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In the Phase III ICARIA-MM study (NCT02990338), the addition of the anti-CD38 monoclonal antibody isatuximab to pomalidomide and dexamethasone led to increased progression-free survival and improved response rates in patients with relapsed/refractory multiple myeloma. There is an unmet treatment need, particularly among patients with poor prognoses, including those with high-risk cytogenetics, those who have renal impairment, those who are elderly and those who are refractory to prior lines of treatment. In this review, the subgroup analyses from the ICARIA-MM study, representing subpopulations with poor prognostic factors, are discussed. Overall, the addition of isatuximab to pomalidomide and dexamethasone improved progression-free survival and disease response rates across different subgroups, regardless of prognostic factor.Lay abstract Currently, the majority of patients with multiple myeloma are not cured, and current treatments may not be helpful for patients with poor prognoses, including those with high-risk chromosomal changes, those who have impaired kidney function, those who are elderly and those who are refractory to prior treatments. In this review, we will discuss the benefits of the combination of isatuximab plus pomalidomide and dexamethasone in these difficult-to-treat patients.

OBJECTIVES Pulmonary valve replacement (PVR) performed for pulmonary valve regurgitation is the most common indication for reoperation during mid-to-long-term follow-up after tetralogy of Fallot repair. An aneurysmal dilation of the infundibulum is often associated secondary to the infundibulotomy performed in the first operation. The right ventricular outflow tract reconstruction with endo-exclusion aims to exclude the non-contractile segments of the dilated right ventricular. This study intends to assess the safety and efficiency of the endo-exclusion technique. METHODS Between January 2010 and December 2018, 86 patients underwent a PVR with (n = 46) or without (n = 40) endo-exclusion. The current study compares the outcomes in terms of survival, reintervention, structural valve deterioration, right ventricular function (volume and right ventricular ejection fraction) and pulmonary valve gradient. The median follow-up time was 4.45 years (1.9 months to 9.87 years). RESULTS There was no 30-day mortality. There was no difference in the freedom from reintervention at 7 years (without endo-exclusion, 97%, versus with endo-exclusion, 94%, log-rank = 0.68) or in the freedom from structural pulmonary valve deterioration at 7 years (without endo-exclusion, 94%, versus with endo-exclusion, 89%, log-rank = 0.94). No significant difference was observed in the indexed right ventricular end-diastolic volume (102.2 ± 34 ml/m2 in the PVR without endo-exclusion group and 93.3 ± 22 ml/m2 in the PVR with endo-exclusion group, P = 0.61). No significant difference was observed in the right ventricular function (right ventricular ejection fraction: 46 ± 11% in the PVR without endo-exclusion group and 46 ± 9% in the PVR with endo-exclusion group, P = 0.88). CONCLUSIONS PVR with or without endo-exclusion is a safe and effective procedure. PVR with endo-exclusion allows implantation without structural deformation of the valve and therefore excellent short- and medium-term results.

Background Berlin Heart EXCOR (BH) ventricular assist devices provide mechanical long-term circulatory support in children with end-stage heart failure, as a bridge to transplantation or to recovery. Most studies are from large-volume paediatric cardiac centres. Aim The aim of this study was to analyse the experiences of three French centres and to compare these with available published data. Method We performed a retrospective observational study of three paediatric cardiac intensive care units. All children supported with BH devices were included. Morbidity and mortality data were collected and risk factors analysed. Results Fifty-four (54) patients (54% male) were included. Survival rate was 73% while on a BH device. Median age at BH device implantation was 17 months (range 2–180 months). The predominant indication was dilated cardiomyopathy (61%). Bi-ventricular assist device was used in 25 (46%) cases. The total length of long-term circulatory support was 3,373 days, with a mean length per patient of 62.5 days (range 5–267 days). Thirty-two (32) patients were transplanted (59%) and seven (13%) were successfully weaned. Type and length of support did not influence morbidity. Main complications were renal dysfunction (57%), bleeding (41%), and infection (39%). In multivariate analysis, a weight Conclusions The weight seems to be the most important risk factor of mortality in this precarious condition.

Isatuximab, an anti‐CD38 monoclonal antibody, targets cells that strongly express CD38 including malignant plasma cells. This open‐label, single‐arm, multicenter, phase 1/2 trial investigated the tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). In Phase 1, patients were sequentially assigned to receive isatuximab once weekly (QW) in cycle 1 (4 weeks) and every 2 weeks (Q2W) in subsequent cycles. Cohort 1 (n = 3) received 10 mg/kg QW/Q2W; cohort 2 (n = 5) received 20 mg/kg QW/Q2W. No dose‐limiting toxicities occurred; the recommended dose for the single‐arm phase 2 study (n = 28) was 20 mg/kg QW/Q2W. The overall safety profile was consistent with the current knowledge of isatuximab. The most common adverse events were infusion reactions (42.9%; 12/28); all were grade 1/2 and generally occurred during the first infusion. The overall response rate with 20 mg/kg QW/Q2W isatuximab was 36.4% (12/33); patients with high‐risk cytogenetic abnormalities had comparable results. In phase 2, the median progression‐free survival was 4.7 (95% confidence interval, 3.75 to not reached) months. Median overall survival was not reached. Isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM including high‐risk cytogenetic patients. This trial is registered at ClinicalTrials.gov as NCT02812706., This open‐label, single‐arm, multicenter phase 1/2 trial investigated the tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). The results demonstrated that isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM, including high‐risk cytogenetic patients.

Background:Pulmonary atresia with ventricular septal defect and severe tetralogy of Fallot require a palliative procedure for pulmonary artery rehabilitation. For first-stage palliation, two main surgical options are still debated: right ventricle to pulmonary artery connection and modified Blalock–Taussig shunt. We compared the clinical outcomes of the two procedures.Methods:From 1995 to 2018, 88 patients needed palliation (pulmonary atresia with ventricular septal defect n = 47; tetralogy of Fallot n = 41). Among these patients, 70 modified Blalock–Taussig shunt and 18 transannular path augmentation were performed before 6 months of age. Using a 1:1 propensity score match analysis, 20 patients were included in the analysis. The primary outcome was in-hospital mortality and pulmonary artery growth.Results:After matching, the pre-operative Nakata was smaller in transannular path augmentation 54 ± 24 mm2/m2 than modified Blalock–Taussig shunt 109 ± 31 mm2/m2 (p < 0.001). The age and weight were similar (p = 0.31 and p = 0.9, respectively). There was no difference in in-hospital mortality (p = 0.3). The Nakata index before biventricular repair and delta Nakata were smaller in modified Blalock–Taussig shunt group (206 ± 80 mm2/m2, 75 ± 103 mm2/m2) than transannular path augmentation (365 ± 170 mm2/m2, 214 ± 165 mm2/m2; p = 0.03; p < 0.001). Median time to biventricular repair was similar (p = 0.46). The rate of interstage reintervention was similar (p = 0.63).Conclusions:The transannular path augmentation is better for the rehabilitation of the native pulmonary artery. Despite a smaller pulmonary artery, right ventricle to pulmonary artery connection is equivalent to modified Blalock–Taussig shunt for rate of biventricular repair and time to biventricular repair.

8042 Background: A prespecified interim efficacy analysis of the Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) + carfilzomib (K) and dexamethasone (d) (Isa-Kd) significantly improved progression-free survival (PFS) compared with Kd in patients (pts) with relapsed multiple myeloma (RMM) (HR 0.531; 99% CI, 0.318–0.889; P= 0.0007), with a clinically meaningful increase in minimal residual disease negativity (MRD-) (29.6% vs 13.0%) and complete response (CR) (39.7% vs 27.6%) rates, and a manageable safety profile. This subgroup analysis of IKEMA examined efficacy and safety in pts with high-risk cytogenetics [t(4;14), del(17p), and t(14;16)] and/or gain(1q21). Methods: Pts with 1–3 prior lines of therapy were randomized 3:2 to receive Isa-Kd (n = 179) or Kd (n = 123). High-risk cytogenetics was assessed by central laboratory analysis and defined as ≥1 of the following: del(17p): 50% cutoff; t(4;14) or t(14;16): 30% cutoff. Assessment of gain(1q21) was prespecified as ≥3 copies: 30% cutoff. Results: Of the randomized pts, 23.5% (Isa-Kd) and 25.2% (Kd) had ≥1 high-risk cytogenetic abnormality (CA); 26.3% (Isa-Kd) and 25.2% (Kd) had isolated gain(1q21). The addition of Isa to Kd improved PFS for pts with ≥1 high-risk CA and standard-risk pts (Table); pts with t(4;14) (HR 0.549; 95% CI, 0.232–1.301) had a more pronounced treatment effect than pts with del(17p) (HR 0.837; 95% CI, 0.281–2.496). A clear PFS benefit with Isa-Kd was also seen for pts with isolated gain(1q21) and gain(1q21) combined with other high-risk CA (Table). The trend toward improved CR, ≥very good partial response (VGPR), and MRD- rates with the addition of Isa was more pronounced in pts with gain(1q21) than in pts with high-risk CA alone. Grade ≥3 treatment-emergent adverse events (TEAEs) were more common with Isa-Kd vs Kd, but the incidence of serious and fatal TEAEs was similar with both arms for high-risk pts (Table). Conclusions: The addition of Isa to Kd improved PFS in pts with high-risk CA and disease response in pts with gain(1q21) isolated or combined with high-risk CA, with a manageable safety profile, consistent with the benefit observed in the overall IKEMA population. Isa-Kd is a potential new treatment option for the difficult-to-treat subgroup of pts with RMM and high-risk cytogenetics. Funding: Sanofi. Clinical trial information: NCT03275285. [Table: see text]

