Long-term results of sirolimus treatment in lymphangioleiomyomatosis: a single referral centre experience

Diagnòstic; Farmacoteràpia; Malalties del tracte respiratoriDiagnóstico; Farmacoterapia; Enfermedades del tracto respiratorioDiagnosis; Drug therapy; Respiratory tract diseasesThere are few published data on long-term treatment with sirolimus in lymphangioleiomyomatosis (LAM). The objective of this study was to describe the long-term effect of sirolimus in a series of LAM patients followed up in a referral centre, focusing on pulmonary function. We retrospectively reviewed a series of 48 patients with LAM diagnosed, followed up and treated with sirolimus in a single centre. Response to sirolimus was evaluated at 1 and 5 years. A negative sirolimus response was defined as an FEV1 decline greater than − 75 ml/year. A mixed-effects model was used to estimate the longitudinal changes in FEV1 (average slope), both as absolute (ml/year) and as predicted values (%predicted/year). From a total of 48 patients, 9 patients underwent lung transplantation and 4 died during the study. Mean (95% CI) FEV1 slope over 5 years was − 0.14 (− 26.13 to 25.85) ml/year in the whole LAM group, 42.55 (14.87 to 70.22) ml/year in the responder group, − 54.00 (− 71.60 to − 36.39) ml/year in the partial responder group and − 84.19 (− 113.5 to − 54.0) ml/year in the non-responder group. After 5 years of sirolimus treatment 59% had a positive response, 30% had a partial response and 11% had a negative response. Our study found that sirolimus treatment had a positive long-term effect on most LAM patients.E.R.L. received a pre-doctoral Grant from the Spanish Society of Pulmonology and Thoracic Surgery

Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis

Biomarcador; Histamina; LimfangioleiomiomatosiBiomarcador; Histamina; LinfangioleiomiomatosisBiomarker; Histamine; LymphangioleiomyomatosisInhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non-invasive tests. Here, we propose monoamine-derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine-derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF-D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L-histidine analog, or a low L-histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management.This research was supported by AELAM, The LAM Foundation (Seed Grant 2019), Instituto de Salud Carlos III grants PI15/00854, PI18/01029, and ICI19/00047 (co-funded by European Regional Development Fund (ERDF), a way to build Europe), Generalitat de Catalunya SGR grants 2014-364 and 2017-449, the CERCA Program, and ZonMW-TopZorg grant 842002003. C.L.M. acknowledges the financial support (PRA-2017-51 project) of the University of Pisa. A.U.K. is supported by Nottingham Trent University’s Independent Fellowship Scheme

Near-normal aerobic capacity in long-term survivors after lung transplantation

Lung transplant; Survivors; Aerobic capacityTrasplantaments de pulmó; Supervivents; Capacitat aeròbicaTrasplantes de pulmón; Supervivientes; Capacidad aeróbicaThe clinical course of lung transplantation (LT) is diverse: some patients present chronic lung allograft dysfunction (CLAD) and progressive decline in pulmonary function, but others maintain normal spirometric values and active lives. Objectives The aim of this study was to elucidate whether long-term LT survivors with normal spirometry achieve normal exercise capacity, and to identify predictive factors of exercise capacity. Methods This was a cross-sectional multicentre study, where bilateral LT recipients who survived at least 10 years after LT, with normal spirometry, no diagnosis of CLAD and modified Medical Research Council dyspnoea degree ≤2 underwent cardiopulmonary exercise testing (CPET). Results 28 LT recipients were included with a mean±sd age of 48.7±13.6 years. Oxygen uptake (V′O2) had a mean±sd value of 21.49±6.68 mL·kg−1·min−1 (75.24±15.6%) and the anaerobic threshold was reached at 48.6±10.1% of the V′O2max predicted. The mean±sd heart rate reserve at peak exercise was 17.56±13.6%. The oxygen pulse increased during exercise and was within normal values at 90.5±19.4%. The respiratory exchange ratio exceeded 1.19 at maximum exercise. The median (25–75th percentile) EuroQol-5D score was 1 (0.95–1), indicating a good quality of life. The median (25–75th percentile) International Physical Activity Questionnaire score was 5497 (4007–9832) MET-min·week−1 with 89% of patients reporting more than 1500 MET-min·week−1. In the multivariate regression models, age, sex and diffusing capacity of the lung for carbon monoxide remained significantly associated with V′O2max (mL·kg−1·min−1); haemoglobin and forced expiratory volume in 1 s were significantly associated with maximum work rate (watts), after adjusting for confounders. Conclusion We report for the first time near-normal peak V′O2 values during CPET and normal exercise capacity in long-term LT recipients without CLAD.Support statement: This study was financed by Instituto de Salud Carlos III (PI13/01076); the European Regional Development Fund (FEDER), FUCAP, Astellas, Novartis and Chiesi. Funding information for this article has been deposited with the Crossref Funder Registry.Ojanguren is a researcher supported by the “Pla Estratègic de Recerca i Innovació en Salut (PERIS)” 2016–2020 (SLT008/18/00108;G60594009)

