Better recognition and diagnosis has raised awareness of this condition. However, the pathophysiology of SCAD and its prognosis are still little understood. We aimed to investigate the characteristics and prognosis of patients with SCAD, and subsequently performed a review of literature., Methods: Single-center, retrospective study performed in patients hospitalized from January 2010 to December 2016 with suspected ACS (n=5002) whose final diagnosis was SCAD (n=27; 0.5%)., Results: Patients with SCAD were mainly female (81.5%; n=22), with median age of 56. Predisposing factors were identified in 12 (44%) patients and precipitating factors in three (11.1%). Non-ST elevation myocardial infarction (NSTEMI) was the main form of presentation (51.9%). The left anterior descending artery (LAD) territory was the most commonly involved (n=12, 44.4%). Type 2 dissection was the most prevalent angiographic pattern (n=17, 63%). The majority of patients (n=15; 55.6%) were managed medically and the remaining patients underwent percutaneous coronary intervention (PCI) with drug-eluting stents. Seven patients re-infarcted while in the hospital. Over the median follow-up period of 20 months, 7.4% of patients (n=2) had symptoms of heart failure (HF) and 14.8% developed ACS (in three patients the event occurred in a coronary territory other than that of the index case, and in one patient it occurred in the previously affected territory). There were no deaths., Conclusion: In the studied population, SCAD was more prevalent in middle-aged women. Despite the high prevalence of in-hospital re-infarction or during follow-up, the prognosis was good overall., (Copyright © 2018 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Human brown adipose tissue (BAT) is commonly assessed by cold-induced 18 F-fluorodeoxyglucose (FDG) PET-CT using several quantification criteria. Uniform criteria for data analysis became available recently (BARCIST 1.0). We compared BAT volume and activity following BARCIST 1.0 criteria against the most commonly used criteria [Hounsfield Units (HU):-250, -50, standardized uptake value (SUV):2.0; HU: Not applied, SUV:2.0 and HU:-180, -10, SUV:1.5] in a prospective study using three independent cohorts of men including young lean adults, young overweight/obese adults and middle-aged overweight/obese adults. BAT volume was the most variable outcome between criteria. While BAT volume calculated using the HU: NA; SUV: 2.0 criteria was up to 207% higher than the BAT volume calculated based on BARCIST 1.0 criteria, it was up to 57% lower using the HU: -250, -50; SUV: 2.0 criteria compared to the BARCIST 1.0. Similarly, BAT activity (expressed as SUV mean ) also differed between different thresholds mainly because SUV mean depends on BAT volume. SUV peak was the most consistent BAT outcome across the four study criteria. Of note, we replicated these findings in three independent cohorts. In conclusion, BAT volume and activity as determined by 18 F-FDG-PET/CT highly depend on the quantification criteria used. Future human BAT studies should conduct sensitivity analysis with different thresholds in order to understand whether results are driven by the selected HU and/or SUV thresholds. The design of the present study precludes providing any conclusive threshold, but before more definitive thresholds for HU and SUV are available, we support the use of BARCIST 1.0 criteria to facilitate interpretation of BAT characteristics between research groups.