This phase 2 study evaluated isatuximab as monotherapy or combined with dexamethasone in relapsed/refractory multiple myeloma (RRMM). Patients had RRMM refractory to an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI) or had received ≥3 prior lines of therapy incorporating an IMiD and PI. Patients received isatuximab either as monotherapy (20 mg/kg on days 1, 8, 15, and 22 [once weekly] of cycle 1 followed by 20 mg/kg on days 1 and 15 of subsequent cycles; Isa group) or in combination with dexamethasone (40 mg/d [20 mg/d in patients aged ≥75 years] once weekly; Isa-dex group). Treated patients (N = 164) had received a median of 4 (range, 2-10) prior treatment lines. Patients received a median of 5 (1-24) and 7 (1-22) treatment cycles; at data cutoff, 13 (11.9%) of 109 and 15 (27.3%) of 55 patients remained on treatment in the Isa and Isa-dex arms, respectively. Overall response rate (primary efficacy end point) was 23.9% in the Isa arm and 43.6% in the Isa-dex arm (odds ratio, 0.405; 95% confidence interval, 0.192-0.859; P = .008). Median progression-free survival and overall survival were 4.9 and 18.9 months for Isa, and 10.2 and 17.3 months for Isa-dex. Infusion reactions (mostly grade 1/2) and hematologic abnormalities were the most common adverse events. There was a similar incidence of grade 3 or higher infections in both groups (22.0% and 21.8%). In conclusion, addition of dexamethasone to isatuximab increased response rates and survival outcomes with no detrimental effect on safety. This trial was registered at www.clinicaltrials.gov as #NCT01084252.

Background Chronic obstructive pulmonary disease (COPD) is a major public health issue affecting approximately 4% to 7% of the Swiss population. According to current inpatient guidelines, systemic corticosteroids are important in the treatment of acute COPD exacerbations and should be given for 5 to 7 days. Several studies suggest that corticosteroids accelerate the recovery of FEV1 (forced expiratory volume in 1 second), enhance oxygenation, decrease the duration of hospitalization, and improve clinical outcomes. However, the additional therapeutic benefit regarding FEV1 recovery appears to be most apparent in the first 3 to 5 days. No data are available on the optimum duration of corticosteroid treatment in primary-care patients with acute COPD exacerbations. Given that many COPD patients are treated as outpatients, there is an urgent need to improve the evidence base on COPD management in this setting. The aim of this study is to investigate whether a 3-day treatment with orally administered corticosteroids is non-inferior to a 5-day treatment in acute exacerbations of COPD in a primary-care setting. Methods/design This study is a prospective double-blind randomized controlled trial conducted in a primary-care setting. It is anticipated that 470 patients with acutely exacerbated COPD will be recruited. Participants are randomized to receive systemic corticosteroid treatment of 40 mg prednisone daily for 5 days (conventional arm, n = 235) or for 3 days followed by 2 days of placebo (experimental arm, n = 235). Antibiotic treatment for 7 days is given to all patients with CRP ≥ 50 mg/l, those with a known diagnosis of bronchiectasis, or those presenting with Anthonisen type I exacerbation. Additional treatment after inclusion is left at the discretion of the treating general practitioner. Follow-up visits are performed on days 3 and 7, followed by telephone interviews on days 30, 90, and 180 after inclusion in the study. The primary endpoint is the time to next exacerbation during the 6-month follow-up period. Discussion The study is designed to assess whether a 3-day course of corticosteroid treatment is not inferior to the conventional 5-day treatment course in outpatients with exacerbated COPD regarding time to next exacerbation. Depending on the results, this trial may lead to a reduction in the cumulative corticosteroid dose in COPD patients. Trial registration ClinicalTrials.gov, NCT02386735. Registered on 12 March 2015.

During the last year, mass screening campaigns have been carried out to identify immunological response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and establish a possible seroprevalence. The obtained results gained new importance with the beginning of the SARS-CoV-2 vaccination campaign, as the lack of doses has persuaded several countries to introduce different policies for individuals who had a history of COVID-19. Lateral flow assays (LFAs) may represent an affordable tool to support population screening in low-middle-income countries, where diagnostic tests are lacking and epidemiology is still widely unknown. However, LFAs have demonstrated a wide range of performance, and the question of which one could be more valuable in these settings still remains. We evaluated the performance of 11 LFAs in detecting SARS-CoV-2 infection, analyzing samples collected from 350 subjects. In addition, samples from 57 health care workers collected at 21 to 24 days after the first dose of the Pfizer-BioNTech vaccine were also evaluated. LFAs demonstrated a wide range of specificity (92.31% to 100%) and sensitivity (50% to 100%). The analysis of postvaccination samples was used to describe the most suitable tests to detect IgG response against S protein receptor binding domain (RBD). Tuberculosis (TB) therapy was identified as a potential factor affecting the specificity of LFAs. This analysis identified which LFAs represent a valuable tool not only for the detection of prior SARS-CoV-2 infection but also for the detection of IgG elicited in response to vaccination. These results demonstrated that different LFAs may have different applications and the possible risks of their use in high-TB-burden settings. IMPORTANCE Our study provides a fresh perspective on the possible employment of SARS-CoV-2 LFA antibody tests. We developed an in-depth, large-scale analysis comparing LFA performance to enzyme-linked immunosorbent assay (ELISA) and electrochemiluminescence immunoassay (ECLIA) and evaluating their sensitivity and specificity in identifying COVID-19 patients at different time points from symptom onset. Moreover, for the first time, we analyzed samples of patients undergoing treatment for endemic poverty-related diseases, especially tuberculosis, and we evaluated the impact of this therapy on test specificity in order to assess possible performance in TB high-burden countries.

Patients with anomalous aortic origin of the left anterior descending coronary artery (AAOCA) from the right sinus of Valsava, and associated with a trans-septal course, are recommended for surgery only when symptoms of ischemia are present. The transconal unroofing method is straightforward and provides good anatomic result. In absence of significant coronary compression, surgical management of the trans-septal coronary course is proposed if the patient is a candidate to cardiac surgery for another reason, such as congenital heart disease. We describe a transconal approach in a patient with a trans-septal coronary artery and a ventricular septal defect.

The ICARIA-MM study was sponsored by Sanofi. The authors thank, Helgi van de Velde, Valérie Boutet, Shujia Dai, Deborah DiNoto, Graziella Engelvin, Olivier Fedeli, Sébastien Hugla, Dominique Mouret, Béatrice Pradeilles, and Alain Roccon, all employees of Sanofi, for their contribution to the study, technology, and comments on the manuscript. The authors thank the participating patients and their families, and the study centers and investigators, for their contributions to the study. The medical writing support was provided by John Clarke, PhD and Stephanie Brillhart, PhD of Elevate Medical Affairs, contracted by Sanofi Genzyme for publication support services.

INTRODUCTION Multiple myeloma (MM) remains an incurable disease with a median overall survival of approximately 5 years. Gain or amplification of 1q21 (1q21+) occurs in around 40% of patients with MM and generally portends a poor prognosis. Patients with MM who harbor 1q21+ are at increased risk of drug resistance, disease progression, and death. New pharmacotherapies with novel modes of action are required to overcome the negative prognostic impact of 1q21+. Areas covered: This review discusses the detection, biology, prognosis, and therapeutic targeting of 1q21+ in newly diagnosed and relapsed MM. Patients with MM and 1q21+ tend to present with higher tumor burden, greater end-organ damage, and more co-occurring high-risk cytogenetic abnormalities than patients without 1q21+. The chromosomal rearrangements associated with 1q21+ result in dysregulation of genes involved in oncogenesis. Identification and characterization of the 1q21+ molecular targets are needed to inform on prognosis and treatment strategy. Clinical trial data are emerging that addition of isatuximab to combination therapies may improve outcomes in patients with 1q21+ MM. Expert opinion: In the next 5 years, the results of ongoing research and trials are likely to focus on the therapeutic impact and treatment decisions associated with 1q21+ in MM.

