Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Lenalidomide and Eltrombopag for Treatment of Low- or Intermediate-Risk Myelodysplastic Syndrome: Result of a Phase II Clinical Trial.

PURPOSE: Thrombocytopenia is a serious complication of myelodysplastic syndromes (MDS) associated with an increased bleeding risk and worse prognosis. Eltrombopag (ELT), a thrombopoietin receptor agonist, can increase platelet counts and reverse anti-megakaryopoietic effects of lenalidomide (LEN) in preclinical studies. We hypothesized ELT would reduce the incidence of thrombocytopenia in MDS. PATIENTS AND METHODS: We conducted a Phase II multicenter trial of ELT and LEN in adult patients with low- or intermediate-1-risk MDS with symptomatic or transfusion-dependent anemia or thrombocytopenia (NCT01772420). Thrombocytopenic patients were started on ELT and subsequently treated with LEN after platelets were increased. Patients without thrombocytopenia were started on LEN monotherapy and treated with ELT if they became thrombocytopenic. RESULTS: Fifty-two patients were enrolled; mean age was 71 years (range 34-93). Overall response rate (ORR) in the intention-to-treat population was 35% (18/52). ELT monotherapy led to ORR of 33.3% (7/21), 29% achieving hematologic improvement (HI)-Platelets, and 24% bilineage responses. LEN monotherapy had 38% ORR (6/16) with all responders achieving HI-Erythroid. Fifteen patients received both ELT and LEN with ORR of 33.3%, 20% achieved HI-Erythroid, and 20% HI-Platelets with 13% bilineage responses. Median duration of response was 40 weeks for ELT (range 8-ongoing), 41 weeks (25-ongoing) for LEN, and 88 weeks (8.3-ongoing) for ELT/LEN. Non-hematologic grade 3-4 treatment-related adverse events were infrequent. Among patients on ELT, 2 had major bleeding events, 1 had a reversible increase in peripheral blasts, and 1 developed marrow fibrosis after 6 years on ELT. CONCLUSIONS: ELT and LEN are well tolerated and effective in achieving hematologic improvement in patients with low-/intermediate-risk MDS

Weaning from mechanical ventilation in intensive care units across 50 countries (WEAN SAFE): a multicentre, prospective, observational cohort study

International audienceBackground: Current management practices and outcomes in weaning from invasive mechanical ventilation are poorly understood. We aimed to describe the epidemiology, management, timings, risk for failure, and outcomes of weaning in patients requiring at least 2 days of invasive mechanical ventilation. Methods: WEAN SAFE was an international, multicentre, prospective, observational cohort study done in 481 intensive care units in 50 countries. Eligible participants were older than 16 years, admitted to a participating intensive care unit, and receiving mechanical ventilation for 2 calendar days or longer. We defined weaning initiation as the first attempt to separate a patient from the ventilator, successful weaning as no reintubation or death within 7 days of extubation, and weaning eligibility criteria based on positive end-expiratory pressure, fractional concentration of oxygen in inspired air, and vasopressors. The primary outcome was the proportion of patients successfully weaned at 90 days. Key secondary outcomes included weaning duration, timing of weaning events, factors associated with weaning delay and weaning failure, and hospital outcomes. This study is registered with ClinicalTrials.gov, NCT03255109. Findings: Between Oct 4, 2017, and June 25, 2018, 10 232 patients were screened for eligibility, of whom 5869 were enrolled. 4523 (77·1%) patients underwent at least one separation attempt and 3817 (65·0%) patients were successfully weaned from ventilation at day 90. 237 (4·0%) patients were transferred before any separation attempt, 153 (2·6%) were transferred after at least one separation attempt and not successfully weaned, and 1662 (28·3%) died while invasively ventilated. The median time from fulfilling weaning eligibility criteria to first separation attempt was 1 day (IQR 0–4), and 1013 (22·4%) patients had a delay in initiating first separation of 5 or more days. Of the 4523 (77·1%) patients with separation attempts, 2927 (64·7%) had a short wean (≤1 day), 457 (10·1%) had intermediate weaning (2–6 days), 433 (9·6%) required prolonged weaning (≥7 days), and 706 (15·6%) had weaning failure. Higher sedation scores were independently associated with delayed initiation of weaning. Delayed initiation of weaning and higher sedation scores were independently associated with weaning failure. 1742 (31·8%) of 5479 patients died in the intensive care unit and 2095 (38·3%) of 5465 patients died in hospital. Interpretation: In critically ill patients receiving at least 2 days of invasive mechanical ventilation, only 65% were weaned at 90 days. A better understanding of factors that delay the weaning process, such as delays in weaning initiation or excessive sedation levels, might improve weaning success rates. Funding: European Society of Intensive Care Medicine, European Respiratory Society

Charm production and fragmentation fractions at midrapidity in pp collisions at s \sqrt{\textrm{s}} = 13 TeV

