Extremely low viral reservoir in treated chronically HIV-1-infected individuals

Altres ajuts: This research was sponsored in part by Grifols and by Merck Sharp & Dohme España, S.A. (IISP 54925). The funding organizations had no input in the design of the study; in the collection, analyses, or interpretation of the data; writing of the manuscript; or in the decision to submit the study for publication. NH received a post-doctoral grant from the Jaqueline Beytout Foundation. FG received the support of "José María Segovia de Arana" contracts (2019) and MMT from the NIH (R01AI143457).Small viral reservoirs are found predominantly in HIV-1 controllers and individuals treated during acute/early HIV-1 infection. However, other HIV + individuals could naturally also harbour low viral reservoirs. We screened 451 HIV-1-infected treated-individuals with suppressed plasma viremia for at least 3 years and stored cryopreserved peripheral blood mononuclear cells (PBMCs). Total HIV-DNA was analysed in PBMCs with ddPCR. Individuals with 50 HIV-DNA copies/10 6 PBMCs) to analyse total HIV-DNA, T-cell and NK-cell populations, HIV-1 specific antibodies, and plasma inflammation markers. We found that 9.3% of the individuals screened had <50 HIV-DNA copies/10 6 PBMCs. At least 66% initiated cART during the chronic phase of HIV-1 infection (cp-LoViReT). Cp-LoViReT harboured lower levels of HIV-DNA before cART and after treatment introduction the decays were greater compared to controls. They displayed a marked decline in quantity and avidity in HIV-specific antibodies after initiation of cART. Cp-LoViReT had fewer CD8 + T and T in the absence of cART, and higher CD8 + T after 18 months on therapy. Treated chronically HIV-1-infected LoViReT represent a new phenotype of individuals characterized by an intrinsically reduced viral reservoir, less impaired CD8 + T-cell compartment before cART, and low circulating HIV-1 antigens despite being treated in the chronic phase of infection. The identification of this unique group of individuals is of great interest for the design of future eradication studies. MSD Spai

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Developments in mobile hydraulics

Im Fokus der Entwickler hydraulischer Systeme liegen im Berichtszeitraum 2022 vor allem die Digitalisierung und die Senkung der Total Cost of Ownership. Hierfür stellten Vertreter aus Forschung und Industrie innovative Konzepte und Lösungen vor. Die Bandbreite reicht dabei von der Komponenten- bis zur Systemebene für die Anwendung in mobilen Maschinen.In the 2022 reporting period, developers of hydraulic systems focused primarily on digitalisation and the reduction of the total cost of ownership. For this purpose, representatives from research and industry presented innovative concepts and solutions. The spectrum ranges from the component level to the system level for application in mobile machines

Minimum Dose of Levothyroxine Restored the Autonomic Balance on a Dalmatian Female Dog with Primary Hypothyroidism

Background: Hypothyroidism is an endocrine disease that leads to a reduction in the hormones thyroxine (T3) and triiodothyronine (T4), which therapy with levothyroxine restores the clinical signs related to the metabolic rate. Due to the influence of thyroid hormones on the heart, which is under the constant influence of the autonomic nervous system (ANS), dogs with hypothyroidism can develop bradycardia, arrhythmia, and dysautonomia.  Heart rate variability (HRV) assesses autonomic modulation by the Holter method, which is scarce in dogs. We aimed to report the cardiac and autonomic effects of the primary hypothyroidism untreated and treated with levothyroxine in a canine case by Holter monitoring.Case: A 7-year-old female Dalmatian, weighing 36 kg, was referred for clinical evaluation due to apathy, weight gain, low hair quality, and lethargy. On physical examination, alopecic lesions on the hind limbs and tail, as well as bradycardia with a heart rate (HR) of 40-50 beats per minute (bpm) were observed, in addition to a 3/6 mitral murmur and 2/6 tricuspid murmur. Given the suspicion of thyroid gland disorder, the blood hormonal measurement revealed an increase in thyroid-stimulating hormone (TSH; 0.65 ng/mL) and a decrease in free T4 (0.11 ng/mL) and total T4 (0.44 ng/mL), confirming primary hypothyroidism. Therapy was started with a minimum dose of levothyroxine (0.913 mg, every 12 h), which clinical signs were restored in five months of treatment, with weight loss, hair growth, and active behavior. To assess the impact of untreated and treated hypothyroidism on the patient’s ANS, a Holter monitoring exam was performed for 24 h before and after therapy. Before treatment, the average HR was 75 bpm, and the HR&lt;50 bpm occurred during 05 h 20 min 36 s. Still, 320 pause events (&gt;2.0s), 1st-degree atrioventricular blocks (AVB), six ventricular ectopias events, and 2nd-degree sinoatrial block (SAB) were also observed. The ANS parasympathetic tone was significantly stimulated, highlighting bradycardia, arrhythmia, and dysautonomia. After five months of treatment with levothyroxine, the average HR was 89 bpm, and the HR&lt;50 bpm occurred during 02 h 06 min 13 s. No ventricular pauses, blocks, or ectopias were observed, showing the stimulation of sympathetic tonus, which restored HR and ANS balance. Still, it was observed that the minimum levothyroxine dose corrected cardiac changes by increasing the low frequency (LF), decreasing the high frequency (HF), and, consequently, increasing the LF/HF ratio, normalizing the frequency conditions in HRV.Discussion: In the frequency index, HF indicates the vagal activity, whereas LF indicates both systems with parasympathetic predominance. Before treatment, the dog had a low LF/HF ratio (0.46), indicating dysautonomia with parasympathetic stimulation. After therapy, the conditions of bradycardia and functional cardiac capacity were corrected, restoring ANS, due to the serum recovery of thyroid hormones. This study reported the cardiac and autonomic effects of primary hypothyroidism untreated and treated with levothyroxine on a dog, that had intense bradycardia and abnormal stimulation of the parasympathetic tone, associated with episodes of 1st-degree AVB, ventricular ectopias, and 2nd-degree SAB. After therapy with a minimum dose of levothyroxine, there was a decrease in parasympathetic activity and an increase in sympathetic stimulus, correcting cardiac changes, and restoring the balance of ANS. As it is a simple, non-invasive, and safe tool that helps the clinician to understand cardiac autonomic modulation, it is recommended to adopt the Holter monitoring exam in cases of hypothyroidism cases to assess sympathetic-vagal balance and check potential cardiac risks