Immunocompromised patients may be at increased risk for complications of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. However, comprehensive data of SARS‐CoV‐2 infection in solid organ transplant (SOT) recipients are still lacking. We performed a multicenter nationwide observational study within the Swiss Transplant Cohort Study (STCS) to describe the epidemiology, clinical presentation, treatment and outcomes of the first microbiologically documented SARS‐CoV‐2 infection among SOT recipients. Overall, 21 patients were included with a median age of 56 years (10 kidney, 5 liver, 1 pancreas, 1 lung, 1 heart and 3 combined transplantations). The most common presenting symptoms were fever (76%), dry cough (57%), nausea (33%) and diarrhea (33%). Ninety‐five percent and 24% of patients required hospital and ICU admission, respectively, and 19% were intubated. After a median of 33 days of follow‐up, 16 patients were discharged, 3 were still hospitalized and 2 patients died. These data suggest that clinical manifestations of SARS‐CoV‐2 infection in middle‐aged SOT recipients appear to be similar to the general population without an apparent higher rate of complications. These results need to be confirmed in larger cohorts.

BackgroundPhase IIb clinical trial with isatuximab (Isa)-lenalidomide (Len)-dexamethasone (Dex) showed an improved progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (RRMM), but the efficacy varied by patient. Antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells plays a crucial role in arbitrating antitumor activities of therapeutic-antibodies. We tested if patient-specific genetic makeup known to set NK cell functional threshold influence response to Isa-Len-Dex therapy.MethodsWe characterized 57 patients with RRMM receiving Isa-Len-Dex for polymorphisms of killer-cell immunoglobulin-like receptors (KIR), human leukocyte antigen (HLA) class I, and FCGR3A loci. In vitro ADCC assay, coincubating primary NK cells expressing specific KIR repertoire with multiple myeloma cell lines (MM cells) expressing selected HLA class I ligands, was used to confirm the identified genetic correlatives of clinical response.ResultsPatients with KIR3DL2+ and its cognate-ligand HLA-A3/11+ had superior PFS than patients missing this combination (HR=0.43; p=0.02), while patients carrying KIR2DL1+ and HLA-C2C2+ compared with to patients missing this pair showed short PFS (HR=3.54; p=0.05). Patients with KIR3DL2+ and HLA-A3/11+ plus high-affinity FCGR3A-158V allele showed the most prolonged PFS (HR=0.35; p=0.007). Consistent with these clinical data, mechanistic experiments demonstrated that NK cells expressing KIR3DL2 trigger greater ADCC when MM cells express HLA-A3/11. Inversely, NK cells expressing KIR2DL1 do not kill if MM cells express the HLA-C2C2 ligand. NK cells expressing high-affinity FCGR3A-158VV-induced greater ADCC compared with those with low-affinity FCGR3A-158FF.ConclusionsOur results suggest that KIR3DL2+ and HLA-A3/11+ with FCGR3A-158V markers lead to enhanced Isa-dependent NK-mediated cytolysis against MM cells and results in improved PFS in patients with RRMM treated by Isa-Len-Dex. Moreover, the presence of KIR2DL1+ and HLA-C2C2+ identifies patients who may have a lower response to Isa-Len-Dex therapy linked to a reduced NK-mediated ADCC. These biomarkers could potentially identify, via precision medicine, patients more likely to respond to Isa-Len-Dex immunotherapy.Trial registration numberNCT01749969.

SUMMARYDepression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota, but causality remains yet to be established. Here, using unpredictable chronic mild stress (UCMS) as a mouse model of depression, we show that the UCMS mice display phenotypic alterations — characterized by an altered gut microbiota composition, a reduced adult hippocampal neurogenesis and a depressive-like behaviors — which could be transferred from UCMS donors to naïve recipient mice by fecal microbiota transplantation. The cellular and behavioral alterations observed in recipient mice were accompanied by a decrease in the endocannabinoid (eCB) signaling due to lower peripheral levels of fatty acid precursors of eCB ligands. The adverse effects of UCMS-transferred microbiota on adult neurogenesis and behavior in naïve recipient mice were alleviated by selectively enhancing the central eCB tone or by adding arachidonic acid, a fatty acid precursor of eCB ligands, to the diet. In the gut of both UCMS donors and recipients, the microbiota composition was characterized by a relative decrease in Lactobacilli abundance, and complementation of the UCMS recipient microbiota with a strain of the Lactobacilli genus was sufficient to restore normal eCB brain levels, hippocampal neurogenesis and to alleviate depressive-like behaviors. Our findings provide a mechanistic scenario for how chronic stress, diet and gut microbiota dysbiosis generate a pathological feed-forward loop that contributes to despair behavior via the central eCB system.

Background: Data on individualized immunosuppressive protocols for the pediatric heart recipients are missing in Europe. To contribute to this very small but specialized field, we describe the use of induction therapy (IT) in pediatric heart transplant patients in Switzerland and the retrospective outcomes. Method: This is a retrospective national database analysis of children

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can cause mild, moderate or severe disease (COVID-19). In severe disease, there is hyperinflammation causing severe symptoms. Severe COVID-19 is an immunological phenomenon, rather than a direct viral damage disease. Therapies for COVID-19 are all investigational therapies. In case of severe disease, treatment with a calcineurin inhibitor could be promising. In this article we explain the mechanisms of calcineurin inhibitor treatment for COVID-19, based on experiences seen in solid organ transplant recipients who suffered from COVID-19.

Glucose intolerance during pregnancy – a major driver of gestational diabetes mellitus (GDM) – has significant short- and long-term health consequences for both the mother and child. As GDM prevalence continues to escalate, there is growing need for preventative strategies. There is limited but suggestive evidence that myo-inositol (MI) and probiotics (PB) could improve glucose tolerance during pregnancy. The present study tested the hypothesis that MI and/or PB supplementation would reduce the risk of glucose intolerance during pregnancy. Female C57BL/6 mice were randomised to receive either no treatment, MI, PB (Lactobacillus rhamnosus and Bifidobacterium lactis) or both (MIPB) for 5 weeks. They were then provided with a high-fat diet for 1 week before mating commenced and throughout mating/gestation, while remaining on their respective treatments. An oral glucose tolerance test occurred at gestational day (GD) 16·5 and tissue collection at GD 18·5. Neither MI nor PB, separately or combined, improved glucose tolerance. However, MI and PB both independently increased adipose tissue expression of Ir, Irs1, Akt2 and Pck1, and PB also increased Pparγ. MI was associated with reduced gestational weight gain, whilst PB was associated with increased maternal fasting glucose, total cholesterol and pancreas weight. These results suggest that MI and PB may improve insulin intracellular signalling in adipose tissue but this did not translate to meaningful differences in glucose tolerance. The absence of fasting hyperglycaemia or insulin resistance suggests this is a very mild model of GDM, which may have affected our ability to assess the impact of these nutrients.

Summary Background Most tuberculosis-related deaths in people with HIV could be prevented with earlier diagnosis and treatment. The only commercially available tuberculosis point-of-care test (Alere Determine TB LAM Ag [AlereLAM]) has suboptimal sensitivity, which restricts its use in clinical practice. The novel Fujifilm SILVAMP TB LAM (FujiLAM) assay has been developed to improve the sensitivity of AlereLAM. We assessed the diagnostic accuracy of the FujiLAM assay for the detection of tuberculosis in hospital inpatients with HIV compared with the AlereLAM assay. Methods For this diagnostic accuracy study, we assessed biobanked urine samples obtained from the FIND Specimen Bank and the University of Cape Town Biobank, which had been collected from hospital inpatients (aged ≥18 years) with HIV during three independent prospective cohort studies done at two South African hospitals. Urine samples were tested using FujiLAM and AlereLAM assays. The conduct and reporting of each test was done blind to other test results. The primary objective was to assess the diagnostic accuracy of FujiLAM compared with AlereLAM, against microbiological and composite reference standards (including clinical diagnoses). Findings Between April 18, 2018, and May 3, 2018, urine samples from 968 hospital inpatients with HIV were evaluated. The prevalence of microbiologically-confirmed tuberculosis was 62% and the median CD4 count was 86 cells per μL. Using the microbiological reference standard, the estimated sensitivity of FujiLAM was 70·4% (95% CI 53·0 to 83·1) compared with 42·3% (31·7 to 51·8) for AlereLAM (difference 28·1%) and the estimated specificity of FujiLAM was 90·8% (86·0 to 94·4) and 95·0% (87·7–98·8) for AlereLAM (difference −4·2%). Against the composite reference standard, the specificity of both assays was higher (95·7% [92·0 to 98·0] for FujiLAM vs 98·2% [95·7 to 99·6] for AlereLAM; difference −2·5%), but the sensitivity of both assays was lower (64·9% [50·1 to 76·7] for FujiLAM vs 38·2% [28·1 to 47·3] for AlereLAM; difference 26·7%). Interpretation In comparison to AlereLAM, FujiLAM offers superior diagnostic sensitivity, while maintaining specificity, and could transform rapid point-of-care tuberculosis diagnosis for hospital inpatients with HIV. The applicability of FujiLAM for settings of intended use requires prospective assessment. Funding Global Health Innovative Technology Fund, UK Department for International Development, Dutch Ministry of Foreign Affairs, Bill & Melinda Gates Foundation, German Federal Ministry of Education and Research, Australian Department of Foreign Affairs and Trade, Wellcome Trust, Department of Science and Technology and National Research Foundation of South Africa, and South African Medical Research Council.