Measurements of the production cross sections of prompt D$^{0}$, D$^{+}$, D$^{*+}$, ${\textrm{D}}_{\textrm{s}}^{+}$, ${\Lambda}_{\textrm{c}}^{+}$, and ${\Xi}_{\textrm{c}}^{+}$ charm hadrons at midrapidity in proton-proton collisions at $\sqrt{s}$ = 13 TeV with the ALICE detector are presented. The D-meson cross sections as a function of transverse momentum (p$_{T}$) are provided with improved precision and granularity. The ratios of p$_{T}$-differential meson production cross sections based on this publication and on measurements at different rapidity and collision energy provide a constraint on gluon parton distribution functions at low values of Bjorken-x (10$^{−5}$–10$^{−4}$). The measurements of ${\Lambda}_{\textrm{c}}^{+}$ (${\Xi}_{\textrm{c}}^{+}$) baryon production extend the measured p$_{T}$ intervals down to p$_{T}$ = 0(3) GeV/c. These measurements are used to determine the charm-quark fragmentation fractions and the $\textrm{c}\overline{\textrm{c}}$ production cross section at midrapidity (|y| < 0.5) based on the sum of the cross sections of the weakly-decaying ground-state charm hadrons D$^{0}$, D$^{+}$, ${\textrm{D}}_{\textrm{s}}^{+}$, ${\Lambda}_{\textrm{c}}^{+}$, ${\Xi}_{\textrm{c}}^0$ and, for the first time, ${\Xi}_{\textrm{c}}^{+}$, and of the strongly-decaying J/ψ mesons. The first measurements of ${\Xi}_{\textrm{c}}^{+}$ and ${\Sigma}_{\textrm{c}}^{0,++}$ fragmentation fractions at midrapidity are also reported. A significantly larger fraction of charm quarks hadronising to baryons is found compared to e$^{+}$e$^{−}$ and ep collisions. The $\textrm{c}\overline{\textrm{c}}$ production cross section at midrapidity is found to be at the upper bound of state-of-the-art perturbative QCD calculations.[graphic not available: see fulltext

Probing the chiral magnetic wave with charge-dependent flow measurements in Pb-Pb collisions at the LHC

The Chiral Magnetic Wave (CMW) phenomenon is essential to provide insights into the strong interaction in QCD, the properties of the quark-gluon plasma, and the topological characteristics of the early universe, offering a deeper understanding of fundamental physics in high-energy collisions. Measurements of the charge-dependent anisotropic flow coefficients are studied in Pb-Pb collisions at center-of-mass energy per nucleon-nucleon collision $\sqrt{s_{\textrm{NN}}}$ = 5.02 TeV to probe the CMW. In particular, the slope of the normalized difference in elliptic (v$_{2}$) and triangular (v$_{3}$) flow coefficients of positively and negatively charged particles as a function of their event-wise normalized number difference, is reported for inclusive and identified particles. The slope ${r}_3^{\textrm{Norm}}$ is found to be larger than zero and to have a magnitude similar to ${r}_2^{\textrm{Norm}}$, thus pointing to a large background contribution for these measurements. Furthermore, ${r}_2^{\textrm{Norm}}$ can be described by a blast wave model calculation that incorporates local charge conservation. In addition, using the event shape engineering technique yields a fraction of CMW (f$_{CMW}$) contribution to this measurement which is compatible with zero. This measurement provides the very first upper limit for f$_{CMW}$, and in the 10–60% centrality interval it is found to be 26% (38%) at 95% (99.7%) confidence level

Prompt and non-prompt J/ψ/\psi production at midrapidity in Pb−-Pb collisions at sNN\sqrt{s_{\mathrm{NN}}} = 5.02 TeV

International audienceThe transverse momentum ($p_{\rm T}$) and centrality dependence of the nuclear modification factor $R_{\rm AA}$ of prompt and non-prompt J$/\psi$, the latter originating from the weak decays of beauty hadrons, have been measured by the ALICE collaboration in Pb$-$Pb collisions at $\sqrt{s_{\mathrm{NN}}}$ = 5.02 TeV. The measurements are carried out through the ${\rm e}^{+}{\rm e}^{-}$ decay channel at midrapidity ($|y|$ 5 GeV/$c$, which becomes stronger with increasing collision centrality. The results are consistent with similar LHC measurements in the overlapping $p_{\rm T}$ intervals, and cover the kinematic region down to $p_{\rm T}$ = 1.5 GeV/$c$ at midrapidity, not accessible by other LHC experiments. The suppression of prompt J$/\psi$ in central and semicentral collisions exhibits a decreasing trend towards lower transverse momentum, described within uncertainties by models implementing J$/\psi$ production from recombination of c and $\overline{\rm c}$ quarks produced independently in different partonic scatterings. At high transverse momentum, transport models including quarkonium dissociation are able to describe the suppression for prompt J$/\psi$. For non-prompt J$/\psi$, the suppression predicted by models including both collisional and radiative processes for the computation of the beauty-quark energy loss inside the quark$-$gluon plasma is consistent with measurements within uncertainties

Search for jet quenching effects in high-multiplicity pp collisions at s\sqrt{s} = 13 TeV via di-jet acoplanarity

International audienceThe ALICE Collaboration reports a search for jet quenching effects in high-multiplicity (HM) proton$-$proton collisions at $\sqrt{s}$ = 13 TeV, using the semi-inclusive azimuthal-difference distribution $\Delta\varphi$ of charged-particle jets recoiling from a high transverse momentum (high-$p_{\mathrm{T,trig}}$) trigger hadron. Jet quenching may broaden the $\Delta\varphi$ distribution measured in HM events compared to that in minimum bias (MB) events. The measurement employs a $p_{\mathrm{T,trig}}$-differential observable for data-driven suppression of the contribution of multiple partonic interactions, which is the dominant background. While azimuthal broadening is indeed observed in HM compared to MB events, similar broadening for HM events is observed for simulations based on the PYTHIA 8 Monte Carlo generator, which does not incorporate jet quenching. We elucidate the origin of the broadening by comparing biases induced by HM selection in the data and simulations, and discuss its implications for the study of jet quenching in small collision systems