Introduction: Prompt identification of higher-risk patients presenting with ST-segment elevation myocardial infarction (STEMI) is crucial to pursue a more aggressive approach., Objective: We aimed to assess whether the modified shock index (MSI), the ratio of heart rate to mean arterial pressure, could predict six-month mortality among patients admitted with STEMI., Methods: A retrospective observational cohort study was performed in a single center including 1158 patients diagnosed with STEMI, without cardiogenic shock on admission, between July 2009 and December 2014. They were divided into two groups: group 1 - patients with MSI<0.93 (72%); group 2 - patients with MSI≥0.93 (28%). The primary endpoint was six-month all-cause mortality., Results: MSI≥0.93 identified patients who were more likely to have signs of heart failure (p=0.002), anemia (p<0.001), renal insufficiency (p=0.014) and left ventricular systolic dysfunction (p=0.045). They more often required inotropic support (p<0.001), intra-aortic balloon pump (p<0.001) and mechanical ventilation (p<0.001). Regarding in-hospital adverse events, they had a higher prevalence of malignant arrhythmias (p=0.01) and mechanical complications (p=0.027). MSI≥0.93 was an independent predictor of overall six-month mortality (adjusted HR 2.00, 95% CI 1.20-3.34, p=0.008)., Conclusion: MSI was shown to be a valuable bedside tool which can rapidly identify high-risk STEMI patients at presentation., (Copyright © 2018 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Many favorable metabolic effects have been attributed to thermogenic activity of brown adipose tissue (BAT). Yet, time of day has rarely been considered in this field of research. Here, we show that a diurnal rhythm in BAT activity regulates plasma lipid metabolism. We observed a high-amplitude rhythm in fatty acid uptake by BAT that synchronized with the light/dark cycle. Highest uptake was found at the onset of the active period, which coincided with high lipoprotein lipase expression and low angiopoietin-like 4 expression by BAT. Diurnal rhythmicity in BAT activity determined the rate at which lipids were cleared from the circulation, thereby imposing the daily rhythm in plasma lipid concentrations. In mice as well as humans, postprandial lipid excursions were nearly absent at waking. We anticipate that diurnal BAT activity is an important factor to consider when studying the therapeutic potential of promoting BAT activity., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: There have been no prospective randomized trials that enable the best strategy and timing to be determined for revascularization in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and multivessel coronary artery disease (CAD)., Objectives: To compare short- and long-term adverse events following multivessel vs. culprit-only revascularization in patients with NSTE-ACS and multivessel CAD., Methods: This was a retrospective observational study that included all patients diagnosed with NSTE-ACS and multivessel CAD who underwent percutaneous coronary intervention (PCI) between January 2010 and June 2013 (n=232). After exclusion of patients with previous coronary artery bypass grafting (n=30), a multivessel revascularization strategy was adopted in 35.1% of patients (n=71); in the others (n=131, 64.9%), only the culprit artery was revascularized. After propensity score matching (PSM), two groups of 66 patients were obtained, matched according to revascularization strategy., Results: During follow-up (1543±545 days), after PSM, patients undergoing multivessel revascularization had lower rates of reinfarction (4.5% vs. 16.7%; log-rank p=0.018), unplanned revascularization (6.1% vs. 16.7%; log-rank p=0.048), unplanned PCI (3.0% vs. 13.6%; log-rank p=0.023) and the combined endpoint of death, reinfarction and unplanned revascularization (16.7 vs. 31.8%; log-rank p=0.046)., Conclusions: In real-world patients presenting with NSTE-ACS and multivessel CAD, a multivessel revascularization strategy was associated with lower rates of reinfarction, unplanned revascularization and unplanned PCI, as well as a reduction in the combined endpoint of death, reinfarction and unplanned revascularization., (Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