BACKGROUND Smoking remains the leading cause of preventable disease and death in the developed world that kills half of all long-term users. Tobacco use after solid organ transplantation is associated with allograft dysfunction, cancer, and reduced overall survival. METHODS In this single-center, retrospective study, we describe the frequency of tobacco use after lung transplantation (LTx), pretransplant patient characteristics associated with tobacco use, and the safety, efficacy, and outcomes of posttransplant tobacco cessation interventions. RESULTS Four percent of our LTx cohort resumed tobacco use posttransplant. Chronic obstructive pulmonary disease (P = 0.043), the cessation duration before LTx (P < 0.001), and the packyear-cessation index (PCI) (P < 0.001) were found to be significantly associated with tobacco use posttransplant. A PCI cutoff value of 0.32 had 100% sensitivity and 45% specificity for tobacco use resumption. Thirty-five percent of the posttransplant tobacco users successfully quit tobacco consumption. CONCLUSIONS Patients with chronic obstructive pulmonary disease and a short duration of smoking cessation before LTx were at greatest risk of tobacco use after LTx. The PCI may be a useful predictor of tobacco use resumption. Pharmacological tobacco cessation interventions were found to have a comparable safety and efficacy profile compared to nontransplant patients.

Zusammenfassung. Folienrauchen bezeichnet einen inhalativen Konsum von Heroin. Nach Erhitzung und Verflüssigung des Heroins durch Anwendung eines Feuerzeugs auf der Unterseite einer Aluminiumfolie wird mittels Strohhalm der dadurch entstehende Rauch inhaliert. Neben dem bekannten intravenösen (IV) Konsum ist das Folienrauchen die zweithäufigste Form des Heroinkonsums. Die Wirkung tritt im Vergleich zum IV-Konsum mit wenigen Minuten Verzögerung ein. Die beim IV-Konsum beobachteten übertragbaren Krankheiten wie HIV, Hepatitis oder andere Infektionen werden beim inhalativem Konsum nicht berichtet. Es kann jedoch zum Auftreten von schweren Bronchospasmen kommen. Eine zerebrale Auswirkung ist die Leukoenzephalopathie, eine spongiforme Degeneration der weissen Hirnsubstanz, die bisher nur beim inhalativen Heroinkonsum beschrieben wurde. Ursächlich soll die Pyrolysat-Bildung beim Erhitzungsprozess von Heroin beteiligt sein. Bei häufig beobachteter Polytoxikomanie und gleichzeitigem Tabakkonsum ist die Kausalität von Konsumfolgen generell schwierig zu beurteilen. Bei Auftreten einer unklaren pulmonalen Symptomatik oder Erkrankung, die sich wie ein schwerer Asthmaanfall manifestiert, sollte differenzialdiagnostisch an den inhalativen Heroinkonsum gedacht werden.

Point-of-care diagnostics have the potential to increase diagnosis and linkage to care and help reach the WHO targets to eliminate hepatitis C virus (HCV) by 2030. Here, we evaluated the diagnostic accuracy of Genedrive HCV ID assay for the qualitative detection of HCV RNA in decentralized settings in two low- and middle-income countries using fresh plasma specimens from 426 participants. The Abbott RealTime HCV assay was used as the gold standard. Genedrive HCV ID assay was conducted by different users. Users also completed questionnaires to assess the usability of Genedrive. At detection thresholds of 12 IU/mL or 30 IU/mL, 1000 IU/mL, and 2362 IU/mL, the sensitivity was 96.2% (95% CI: 92.7–98.4), 100% (98.2–100), and 100% (98.2–100), respectively, the specificity was 99.5% (95% CI: 97.4–100), 99.5% (97.5–100), and 98.7% (96.1–100), respectively. All genotypes detected using the gold-standard assay were also detected with Genedrive. Users found Genedrive easy to use. Genedrive is a simple and accurate test to confirm chronic HCV infection in decentralized, real-life, resource-limited settings. This novel diagnostic tool could contribute to closing the current gap in HCV diagnosis.

Treatment benefit in multiple myeloma (MM) patients with high-risk cytogenetics remains suboptimal. The phase 3 ICARIA-MM trial (NCT02990338) showed that isatuximab plus pomalidomide-dexamethasone prolongs median progression-free survival (mPFS) in patients with relapsed/refractory MM (RRMM). This subgroup analysis of ICARIA-MM compared the benefit of isatuximab in high-risk [defined by the presence of del(17p), t(4;14) or t(14;16)] versus standard-risk patients. The efficacy of isatuximab in patients with gain(1q21) abnormality was also assessed in a retrospective subgroup analysis. In ICARIA-MM, 307 patients received isatuximab-pomalidomide-dexamethasone (n = 154) or pomalidomide-dexamethasone (n = 153). Isatuximab (10 mg/kg intravenously) was given weekly in the first 28-day cycle, and every other week thereafter. Standard pomalidomide-dexamethasone doses were given. Isatuximab-pomalidomide-dexamethasone improved mPFS (7 center dot 5 vs 3 center dot 7 months; HR, 0 center dot 66; 95% CI, 0 center dot 33-1 center dot 28) and overall response rate (ORR, 50 center dot 0% vs 16 center dot 7%) in high-risk patients. In patients with isolated gain(1q21), isatuximab addition improved mPFS (11 center dot 2 vs 4 center dot 6 months; HR, 0 center dot 50; 95% CI, 0 center dot 28-0 center dot 88) and ORR (53 center dot 6% vs 27 center dot 6%). More grade >= 3 adverse events occurred in high-risk patients receiving isatuximab (95 center dot 7%) versus the control group (67 center dot 6%); however, isatuximab did not increase events leading to discontinuation or treatment-related mortality. Isatuximab-pomalidomide-dexamethasone provides a consistent benefit over pomalidomide-dexamethasone treatment in RRMM patients regardless of cytogenetic risk.

Background: High-risk smoldering multiple myeloma (HR-SMM) is associated with a greater risk of progression to symptomatic disease, suggesting the need for early, efficacious therapeutic interventions to improve outcomes. The ongoing, randomized Phase 3 ITHACA study (NCT04270409) is evaluating efficacy and safety of the anti-CD38 monoclonal antibody isatuximab (Isa) in combination with lenalidomide (R) and dexamethasone (d) (Isa-Rd) vs Rd in patients (pts) with HR-SMM. We report here preliminary results from the safety run-in part of this trial. Methods: The primary objective was to confirm the recommended dose of Isa in combination with Rd. Pts were eligible if diagnosed with SMM within 5 years and HR-SMM defined by the Mayo ‘20-2-20’ and/or updated PETHEMA model criteria. Minimal residual disease and imaging by MRI and low-dose whole-body CT/PET-CT will be assessed at fixed time points. Results: As of April 12, 2021, 23 pts (median age, 63 [28–85] years;median time from initial diagnosis, 1.14 [0.1–5.2] years) had received Isa 10 mg/kg once weekly then biweekly (QW-Q2W) in combination with Rd. The median number of cycles was 7 (range, 4–10) and median duration of treatment exposure was 29.7 (range, 16.0–38.0) weeks. Two pts met the Mayo clinical model criteria, 13 pts the PETHEMA model criteria, and 8 pts both models’ criteria for HR-SMM. No pt presented with focal lesions at baseline. Seven (30.4%) pts developed 8 grade ≥3 non-hematologic treatment-emergent adverse events (TEAEs): COVID-19 pneumonia, insomnia (2 each), papular rash, muscle spasm, retinal detachment and hyperglycemia (1 each);no pt experienced a grade 5 TEAE and no pt discontinued treatment due to a TEAE. Serious TEAEs were COVID-19 pneumonia (n=2, grade ≥3) and pneumonia, musculoskeletal chest pain and pyrexia (n=1 each, grade