Aspergillus fumigatus corneal infection is regulated by chitin synthases and by neutrophil-derived acidic mammalian chitinase

International audienceAspergillus fumigatus is an important cause of pulmonary and systemic infections in immune compromised individuals, and of corneal ulcers and blindness in immune competent patients. To examine the role of chitin synthases in Aspergillus corneal infection, we analyzed Aspergillus mutants of chitin synthase family 1 and family 2, and found that compared with the parent strain, the quadruple mutants from both families were more readily killed by neutrophils in vitro, and that both also exhibited impaired hyphal growth in the cornea. Further, inhibition of chitin synthases using Nikkomycin Z enhanced neutrophil killing in vitro and in vivo in a murine model of A. fumigatus corneal infection. Acidic mammalian chitinase (AMCase) is mostly produced by macrophages in asthmatic lungs; however, we now demonstrate that neutrophils are a major source of AMCase, which inhibits hyphal growth. In A. fumigatus corneal infection, neutrophils are the major source of AMCase, and addition of AMCase inhibitors or adoptive transfer of neutrophils from AMCase −/− mice resulted in impaired hyphal killing. Together, these findings identify chitin synthases as important fungal virulence factors and neutrophil-derived AMCase as an essential mediator of host defense

Ornithodoros cerradoensis n. sp. (Acari: Argasidae), a member of the Ornithodoros talaje (Guérin-Méneville, 1849) group, parasite of rodents in the Brazilian Savannah

Ornithodoros cerradoensis n. sp. is described from field-collected and laboratory reared nymphs, males, females, and larvae parasitizing the rodents Cavia aperea and Thrichomys sp. in the Brazilian Savannah. This new species is morphologically and genetically related with the Ornithodoros talaje group and can be separated from other Neotropical species using the following combination of characters: larva with 18 pairs of setae on dorsum (seven anterolateral, four central and seven posterolateral), hypostome with median dentition 2/2; adults provided with large mammillae; dorsal disks surrounded by bulked marginal ridges delimiting barely pebbled areas; three disks in the anterolateral file, and median disk not merging with the posteromedian file. Feeding assays in the laboratory demonstrated that (1) larvae of O. cerradoensis are slow-feeders (∼6 days), (2) first nymphal instar (N1) molts to second instar (N2) without feeding, and (3) N2 and third nymphal instar (N3) engorge rapidly (minutes). With the exception of Ornithodoros hasei nymphs that depict flattened bodies, O. cerradoensis N1, N2, and N3 highly resemble homologous instars of other species in O. talaje sensu lato, therefore are not suitable for morphological comparisons within the group. In addition to morphological signature of larvae and adults that separate this new species; results of cross-mating attempts between O. cerradoensis and Ornithodoros guaporensis a morphologically and phylogenetically closely related species that also parasitizes rodents in the Brazilian Savannah; a Principal Component Analysis using larval characters; and a phylogenetic analysis using mitochondrial markers, support O. cerradoensis as an independent lineage within the Ornithodorinae.EEA RafaelaFil: Muñoz-Leal, Sebastián. Universidade de São Paulo. Faculdade de Medicina Veterinária e Zootecnia. Departamento de Medicina Veterinária Preventiva e Saúde Animal; BrasilFil: Martins, Maria Marlene. Universidade Federal de Uberlândia. Faculdade de Medicina Veterinária. Laboratório de Ixodologia; BrasilFil: Nava, Santiago. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Landulfo, Gabriel Alves Lves. Instituto Butantan. Laboratório de Parasitologia; BrasilFil: Simons, Simone Michaela. Instituto Butantan. Laboratório de Parasitologia; BrasilFil: Rodrigues, Vinícius Da Silva. Universidade Federal de Uberlândia. Faculdade de Medicina Veterinária. Laboratório de Ixodologia; BrasilFil: Ramos, Vanessa Do Nascimento. Universidade Federal de Uberlândia. Faculdade de Medicina Veterinária. Laboratório de Ixodologia; BrasilFil: Suzin, Adriane. Universidade Federal de Uberlândia. Faculdade de Medicina Veterinária. Laboratório de Ixodologia; BrasilFil: Szabó, Matías P.J. Universidade Federal de Uberlândia. Faculdade de Medicina Veterinária. Laboratório de Ixodologia; BrasilFil: Labruna, Marcelo B. Universidade de São Paulo. Faculdade de Medicina Veterinária e Zootecnia. Departamento de Medicina Veterinária Preventiva e Saúde Animal; Brasi

An IDH1-vitamin C crosstalk drives human erythroid development by inhibiting pro-oxidant mitochondrial metabolism

International audienceHighlights d Glutamine-dependent OXPHOS drives early erythroid differentiation d OXPHOS-induced ROS inhibit erythroblast enucleation d IDH1 downregulation augments ROS, leading to pathological erythroid differentiation d Vitamin C rescues erythroid differentiation under conditions of oxidative stres