It is colloquially stated that body size plays a role in the human response to cold, but the magnitude and details of this interaction are unclear. To explore the inherent influence of body size on cold-exposed metabolism, we investigated the relation between body composition and resting metabolic rate in humans at thermoneutrality and during cooling within the nonshivering thermogenesis range. Body composition and resting energy expenditure were measured in 20 lean and 20 overweight men at thermoneutrality and during individualized cold exposure. Metabolic rates as a function of ambient temperature were investigated considering the variability in body mass and composition. We observed an inverse relationship between body size and the lower critical temperature (LCT), i.e. the threshold where thermoneutrality ends and cold activates thermogenesis. LCT was higher in lean than overweight subjects (22.1 ± 0.6 vs 19.5 ± 0.5°C, p < 0.001). Below LCT, minimum conductance was identical between lean and overweight (100 ± 4 vs 97 ± 3kcal/°C/day respectively, p = 0.45). Overweight individuals had higher basal metabolic rate (BMR) explained mostly by the higher lean mass, and lower cold-induced thermogenesis (CIT) per degree of cold exposure. Below thermoneutrality, energy expenditure did not scale to lean body mass. Overweight subjects had lower heat loss per body surface area (44.7 ± 1.3 vs 54.7 ± 2.3kcal/°C/m 2 /day, p < 0.001). We conclude that larger body sizes possessed reduced LCT as explained by higher BMR related to more lean mass rather than a change in whole-body conductance. Thus, larger individuals with higher lean mass need to be exposed to colder temperatures to activate CIT, not because of increased insulation, but because of a higher basal heat generation. Our study suggests that the distinct effects of body size and composition on energy expenditure should be taken in account when exploring the metabolism of humans exposed to cold., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cidea is a gene highly expressed in thermogenesis-competent (UCP1-containing) adipose cells, both brown and brite/beige. Here, we initially demonstrate a remarkable adipose-depot specific regulation of Cidea expression. In classical brown fat, Cidea mRNA is expressed continuously and invariably, irrespective of tissue recruitment. However, Cidea protein levels are regulated posttranscriptionally, being conspicuously induced in the thermogenically recruited state. In contrast, in brite fat, Cidea protein levels are regulated at the transcriptional level, and Cidea mRNA and protein levels are proportional to tissue "briteness." Although routinely followed as a thermogenic molecular marker, Cidea function is not clarified. Here, we employed a gain-of-function approach to examine a possible role of Cidea in the regulation of thermogenesis. We utilized transgenic aP2-hCidea mice that overexpress human Cidea in all adipose tissues. We demonstrate that UCP1 activity is markedly suppressed in brown-fat mitochondria isolated from aP2-hCidea mice. However, mitochondrial UCP1 protein levels were identical in wild-type and transgenic mice. This implies a regulatory effect of Cidea on UCP1 activity, but as we demonstrate that Cidea itself is not localized to mitochondria, we propose an indirect inhibitory effect. The Cidea-induced inhibition of UCP1 activity (observed in isolated mitochondria) is physiologically relevant since the mice, through an appropriate homeostatic compensatory mechanism, increased the total amount of UCP1 in the tissue to exactly match the diminished thermogenic capacity of the UCP1 protein and retain unaltered nonshivering thermogenic capacity. Thus, we verified Cidea as being a marker of thermogenesis-competent adipose tissues, but we conclude that Cidea, unexpectedly, functions molecularly as an indirect inhibitor of thermogenesis., (Copyright © 2017 the American Physiological Society.)

Leptin has been believed to exert its weight-reducing action not only by inducing hypophagia but also by increasing energy expenditure/thermogenesis. Leptin-deficient ob/ob mice have correspondingly been thought to be thermogenically limited and to show hypothermia, mainly due to atrophied brown adipose tissue (BAT). In contrast to these established views, we found that BAT is fully functional and that leptin treatment did not increase thermogenesis in wild-type or in ob/ob mice. Rather, ob/ob mice showed a decreased but defended body temperature (i.e., were anapyrexic, not hypothermic) that was normalized to wild-type levels after leptin treatment. This was not accompanied by increased energy expenditure or BAT recruitment but, instead, was mediated by decreased tail heat loss. The weight-reducing hypophagic effects of leptin are, therefore, not augmented through a thermogenic effect of leptin; leptin is, however, pyrexic, i.e., it alters centrally regulated thresholds of thermoregulatory mechanisms, in parallel to effects of other cytokines., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

In humans, Cidea (cell death-inducing DNA fragmentation factor alpha-like effector A) is highly but variably expressed in white fat, and expression correlates with metabolic health. Here we generate transgenic mice expressing human Cidea in adipose tissues (aP2-hCidea mice) and show that Cidea is mechanistically associated with a robust increase in adipose tissue expandability. Under humanized conditions (thermoneutrality, mature age and prolonged exposure to high-fat diet), aP2-hCidea mice develop a much more pronounced obesity than their wild-type littermates. Remarkably, the malfunctioning of visceral fat normally caused by massive obesity is fully overcome-perilipin 1 and Akt expression are preserved, tissue degradation is prevented, macrophage accumulation is decreased and adiponectin expression remains high. Importantly, the aP2-hCidea mice display enhanced insulin sensitivity. Our data establish a functional role for Cidea and suggest that, in humans, the association between Cidea levels in white fat and metabolic health is not only correlative but also causative.