Background Intravenous (IV) isatuximab (Isa) + pomalidomide and dexamethasone (Pd) is an approved regimen for the treatment of adults with relapsed/refractory multiple myeloma (RRMM). Subcutaneous (SC) delivery would optimize convenience of administration. Methods This multicenter, open-label, Phase 1b study evaluated the safety, pharmacokinetics (PK), and efficacy of SC vs IV Isa + Pd in patients (pts) with RRMM who had received ≥2 lines including lenalidomide and a proteasome inhibitor. Pts were randomized 2:1 to Cohorts 1a (SC–1000 mg) or 1b (IV–10 mg/kg) and, after evaluation of Isa SC safety, PK and CD38 Receptor Occupancy (RO), randomized to Cohorts 2a (SC–1400 mg) or 2b (IV). SC was delivered through a syringe pump. Primary endpoints assessed safety including dose-limiting toxicity (DLT), injection site reactions (ISR), and PK parameters. Key secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and CD38 RO. Results 34 pts were randomized and treated: 12 pts Isa IV 10 mg/kg + Pd, 12 pts Isa SC1000 + Pd, 10 pts Isa SC1400 + Pd. On March 31, 2021, 7 pts (58%) IV, 4 pts (33%) SC1000, and 7 pts (70%) SC1400 remained on study treatment. At study entry, International Staging System (ISS) stage II–III was 58% in IV, 33% in SC1000 and 60% in SC1400 pts. Due to sequential accrual, the median follow-up was longer in IV (15.1 months [mos]) and SC1000 (14.8 mos) cohorts than SC1400 (8.8 mos). Infusion reactions were infrequent (≤10% across cohorts, all Grade (G) 2), and only at first injection. Local tolerability of SC injection was very good with only a single episode of G2 ISR in SC1400 cohort. Similar occurrence of ≥G3 treatment emergent adverse events (TEAE), treatment-related TEAE, and neutropenia occurred across cohorts. One DLT was reported in each SC cohort: G4 neutropenia (SC1000) and G3 pulmonary infection (SC1400). No maximum tolerated dose was identified. ORR, ≥VGPR, and complete response were 67%, 33%, and 17% in the IV cohort; 67%, 42%, and 25% in the SC1000 cohort and 80%, 40%, and 20% in the SC1400 cohort, respectively. 8 mos PFS-free rate was 73% in the IV and SC1000 cohorts and 89% in the SC1400 cohort. Mean Ctrough after the 4th weekly administration was higher in the SC cohorts (339 µg/mL for SC1000, 338 µg/mL for SC1400) vs 235 µg/mL for IV cohort. High CD38 receptor saturation by Isa on bone marrow plasma cells was reached for both SC doses; mean CD38 RO was 76% in IV, 80% in SC1000, and 81% in SC1400. Conclusions The safety of Isa SC at 1000 mg and 1400 mg + Pd was consistent with the known safety profile associated with IV administration, with no new safety signals identified. Local tolerability of SC Isa was very good. Efficacy results were comparable with the Phase 3 ICARIA study. Higher Ctrough at 4 weeks (PK best predictor of Isa efficacy) was achieved following SC administration compared with IV. Isa SC administration appears to be a promising and convenient option. Funded by Sanofi.

In a manufacturer-independent laboratory validation study, the Xpert MTB/XDR® assay demonstrated equivalent limit of detection to Xpert MTB/RIF®, detected 100% of tested resistance mutations and showed some utility for resistance detection in strain mixtures. The Xpert MTB/XDR assay is a reliable, sensitive assay for tuberculosis and expanded resistance detection.

Background Better blood tests to elucidate the behaviour of metastatic castration-resistant prostate cancer (mCRPC) are urgently needed to drive therapeutic decisions. Plasma cell-free DNA (cfDNA) comprises normal and circulating tumour DNA (ctDNA). Low-pass whole-genome sequencing (lpWGS) of ctDNA can provide information on mCRPC behaviour. Objective To validate and clinically qualify plasma lpWGS for mCRPC. Design, setting, and participants Plasma lpWGS data were obtained for mCRPC patients consenting to optional substudies of two prospective phase 3 trials (FIRSTANA and PROSELICA). In FIRSTANA, chemotherapy-naïve patients were randomised to treatment with docetaxel (75 mg/m2) or cabazitaxel (20 or 25 mg/m2). In PROSELICA, patients previously treated with docetaxel were randomised to 20 or 25 mg/m2 cabazitaxel. lpWGS data were generated from 540 samples from 188 mCRPC patients acquired at four different time points (screening, cycle 1, cycle 4, and end of study). Outcome measurements and statistical analysis lpWGS data for ctDNA were evaluated for prognostic, response, and tumour genomic measures. Associations with response and survival data were determined for tumour fraction. Genomic biomarkers including large-scale transition (LST) scores were explored in the context of prior treatments. Results and limitations Plasma tumour fraction was prognostic for overall survival in univariable and stratified multivariable analyses (hazard ratio 1.75, 95% confidence interval 1.08–2.85; p = 0.024) and offered added value compared to existing biomarkers (C index 0.722 vs 0.709; p = 0.021). Longitudinal changes were associated with drug response. PROSELICA samples were enriched for LSTs (p = 0.029) indicating genomic instability, and this enrichment was associated with prior abiraterone and enzalutamide treatment but not taxane or radiation therapy. Higher LSTs were correlated with losses of RB1/RNASEH2B, independent of BRCA2 loss. Conclusions Plasma lpWGS of ctDNA describes CRPC behaviour, providing prognostic and response data of clinical relevance. The added prognostic value of the ctDNA fraction over established biomarkers should be studied further. Patient summary We studied tumour DNA in blood samples from patients with prostate cancer. We found that levels of tumour DNA in blood were indicative of disease prognosis, and that changes after treatment could be detected. We also observed a “genetic scar” in the results that was associated with certain previous treatments. This test allows an assessment of tumour activity that can complement existing tests, offer insights into drug response, and detect clinically relevant genetic changes., Take Home Message Tumour fraction, independent from cell-free DNA concentration and other clinical variables, is prognostic, with low-pass whole-genome sequencing profiles detecting abiraterone/enzalutamide-induced emerging genomic instability that is likely to be acquired as a result of tumour development.

Background Combined pulmonary fibrosis and emphysema (CPFE) is an underrecognized syndrome characterized by chronic, progressive disease with a dismal prognosis. Frequent co-morbidities with a higher incidence than in idiopathic pulmonary fibrosis or emphysema alone are pulmonary hypertension (WHO group 3) in 47-90% of the patients and lung cancer in 46.8% of the patients. Objective Review current evidence and knowledge concerning diagnosis, risk factors, disease evolution and treatment options of CPFE. Methods We searched studies reporting CPFE in original papers, observational studies, case reports, and meta-analyses published between 1990 and August 2020, in the PubMed, Embase, Cochrane Library, Wiley Online Library databases and Google Scholar using the search terms [CPFE], [pulmonary fibrosis] OR [IPF] AND [emphysema]. Bibliographies of retrieved articles were searched as well. Further inclusion criteria were publications in English, French, German and Italian, with reference to humans. In vitro data and animal data were not considered unless they were mentioned in studies reporting predominantly human data. Results Between May 1, 1990, and September 1, 2020, we found 16 studies on CPFE from the online sources and bibliographies. A total of 890 patients are described in the literature. Although male/female ratio was not reported in all studies, the large majority of patients were male (at least 78%), most of them were current or former heavy smokers. Conclusion CPFE is a syndrome presenting with dyspnea on exertion followed by disruptive cough and recurrent exacerbations. The disease may progress rapidly, be aggravated by pulmonary hypertension WHO group 3 and is associated with an increased risk of lung cancer. Smoking and male sex are important risk factors. There is a need for more research on CPFE especially relating to etiology, influence of genetics, treatment and prevention options. Antifibrotic therapy might be an interesting treatment option for these patients.

Summary Background Isatuximab is an anti-CD38 monoclonal antibody approved in combination with pomalidomide–dexamethasone and carfilzomib–dexamethasone for relapsed or refractory multiple myeloma. This phase 3, open-label study compared the efficacy of isatuximab plus carfilzomib–dexamethasone versus carfilzomib–dexamethasone in patients with relapsed multiple myeloma. Methods This was a prospective, randomised, open-label, parallel-group, phase 3 study done at 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients with relapsed or refractory multiple myeloma aged at least 18 years who had received one to three previous lines of therapy and had measurable serum or urine M-protein were eligible. Patients were randomly assigned (3:2) to isatuximab plus carfilzomib–dexamethasone (isatuximab group) or carfilzomib–dexamethasone (control group). Patients in the isatuximab group received isatuximab 10 mg/kg intravenously weekly for the first 4 weeks, then every 2 weeks. Both groups received the approved schedule of intravenous carfilzomib and oral or intravenous dexamethasone. Treatment continued until progression or unacceptable toxicity. The primary endpoint was progression-free survival and was assessed in the intention-to-treat population according to assigned treatment. Safety was assessed in all patients who received at least one dose according to treatment received. The study is registered at ClinicalTrials.gov, NCT03275285. Findings Between Nov 15, 2017, and March 21, 2019, 302 patients with a median of two previous lines of therapy were enrolled. 179 were randomly assigned to the isatuximab group and 123 to the control group. Median progression-free survival was not reached in the isatuximab group compared with 19·15 months (95% CI 15·77–not reached) in the control group, with a hazard ratio of 0·53 (99% CI 0·32–0·89; one-sided p=0·0007). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 136 (77%) of 177 patients in the isatuximab group versus 82 (67%) of 122 in the control group, serious TEAEs occurred in 105 (59%) versus 70 (57%) patients, and TEAEs led to discontinuation in 15 (8%) versus 17 (14%) patients. Fatal TEAEs during study treatment occurred in six (3%) versus four (3%) patients. Interpretation The addition of isatuximab to carfilzomib–dexamethasone significantly improves progression-free survival and depth of response in patients with relapsed multiple myeloma, representing a new standard of care for this patient population. Funding Sanofi. Video Abstract Video abstractYouTube link: https://youtu.be/5kXtQQlzRh4

Mycobacterium ulcerans, the causative agent of Buruli ulcer (BU) disease, is unique amongst human pathogens in its capacity to produce a lipid toxin called mycolactone. While previous studies have demonstrated that bacterially-released mycolactone diffuses beyond infection foci, the spatiotemporal distribution of mycolactone remained largely unknown. Here, we used the zebrafish model to provide the first global kinetic analysis of mycolactone’s diffusion in vivo, and multicellular co-culture systems to address the critical question of the toxin’s access to the brain. Zebrafish larvae were injected with a fluorescent-derivative of mycolactone to visualize the in vivo diffusion of the toxin from the peripheral circulation. A rapid, body-wide distribution of mycolactone was observed, with selective accumulation in tissues near the injection site and brain, together with an important excretion through the gastro-intestinal tract. Our conclusion that mycolactone reached the central nervous system was reinforced by an in cellulo model of human blood brain barrier and a mouse model of M. ulcerans-infection. Here we show that mycolactone has a broad but heterogenous profile of distribution in vivo. Our investigations in vitro and in vivo support the view that a fraction of bacterially-produced mycolactone gains access to the central nervous system. The relative persistence of mycolactone in the bloodstream suggests that assays of circulating mycolactone are relevant for BU disease monitoring and treatment optimization., Author summary Mycolactone is the major virulence factor of Mycobacterium ulcerans, the human pathogen causing Buruli ulcer (BU) disease. While it is now established that mycolactone is able to diffuse from infected tissues to exert immunomodulatory and analgesic effects at the systemic level, the in vivo spatiotemporal distribution of mycolactone remained largely unknown. Here, using the zebrafish larva, we describe the spatiotemporal distribution of a fluorescent derivative of mycolactone in vivo. We show that fluorescent mycolactone quickly diffuses from the blood circulation into various organs, and accumulates in muscles and brain. Mycolactone’s diffusion into the central nervous system was further confirmed in the mouse model of M. ulcerans infection. We reported previously that mycolactone suppresses the production of inflammatory mediators by primary microglia at nanomolar concentrations in vitro [1]. In the present study, we provide evidence suggesting that bacterially-produced mycolactone is able to reach the brain. While additional in vivo investigations will be required, we can speculate that the amount of mycolactone reaching the brain in the context of M. ulcerans infection is sufficient to modulate inflammation and pain transmission.

BACKGROUND: Isatuximab is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with pomalidomide and low-dose dexamethasone. The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma. METHODS: We did a randomised, multicentre, open-label, phase 3 study at 102 hospitals in 24 countries in Europe, North America, and the Asia-Pacific regions. Eligible participants were adult patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. We randomly assigned patients (1:1) to either isatuximab 10 mg/kg plus pomalidomide 4 mg plus dexamethasone 40 mg (20 mg for patients aged ≥75 years), or pomalidomide 4 mg plus dexamethasone 40 mg. Randomisation was done using interactive response technology and stratified according to the number of previous lines of treatment (2-3 vs >3) and age (

The impact of early life protein source (whey vs. casein) on short- and long-term glucose homeostasis and adiposity is unknown and was investigated in this study. At the end of the suckling period, non-IUGR (intrauterine growth restriction) and IUGR pups were separated from dams and were randomized into four groups. From age 21&ndash, 49 days, non-IUGR and IUGR pups were fed ad-libitum chow or a semi-synthetic diet (20% from protein, casein or whey) and from age 50&ndash, 199 days, all groups were fed ad-libitum chow. Food intake, body composition, glucose, and insulin homeostasis were assessed. Among the chow groups, IUGR had slower growth and higher fasting glucose at age 42 days, as well as higher fasting and AUC glucose at age 192 days relative to non-IUGR. The whey IUGR group had a slower growth rate and higher fasting glycemia in early life (age 21&ndash, 49 days) and higher HOMA-IR later in life (age 120&ndash, 122 and 190&ndash, 192 days) relative to casein IUGR. This study shows the potential advantage of casein relative to whey during weaning on short term energy intake, growth, and glucose homeostasis in an IUGR model and reveals, for the first time, its long term impact on insulin sensitivity, which may have implications for later metabolic health, particularly in small-for-gestational-age populations at risk of type 2 diabetes.

International audience; Background: The significant number of qualitative and quantitative ultrasound markers described for first-trimester screening of open spina bifida (OSB) and other posterior brain defects (oPBD) has resulted in their complex implementation and interpretation for a widespread screening and in a lack of consensus regarding diagnostic accuracy.Objectives: To assess and compare the accuracy of qualitative and quantitative cranial sonographic markers at 11-14 weeks of gestation for the detection of OSB and oPBD.Search strategy: A systematic literature search was performed in MEDLINE and COCHRANE from 2009 to April 2020.Selection criteria: Studies assessing the diagnostic accuracy of quantitative and/or qualitative ultrasound signs to predict OSB and oPBD were included. Cohort studies and case-control studies were also considered.Data collection and analysis: Two reviewers independently extracted data and assessed the risk of bias. The overall pooled estimate and a summary receiver operating characteristic curve was estimated for each subgroup (qualitative and quantitative assessment).Main results: Twenty-three studies were included in our meta-analysis. The pooled sensitivity and specificity for qualitative assessment were 76.5% and 99.6%, and for quantitative assessment were 84.5% and 96.3%, respectively; specificity for the qualitative ultrasound signs was significantly higher (P = 0.001). The overall sensitivity of cranial sonographic markers for the screening of oPBD was 76.7% and specificity was 97.5%.Conclusions: The qualitative approach demonstrated greater specificity, so this would appear to be more appropriate for daily screening, as a first-line tool, whereas the quantitative approach should be reserved for expert ultrasound.Tweetable abstract: This study highlights the relevance of first-trimester qualitative ultrasound signs in the screening of open spina bifida.

Hidradenitis suppurativa (HS) is a chronic skin disorder of unknown etiology that manifests as recurrent, painful lesions. Cutaneous dysbiosis and unresolved inflammation are hallmarks of active HS, but their origin and interplay remain unclear. Our metabolomic profiling of HS skin revealed an abnormal induction of the kynurenine pathway of tryptophan catabolism in dermal fibroblasts, correlating with the release of kynurenine pathway–inducing cytokines by inflammatory cell infiltrates. Notably, overactivation of the kynurenine pathway in lesional skin was associated with local and systemic depletion in tryptophan. Yet the skin microbiota normally degrades host tryptophan into indoles regulating tissue inflammation via engagement of the aryl hydrocarbon receptor (AHR). In HS skin lesions, we detected contextual defects in AHR activation coinciding with impaired production of bacteria-derived AHR agonists and decreased incidence of AHR ligand-producing bacteria in the resident flora. Dysregulation of tryptophan catabolism at the skin-microbiota interface thus provides a mechanism linking the immunological and microbiological features of HS lesions. In addition to revealing metabolic alterations in patients with HS, our study suggests that correcting AHR signaling would help restore immune homeostasis in HS skin., Loss of homeostasis of tryptophan metabolism at the host-microbiota interface may contribute to Hidradenitis Suppurativa.

Summary Background The main difference between extreme tetralogy of Fallot (TOF) and pulmonary atresia with ventricle septal defect (PA/VSD) is anterograde pulmonary blood flow (APBF). It is speculated that the association of modified Blalock–Taussig shunt (mBTS) with APBF favours shunt thrombosis, but promotes better pulmonary artery growth. Aim To compare pulmonary artery growth after mBTS between TOF and PA/VSD. Methods From 1995 to 2018, 77 mBTS procedures were performed in infants (aged Results After matching, the preoperative Nakata index was similar in the two groups (TOF 101 ± 34 vs. PA/VSD 106 ± 35 mm2/m2; P = 0.75). Age and weight were similar (TOF 24 ± 20 days, 3.3 ± 0.6 kg vs. PA/VSD 24 ± 33 days, 3.3 ± 0.9 kg; P = 0.84 and P = 0.77, respectively). There was no difference in rates of in-hospital mortality (TOF 0% vs. PA/VSD 10%; P = 0.13) or mBTS thrombosis (TOF 15% vs. PA/VSD 10%; P = 0.63). The left and right pulmonary artery diameters at time of biventricular repair were similar (TOF 7.5 ± 2.2 and 6.7 ± 2.1 vs. PA/VSD 8 ± 2.7 and 7.1 ± 2.5 mm; P = 0.43 and P = 0.78, respectively), as were delta Nakata (TOF 112 ± 102 vs. PA/VSD 107 ± 66 mm2/m2; P = 0.89), median age for biventricular repair (P = 0.83) and reintervention rates (TOF 10% vs. PA/VSD 15%; P = 0.67). Conclusions We found no difference in pulmonary artery growth between APBF with mBTS versus mBTS alone. Thus, we could not show an increase in mBTS thrombosis with APBF.