Introduction: Atrial fibrillation (AF) is widely recognized as an adverse prognostic factor during acute myocardial infarction, although the impact of AF type - new-onset (nAF) or pre-existing (pAF) - is still controversial., Objectives: To identify the clinical differences and prognosis of nAF and pAF during acute coronary syndromes (ACS)., Methods: We performed a retrospective observational cohort study including 1373 consecutive patients (mean age 64 years, 77.3% male) admitted to a single center over a three-year period, with a six-month follow-up., Results: AF rhythm was identified in 14.5% patients, of whom 71.4% presented nAF and 28.6% pAF. When AF types were compared, patients with nAF more frequently presented with ST-elevation ACS (p=0.003). Patients with pAF, in turn, were older (p=0.032), had greater left atrial diameter (p=0.001) and were less likely to have significant coronary lesions (p=0.034). Regarding therapeutic strategy, nAF patients were more often treated by rhythm control during hospital stay (p<0.001) and were less often anticoagulated at discharge (p=0.001). Compared with the population without AF, nAF was a predictor of death during hospital stay in univariate (p<0.001) and multivariate analysis (OR 2.67, p=0.047), but pAF was not. During follow-up, pAF was associated with higher mortality (p=0.014), while nAF patients presented only a trend towards worse prognosis., Conclusions: AF during the acute phase of ACS appears to have a negative prognostic impact only in patients with nAF and not in those with pAF., (Copyright © 2014 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.)

Brown adipose tissue (BAT) thermogenesis relies on blood flow to be supplied with nutrients and oxygen and for the distribution of the generated heat to the rest of the body. Therefore, it is fundamental to understand the mechanisms by which blood flow is regulated and its relation to thermogenesis. Here, we present high-resolution laser-Doppler imaging (HR-LDR) as a novel method for noninvasive in vivo measurement of BAT blood flow in mice. Using HR-LDR, we found that norepinephrine stimulation increases BAT blood flow in a dose-dependent manner and that this response is profoundly modulated by environmental temperature acclimation. Surprisingly, we found that mice lacking uncoupling protein 1 (UCP1) have fully preserved BAT blood flow response to norepinephrine despite failing to perform thermogenesis. BAT blood flow was not directly correlated to systemic glycemia, but glucose injections could transiently increase tissue perfusion. Inguinal white adipose tissue, also known as a brite/beige adipose tissue, was also sensitive to cold acclimation and similarly increased blood flow in response to norepinephrine. In conclusion, using a novel noninvasive method to detect BAT perfusion, we demonstrate that adrenergically stimulated BAT blood flow is qualitatively and quantitatively fully independent of thermogenesis, and therefore, it is not a reliable parameter for the estimation of BAT activation and heat generation., (Copyright © 2015 the American Physiological Society.)

Objectives: We quantified the effect of environmental temperature on mouse energy homeostasis and body temperature., Methods: The effect of environmental temperature (4-33 °C) on body temperature, energy expenditure, physical activity, and food intake in various mice (chow diet, high-fat diet, Brs3 (-/y) , lipodystrophic) was measured using continuous monitoring., Results: Body temperature depended most on circadian phase and physical activity, but also on environmental temperature. The amounts of energy expenditure due to basal metabolic rate (calculated via a novel method), thermic effect of food, physical activity, and cold-induced thermogenesis were determined as a function of environmental temperature. The measured resting defended body temperature matched that calculated from the energy expenditure using Fourier's law of heat conduction. Mice defended a higher body temperature during physical activity. The cost of the warmer body temperature during the active phase is 4-16% of total daily energy expenditure. Parameters measured in diet-induced obese and Brs3 (-/y) mice were similar to controls. The high post-mortem heat conductance demonstrates that most insulation in mice is via physiological mechanisms., Conclusions: At 22 °C, cold-induced thermogenesis is ∼120% of basal metabolic rate. The higher body temperature during physical activity is due to a higher set point, not simply increased heat generation during exercise. Most insulation in mice is via physiological mechanisms, with little from fur or fat. Our analysis suggests that the definition of the upper limit of the thermoneutral zone should be re-considered. Measuring body temperature informs interpretation of energy expenditure data and improves the predictiveness and utility of the mouse to model human energy homeostasis.

This study aimed to evaluate the ingestive behavior of steers on Brachiaria brizantha pasture fed diets with increasing levels of concentrate supplementation. Thirty-two crossbred steers in the finishing phase with average weight of 420 ± 8 kg were distributed in a completely randomized design with four treatments and eight replicates per treatment. Their behavior was assessed every 5 min for 24 h, in the middle of the experimental period. Variance and regression analyses at 0.05 % probability were adopted. The times spent grazing and ruminating reduced linearly (P <0.05), whereas the times spent at the trough (eating) and on other activities increased linearly (P <0.05) as the supplementation levels were elevated. The total feeding and chewing times decreased linearly (P <0.05) as the concentrate levels in the diet were elevated. By increasing the supplementation levels, the number of bites per day decreased linearly (P <0.05), and the feed efficiency of dry matter increased quadratically. Rumination efficiency of dry matter increased linearly (P <0.05) with increasing levels of concentrate supplementation. Grazing and rumination activities are reduced when the time devoted to other activities and at the trough are increased, as a result of the substitution effect.

Clinical trials of fostamatinib in patients with rheumatoid arthritis showed blood pressure (BP) elevation using clinic measurements. The OSKIRA-ambulatory BP monitoring trial assessed the effect of fostamatinib on 24-hour ambulatory systolic BP (SBP) in patients with active rheumatoid arthritis. One hundred thirty-five patients were randomized to fostamatinib 100 mg twice daily (bid; n = 68) or placebo bid (n = 67) for 28 days. Ambulatory, clinic, and home BPs were measured at baseline and after 28 days of therapy. Primary end point was change from baseline in 24-hour mean SBP. Fostamatinib increased 24-hour mean SBP by 2.9 mm Hg (P = .023) and diastolic BP (DBP) by 3.5 mm Hg (P < .001) versus placebo. Clinic/home-measured BPs were similar to those observed with ambulatory BP monitoring. After treatment discontinuation (1 week), clinic BP values returned to baseline levels. Fostamatinib induced elevations in 24-hour mean ambulatory SBP and DBP. BP elevations resolved with fostamatinib discontinuation., (Copyright © 2014 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Background: Foot and ankle injuries are frequent in emergency departments. Although only a few patients with foot and ankle sprain present fractures and the fracture patterns are almost always simple, lack of fracture diagnosis can lead to poor functional outcomes., Aim: The present study aims to evaluate the reliability of the Ottawa ankle rules and the orthopedic surgeon subjective perception to assess foot and ankle fractures after sprains., Subjects and Methods: A cross-sectional study was conducted from July 2012 to December 2012. Ethical approval was granted. Two hundred seventy-four adult patients admitted to the emergency department with foot and/or ankle sprain were evaluated by an orthopedic surgeon who completed a questionnaire prior to radiographic assessment. The Ottawa ankle rules and subjective perception of foot and/or ankle fractures were evaluated on the questionnaire., Results: Thirteen percent (36/274) patients presented fracture. Orthopedic surgeon subjective analysis showed 55.6% sensitivity, 90.1% specificity, 46.5% positive predictive value and 92.9% negative predictive value. The general orthopedic surgeon opinion accuracy was 85.4%. The Ottawa ankle rules presented 97.2% sensitivity, 7.8% specificity, 13.9% positive predictive value, 95% negative predictive value and 19.9% accuracy respectively. Weight-bearing inability was the Ottawa ankle rule item that presented the highest reliability, 69.4% sensitivity, 61.6% specificity, 63.1% accuracy, 21.9% positive predictive value and 93% negative predictive value respectively., Conclusion: The Ottawa ankle rules showed high reliability for deciding when to take radiographs in foot and/or ankle sprains. Weight-bearing inability was the most important isolated item to predict fracture presence. Orthopedic surgeon subjective analysis to predict fracture possibility showed a high specificity rate, representing a confident method to exclude unnecessary radiographic exams.