To determine the plasma metabolomic profile of exudative age-related macular degeneration (AMD), we performed a targeted metabolomics study on the plasma from patients (n = 40, mean age = 81.1) compared to an age- and sex-matched control group (n = 40, mean age = 81.8). All included patients had documented exudative AMD, causing significant visual loss (mean logMAR visual acuity = 0.63), compared to the control group. Patients and controls did not differ in terms of body mass index and co-morbidities. Among the 188 metabolites analyzed, 150 (79.8%) were accurately measured. The concentrations of 18 metabolites were significantly modified in the AMD group, but only six of them remained significantly different after Benjamini&ndash, Hochberg correction. Valine, lysine, carnitine, valerylcarnitine and proline were increased, while carnosine, a dipeptide disclosing anti-oxidant and anti-glycating properties, was, on average, reduced by 50% in AMD compared to controls. Moreover, carnosine was undetectable for 49% of AMD patients compared to 18% in the control group (p-value = 0.0035). Carnitine is involved in the transfer of fatty acids within the mitochondria, proline, lysine and valerylcarnitine are substrates for mitochondrial electrons transferring flavoproteins, and proline is one of the main metabolites supplying energy to the retina. Overall, our results reveal six new metabolites involved in the plasma metabolomic profile of exudative AMD, suggesting mitochondrial energetic impairments and carnosine deficiency.

Background The novel Fujifilm SILVAMP TB-LAM (FujiLAM) assay detects mycobacterial lipoarabinomannan in urine and has demonstrated superior sensitivity to the Alere Determine TB-LAM Ag (AlereLAM) assay for detection of tuberculosis among hospitalized people with human immunodeficiency virus (PWH). This is the first study to evaluate the assay among a broad population referred for antiretroviral therapy including both outpatients (mainly) and inpatients. Methods We assessed diagnostic accuracy of FujiLAM and AlereLAM assays in biobanked urine samples from a cohort of adults referred for antiretroviral therapy in Ghana against a microbiological and a composite (including clinical judgement) reference standard, and we assessed the association of FujiLAM test positivity with mortality. Results We evaluated urine samples from 532 PWH (462 outpatients, 70 inpatients). Against a microbiological reference standard, the sensitivity of FujiLAM was 74.2% (95% confidence interval [CI], 62.0–84.2) compared to 53.0% (95% CI, 40.3–65.4) for AlereLAM, a difference of 21.2% (CI, 13.1–32.5). Specificity was 89.3% (95% CI, 85.8–92.2) versus 95.6% (95% CI, 93.0–97.4) for FujiLAM and AlereLAM, a difference of −6.3% (95% CI −9.6 to −3.3). Specificity estimates for FujiLAM increased markedly to 98.8% (95% CI, 96.6–99.8) in patients with CD4 >100 cells/µL and when using a composite reference standard. FujiLAM test positivity was associated with increased cumulative risk of mortality at 6 months (hazard ratio, 4.80; 95% CI, 3.01–7.64). Conclusions FujiLAM offers significantly increased diagnostic sensitivity in comparison to AlereLAM. Specificity estimates for FujiLAM were lower than for AlereLAM but were affected by the limited ability of the reference standard to correctly diagnose tuberculosis in individuals with low CD4 counts., Diagnosis of HIV-associated tuberculosis remains a major challenge. The novel rapid Fujifilm SILVAMP TB-LAM urinary assay demonstrated significantly higher sensitivity than Alere Determine TB-LAM for diagnosing tuberculosis among people with HIV among outpatients and across CD4 cell count strata.

Depression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota. Here, using unpredictable chronic mild stress (UCMS) as a mouse model of depression, we show that UCMS mice display phenotypic alterations, which could be transferred from UCMS donors to naïve recipient mice by fecal microbiota transplantation. The cellular and behavioral alterations observed in recipient mice were accompanied by a decrease in the endocannabinoid (eCB) signaling due to lower peripheral levels of fatty acid precursors of eCB ligands. The adverse effects of UCMS-transferred microbiota were alleviated by selectively enhancing the central eCB or by complementation with a strain of the Lactobacilli genus. Our findings provide a mechanistic scenario for how chronic stress, diet and gut microbiota generate a pathological feed-forward loop that contributes to despair behavior via the central eCB system., The gut microbiota may contribute to depression, but the underlying mechanism is not well understood. Here the authors use a mouse model of stress induced depression to demonstrate that behavioural changes conferred by fecal transplant from stressed to naïve mice require the endocannabinoid system.

Background: Bringing reliable and accurate tuberculosis (TB) diagnosis closer to patients is a key priority for global TB control. Molbio Diagnostics have developed the Truenat point-of-care molecular assays for detection of TB and rifampicin (RIF) resistance. Methods: We conducted a prospective multicentre study at 19 microscopy centres and seven reference laboratories in Peru, India, Ethiopia and Papua New Guinea to determine the diagnostic accuracy of the Truenat MTB, MTB Plus and MTB-RIF Dx assays in comparison with Xpert MTB/RIF (‘Xpert’) and Xpert MTB/RIF Ultra (‘Ultra’) using culture as the reference standard (NCT03712709). Findings: Of 1,807 enrolled participants with TB signs/symptoms, 24% were culture positive for Mycobacterium tuberculosis , of which 15% were RIF-resistant by phenotypic drug sensitivity testing. In microscopy centres, the pooled sensitivity of Truenat MTB and Truenat MTB Plus was 73% [95% CI: 67, 78] and 80% [95% CI: 75, 84], respectively. Among smear-negative specimens, sensitivities were 36% [95% CI: 27, 47] and 47% [95% CI: 37, 58], respectively. Specificity of Truenat MTB and MTB Plus was 98% [95% CI: 97, 99] and 96% [95% CI: 95, 97], respectively. Sensitivity of Truenat MTB-RIF was 84% [95% CI: 62, 95], and specificity was 95% [95% CI: 90, 97]. Interpretation: Truenat assays have comparable accuracy with Xpert and can be performed in microscopy centres and primary health centres. Funding Statement: Bill & Melinda Gates Foundation (OPP1208706), India TB Research Consortium, Indian Council for Medical Research, Australian Department of Foreign Affairs and Trade via the PNGAus Partnership, and German KfW. Declaration of Interests: APN, AMa, CMd, MR, PN and SGS are employed by the Foundation for Innovative New Diagnostics (FIND). FIND is a not-for-profit foundation that supports the evaluation of publicly prioritized tuberculosis assays and the implementation of WHO-approved (guidance and prequalification) assays using donor grants. FIND has product evaluation agreements with several private sector companies that design diagnostics for tuberculosis and other diseases. These agreements strictly define FIND's independence and neutrality with regard to these private sector companies. All other authors have nothing to declare. Ethics Approval Statement: The study was conducted in accordance with the 1964 Helsinki declaration and its subsequent amendments and approved by the relevant institutional review boards and independent ethics committees. All participants provided informed consent, either written, or if illiterate, as a thumbprint on the consent form signed and dated by an impartial witness.

Malaria-associated (MA) noncardiogenic pulmonary edema, or its more severe forms, i.e. acute lung injury and acute respiratory distress syndrome due to Plasmodium malariae, is a potentially fatal complication of malaria. It can mimic respiratory infections and present with concurrent malarial pulmonary edema and bacteriological respiratory infection. In our patient, malaria was diagnosed by microscopy (peripheral thick and thin Giemsa-stained blood smear) and serology testing. The chest computed tomography showed interstitial edema and a pleural effusion. Bronchoalveolar lavage was performed, which was negative for both bacteria and hemozoin. After initiation of antimalarial treatment, the patient rapidly responded. Recognizing and promptly treating malaria is critical to reduce the mortality of MA pulmonary complications.