Intercoronary communication or 'coronary arcade' is a rare congenital coronary anomaly. We present the case of a 65-year-old man with atypical chest pain for four months. The 12-lead ECG and echocardiogram were normal. Treadmill exercise testing was interrupted at peak exercise due to consecutive salvos of ventricular premature beats, without significant ST-T changes. Coronary angiography showed no significant coronary stenosis, but a connection between the right coronary and circumflex arteries was observed, consistent with coronary arcade. The functional importance of this variant is not clear, but it may cause myocardial ischemia by coronary steal or function as a natural bypass, in which case it may play a protective role in the myocardium if significant atherosclerosis develops., (Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.)

Bombesin receptor subtype-3 (BRS-3) regulates energy homeostasis, with Brs3 knockout (Brs3(-/y)) mice being hypometabolic, hypothermic, and hyperphagic and developing obesity. We now report that the reduced body temperature is more readily detected if body temperature is analyzed as a function of physical activity level and light/dark phase. Physical activity level correlated best with body temperature 4 min later. The Brs3(-/y) metabolic phenotype is not due to intrinsically impaired brown adipose tissue function or in the communication of sympathetic signals from the brain to brown adipose tissue, since Brs3(-/y) mice have intact thermogenic responses to stress, acute cold exposure, and β3-adrenergic activation, and Brs3(-/y) mice prefer a cooler environment. Treatment with the BRS-3 agonist MK-5046 increased brown adipose tissue temperature and body temperature in wild-type but not Brs3(-/y) mice. Intrahypothalamic infusion of MK-5046 increased body temperature. These data indicate that the BRS-3 regulation of body temperature is via a central mechanism, upstream of sympathetic efferents. The reduced body temperature in Brs3(-/y) mice is due to altered regulation of energy homeostasis affecting higher center regulation of body temperature, rather than an intrinsic defect in brown adipose tissue.

Background: Cuba is a unique country, and despite limited economic development, has an excellent health system. However, the prevalence of asthma symptoms in children in Havana, Cuba, is unusually high., Aim: As early life exposures are critical to the aetiology of asthma, we have studied environmental influences on the risk of wheezing in Cuban infants., Design: Cross-sectional study., Methods: A random sample of 2032 children aged 12-15 months living in Havana was selected for inclusion in the cohort. Data were collected using questionnaires administered by researchers., Results: Of 2032 infants invited to participate, 1956 (96%) infants provided data. The prevalence of any wheeze was 45%, severe wheeze requiring use of emergency services was 30% and recurrent wheeze on three or more occasions was 20%. The largest adjusted risk factors for any wheeze were presence of eczema [odds ratio (OR) 2.09; 95% confidence interval (CI) 1.48-2.94], family history of asthma (OR 2.05; 95% CI 1.60-2.62), poor ventilation in the house (OR 1.99; 95% CI 1.48-2.67), attendance at nursery (OR 1.78; 95% CI 1.24-2.57), male sex (OR1.52; 95% CI 1.19-1.96) and the number of smokers in the house (P < 0.03 for trend), OR 1.64 (95% CI 1.17-2.31) for three or more smokers in the house compared to no smokers in the household., Conclusion: We have identified several risk factors for any wheeze in young infants living in modern day Cuba. As the prevalence of smoking in the house is high (51%), intervention studies are required to determine effective strategies to improve infant health.