This work presents two complementary techniques to study 36Cl and stable chloride diffusion through unsaturated cement-based materials for saturation degrees (Sw) ranging from 0.18 to 1. The first technique is based on steady-state through-diffusion method where suction (up to 9 MPa) is controlled using osmosis process. In the second technique, in-diffusion experiments are performed by putting into contact a spiked-fresh-cement paste with a CEM-V/A-hardened-cement paste (HCP) sample (initial water to cement ratio of 0.4) having a given water saturation imposed by saline solution method. After a controlled diffusion time, the 36Cl activity profiles within the samples are acquired by means of the abrasive peeling method and 36Cl activity is determined by liquid scintillation counting (LSC) technique. The application of the first technique resulted in data showing a sharp decrease of the effective diffusion coefficient (De) (by a factor of ten) between the experiments done on the fully-saturated HCP sample and the HCP sample at Sw = 0.85. Moreover, duplicate in-diffusion experiments carried out on HCP samples partially-saturated at Sw = 0.86 provided 36Cl De range well bracketing the one determined by the first approach at Sw = 0.85. Four other in-diffusion experiments were thus performed on HCP samples with saturation degrees down to 0.18. Interpretation of the experimental results showed a very small decrease of De values for Sw from 0.74 to 0.41 and a sharp decrease for Sw from 0.41 to 0.18. Lastly, comparison with the diffusive behavior of tritiated water (HTO) through unsaturated CEM V/A HCP samples clearly indicated that diffusion of chloride was more affected by desaturation than HTO. Its ionic form would restrict chloride to the liquid phase whom continuity is broken when dehydration is strong enough.

OBJECTIVES Abdominal surgery after lung transplantation is an important factor for major morbidity and mortality. Herein, we describe the incidence and outcome of abdominal surgery occurring early or late after transplantation. METHODS Overall, 315 patients who underwent lung transplantation between January 2000 and December 2013 at our institution were included in a prospective database. Perioperative parameters were assessed, and complications were graded according to the Clavien-Dindo Classification. RESULTS Among 315 patients after lung transplantation, 52 patients underwent abdominal surgery, 16 during the early postoperative phase and 42 at later time points. Bowel ischaemia and perforation of the right colon were the most common reason for early surgery, with a median interval of 7 days after lung transplantation. The median survival time for patients with early abdominal surgery was 31 months compared to 40 and 90 months for patients with no or late abdominal surgery (P = 0.001 and P = 0.002, respectively). The most common late indications for surgery were perforated diverticulitis, ileus and hernia, with a median interval of 37.9 months after lung transplantation and a median survival comparable with patients without any abdominal surgery (P = 0.9). However, prior hospitalization due to a non-abdominal disease was associated with increased morbidity (P = 0.006) after late surgery. CONCLUSIONS Early abdominal surgeries after lung transplantation are associated with a significant mortality risk. Abdominal operations at late time points have a favourable outcome unless patients were hospitalized prior to the abdominal complication. Clinical trial registration number ZH-KEK-Nr. 2014-0244.

Purpose Acute cellular rejection (ACR) is a frequent complication within the first year after lung transplantation (LTx) and an important risk factor for chronic lung allograft dysfunction (CLAD) and mortality. The revised classification for the standardization of nomenclature in the diagnosis of allograft rejection of 2007 was based on histologic findings using transbronchial forceps biopsy (TBFB). However, its diagnostic accuracy (DA) is limited due to the small sample size and crush artifacts. Transbronchial lung cryobiopsy (TBLC) is a technique for diagnosis of interstitial lung diseases with improved DA compared to TBFB, but with insufficient evidence in diagnosis and screening of ACR. This study aims to provide data on safety, diagnostic utility and impact on treatment decisions after TBLC in lung transplant recipients (LTRs). Methods Between December 2019 and June 2020, both TBFB and LBLC were obtained serially in LTRs during the same bronchoscopy session to detect ACR. According to our protocol, after 5 TBFB samples, 2 samples by TBLC were taken from different lung segments. The biopsies were scored according to the recent ISHLT criteria by a dedicated transplant pathologist, assessing TBFB and TBLC samples independently. The severity of bleeding we assessed with the Nashville Bleeding Scale (grade 1 - 4), and pneumothoraces were excluded with routine chest radiography. Results Totally, 25 consecutive procedures in 17 LTRs (13 males, median age 58) were performed either as routine surveillance bronchchoscopy (n = 19) or as clinically indicated (n = 6) using flexible bronchoscopy. Retrospective analysis of 125 TBFB and 50 TBLC samples was performed. ACR (A1 - A3) was detected in 6 cases (24%) by TBLC resulting in a change of immunosuppressive strategy, compared to 0% by TBFB. Non-diagnostic biopsy samples were noted in 3 cases (12%) of TBLC compared to 21 (84%) of TBFB. The biopsy procedure was complicated by moderate (grade 2) bleeding in 6 (24%) cases as a complication of TBCB, since it occurs immediately after this procedure. No pneumothorax was detected. Conclusion TBLC provided improved DA for diagnosis of ACR with an acceptable safety profile, leading to reclassification and a change of treatment strategy in 24% of the cases. Further prospective studies are needed to confirm these findings and recommend TBLC as gold standard to detect ACR.

Objective Percutaneous closure of interatrial communications (ASD) has become the standard for therapeutic management. However, some patients are ineligible for this technique due to the morphology of the ASD, thus requiring conventional surgical closure by sternotomy or lateral thoracotomy. Minimally invasive surgery (MIS) has been introduced in several adult heart surgery centers especialy for mitral surgery. The purpose is to present the preliminary experience of ASD closure by MIS. Material and methods We analyzed all of the patients (n = 5) treated from March 2019 (start date of the MIS program) to December 2019. The MIC was performed by an anterior mini thoracotomy of approximately 5 cm with femoral cannulation ( Fig. 1 ). The pre, per, and postoperative data were prospectively collected. All patients underwent postoperative vascular Doppler ultrasound of the femoral cannulation site. Results Average age at intervention was 27.3 years (range: 14.5–41), weight was of 60 kg (43–80) (4 women for 1 man). The median duration of CPB was 108 min (101–139), the duration of aortic cross clamping 45 min (36–61). There were no hospital deaths or major complication. One patient had a pneumothorax on D3. The median duration of extubation was 3.5 hours (3–6), the median duration of hospitalization was 8 days (6–11). Postoperative echocardiography did not show any residual ASD or pericardial effusion. All patients were sinus rhythm. No venous or arterial stenosis was observed at the cannulation sites. The average systolic pulmonary arterial pressure, was measured 34 mmHg (15–74) preoperatively, and estimated 30 mmHg (20–55) postoperatively. Conclusion This clinical study shows the preliminary experience of MIS program for the closure of ASDs. This approach appears to be safe and effective, without major vascular complications. longer term follow-up is required to determine the specific role of MIS approach in the management of this patient population.

Contains fulltext : 184156.pdf (Publisher’s version ) (Closed access) Magnesium (Mg(2+)) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg(2+), which is crucial for Mg(2+) homeostasis, and the potential influence on metabolic traits in the general population are unknown. We obtained plasma and urine parameters from 9099 individuals from seven cohorts, and conducted a genome-wide meta-analysis of Mg(2+) homeostasis. We identified two loci associated with urinary magnesium (uMg), rs3824347 (P=4.4x10(-13)) near TRPM6, which encodes an epithelial Mg(2+) channel, and rs35929 (P=2.1x10(-11)), a variant of ARL15, which encodes a GTP-binding protein. Together, these loci account for 2.3% of the variation in 24-hour uMg excretion. In human kidney cells, ARL15 regulated TRPM6-mediated currents. In zebrafish, dietary Mg(2+) regulated the expression of the highly conserved ARL15 ortholog arl15b, and arl15b knockdown resulted in renal Mg(2+) wasting and metabolic disturbances. Finally, ARL15 rs35929 modified the association of uMg with fasting insulin and fat mass in a general population. In conclusion, this combined observational and experimental approach uncovered a gene-environment interaction linking Mg(2+) deficiency to insulin resistance and obesity. 01 januari 2018

Critical limb ischemia (CLI) with distal leg necrosis in lung transplant recipients (LTR) is associated with a high risk for systemic infection and sepsis. Optimal management of CLI has not been defined so far in LTR. In immunocompetent individuals with leg necrosis, surgical amputation would be indicated and standard care. We report on the outcome of four conservatively managed LTR with distal leg necrosis due to peripheral arterial disease (PAD) with medial calcification of the distal limb vessels. Time interval from lung transplantation to CLI ranged from four years (n = 1) to more than a decade (n = 3). In all cases a multimodal therapy with heparin, acetylsalicylic acid, iloprost and antibiotic therapy was performed, in addition to a trial of catheter-based revascularization. Surgical amputation of necrosis was not undertaken due to fear of wound healing difficulties under long-term immunosuppression and impaired tissue perfusion. Intensive wound care and selective debridement were performed. Two patients developed progressive gangrene followed by auto-amputation during a follow-up of 43 and 49 months with continued ambulation and two patients died of unrelated causes 9 and 12 months after diagnosis of CLI. In conclusion, we report a conservative treatment strategy for distal leg necrosis in LTR without surgical amputation and recommend this approach based on our experience.