Neonatal cyanosis in healthy newborns can be associated either with methemoglobin due to cytochrome b5 reductase deficiency or to M-hemoglobin, a group of hemoglobin variants resulting from mutations in the globin chain genes. We report the clinical case of a neonate with cyanosis and normal cardiac and respiratory function. At birth the hematological parameters were normal; however, the methemoglobinemia was 16%. Spontaneously, the cyanosis gradually decreased and by the fifth month of age the methemoglobin level was normal. A heterozygous Gγ-globin gene (HBG2) missense mutation 87 C-A (Leu28Met) was identified. His father, with a history of transfusion in the neonatal period, is heterozygous for the same mutation. This hemoglobin variant, not previously described, was called Hb F Viseu and is the sixth Gγ-chain variant reported in association with neonatal cyanosis.

Ectonucleotidases and the nucleotide metabolism have been implicated as important regulators in diabetes disease. We evaluated the ectonucleotidase activities and biochemical parameters in blood serum of streptozotocin (STZ)-induced diabetic rats submitted a physical training protocol. We observed a raise in ATP, ADP, AMP and p-Nph-5'-TMP hydrolysis rate and in the levels of cholesterol and triglycerides in rat blood serum, after 30 days of diabetes induction. However, in serum of rats submitted a physical training protocol by forced swimming, both the nucleotide hydrolysis rate and the lipids levels returned to the control values. Considering that diabetes leads to multiple pathophysiological alterations, the modulations observed in ectonucleotidase activities may be part of the events involved in these alterations. Then the physical training is a very important way to control the vascular alterations developed in diabetes.

Introduction: Following a tripling of tuberculosis incidence in Cuba between 1991 and 1994 (from 4.7 to 14.7 per 100,000), the National TB Control Program was revamped in 1995 and the National Reference Center for Childhood TB and Provincial Childhood TB Commissions were created as a strategy for addressing this emerging health problem., Objective: Assess the impact of Cuba's new strategy for TB control in children aged <15 years during the period 1995-2005., Methods: A descriptive review of health services and systems was conducted in Cuba, examining 157 cases of TB diagnosed in children aged <15 years during the period 1995-2005 and comparing impact and process indicators for selected years (1995, 2000, and 2005). Impact indicators included reduction in: a) incidence; b) serious forms (peritoneal, meningeal, miliary, combined); c) mortality; and d) case outcomes (cure, death, treatment drop-out, treatment failure). Process indicators were proportion of cases with: a) microbiological tests; b) knowledge of infection source; c) diagnoses obtained through adult case contact tracing; d) time to diagnosis <60 days; and e) post-mortem diagnoses., Results: During the period 1995-2005, TB rates in children aged <15 years fell by 50% (from 1.0 to 0.5 per 100,000), more evident in children <10 years. The Havana rate was three times the national rate. Diagnosis was post-mortem in three serious cases (1.9%); there were four deaths (2.5%), none after 2000. Only seven children (4.5%) had serious forms, none after 2002. Except for cases diagnosed post-mortem, all children received treatment directly supervised by health personnel. Cure rate was 99.4%; there were no treatment drop-outs or chronic cases; one relapse was reported (0.6%). Knowledge of infection source increased to 90% over the selected years. Microbiological tests were conducted in 90% of cases, with isolation in 30.9%. No isolate was drug-resistant, nor were there reports of infectious contacts with resistance. We found no HIV coinfection. At the end of the study, time to diagnosis of ≥60 days persisted in 40% of cases., Conclusions: Creation of a National Reference Center for Childhood TB and Provincial Childhood TB Commissions has contributed to improved TB diagnosis and control in children aged <15 years, achieving incidence similar to that during the period prior to TB re-emergence and to those of some developed countries. Improvements are needed in the work and systematic training of health personnel, especially at the primary health care level, in order to eliminate TB as a national health problem by 2015.