Lymphangioleiomyomatosis: Searching for potential biomarkers

Biomarkers; Lymphangioleiomyomatosis; MetalloproteinasesBiomarcadores; Linfangioleiomiomatosis; MetaloproteinasasBiomarcadors; Limfangioleiomiomatosi; MetaloproteinasesBackground: Vascular endothelial growth factor-D (VEGF-D) is the most commonly used biomarker for diagnosing lymphangioleiomyomatosis (LAM). However, lung biopsy is often necessary as well; therefore, defining new biomarkers for LAM is crucial. The aim of this study was to describe the diagnostic accuracy of a variety of biomarkers. Methods: We assessed 13 analytes in serum related to extracellular matrix remodeling, lymphatic involvement and angiogenesis in a cohort of patients with LAM, comparing them with patients with other cystic lung diseases (OCLD) and healthy women. A scoring method based on the cut-point of each VEGF-D and metalloproteinase-2 (MMP-2) was used to evaluate the diagnostic performance of the marker combination. Results: A total of 97 subjects were recruited: 59 (61%) LAM patients, 18 (19%) OCLD patients, and 20 (20%) healthy female controls. MMP-2 was the only extracellular matrix remodeling biomarker able to differentiate LAM patients from OCLD and healthy patients. Serum MMP-2 was higher in LAM patients [median 578 (465–832) ng/ml] than in patients with OCLD and healthy controls [medians 360 (314–546) and 427 (365–513) ng/ml, respectively (p < 0.0001)]. The area under ROC curve (AUC) of MMP-2 was 0.785 and that of VEGF-D 0.815 (p = 0.6214). The sensitivity/specificity profiles of each biomarker (54/92% for MMP-2, 59/95% for VEGF-D) yielded a composite score (−6.36 + 0.0059 × VEGF-D + 0.0069 × MMP-2) with higher accuracy than each component alone (AUC 0.88 and sensitivity/specificity 79/87%). Conclusion: Combining MMP-2 and VEGF-D may increase diagnostic accuracy for LAM.This project was supported by the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), grant number: PI 638/2018. The funders have no role in study design, data and analysis collection, decision to publish, or preparation of the manuscript

Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder

Pathogenic hemizygous or heterozygous mutations in the IQSEC2 gene cause X-linked intellectual developmental disorder-1 (XLID1), characterized by a variable phenotype including developmental delay, intellectual disability, epilepsy, hypotonia, autism, microcephaly and stereotypies. It affects both males and females typically through loss of function in males and haploinsufficiency in heterozygous females. Females are generally less affected than males. Two novel unrelated cases, one male and one female, with de novo IQSEC2 variants were detected by trio-based whole exome sequencing. The female case had a previously undescribed frameshift mutation (NM_001111125:c.3300dup; p.Met1101Tyrfs*5), and the male showed an intronic variant in intron 6, with a previously unknown effect (NM_001111125:c.2459+21C&gt;T). IQSEC2 gene expression study revealed that this intronic variant created an alternative donor splicing site and an aberrant product, with the inclusion of 19bp, confirming the pathogenic effect of the intron variant. Moreover, a strong reduction in the expression of the long, but also the short IQSEC2 isoforms, was detected in the male correlating with a more severe phenotype, while the female case showed no decreased expression of the short isoform, and milder effects of the disease. This suggests that the abnormal expression levels of the different IQSEC2 transcripts could be implicated in the severity of disease manifestations.This research was funded by INSTITUTO DE SALUD CARLOS III, institutional project Spain UDP and grant PT20CIII/00009.S

Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target

[Image: see text] With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes

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

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

Identification and Optimization of Novel Inhibitors of the Polyketide Synthase 13 Thioesterase Domain with Antitubercular Activity

There is an urgent need for new tuberculosis (TB) treatments, with novel modes of action, to reduce the incidence/mortality of TB and to combat resistance to current treatments. Through both chemical and genetic methodologies, polyketide synthase 13 (Pks13) has been validated as essential for mycobacterial survival and as an attractive target for Mycobacterium tuberculosis growth inhibitors. A benzofuran series of inhibitors that targeted the Pks13 thioesterase domain, failed to progress to preclinical development due to concerns over cardiotoxicity. Herein, we report the identification of a novel oxadiazole series of Pks13 inhibitors, derived from a high-throughput screening hit and structure-guided optimization. This new series binds in the Pks13 thioesterase domain, with a distinct binding mode compared to the benzofuran series. Through iterative rounds of design, assisted by structural information, lead compounds were identified with improved antitubercular potencies (MIC &lt; 1 μM) and in vitro ADMET profiles.</p

How do women living with HIV experience menopause? Menopausal symptoms, anxiety and depression according to reproductive age in a multicenter cohort

CatedresBackground: To estimate the prevalence and severity of menopausal symptoms and anxiety/depression and to assess the differences according to menopausal status among women living with HIV aged 45-60 years from the cohort of Spanish HIV/AIDS Research Network (CoRIS). Methods: Women were interviewed by phone between September 2017 and December 2018 to determine whether they had experienced menopausal symptoms and anxiety/depression. The Menopause Rating Scale was used to evaluate the prevalence and severity of symptoms related to menopause in three subscales: somatic, psychologic and urogenital; and the 4-item Patient Health Questionnaire was used for anxiety/depression. Logistic regression models were used to estimate odds ratios (ORs) of association between menopausal status, and other potential risk factors, the presence and severity of somatic, psychological and urogenital symptoms and of anxiety/depression. Results: Of 251 women included, 137 (54.6%) were post-, 70 (27.9%) peri- and 44 (17.5%) pre-menopausal, respectively. Median age of onset menopause was 48 years (IQR 45-50). The proportions of pre-, peri- and post-menopausal women who had experienced any menopausal symptoms were 45.5%, 60.0% and 66.4%, respectively. Both peri- and post-menopause were associated with a higher likelihood of having somatic symptoms (aOR 3.01; 95% CI 1.38-6.55 and 2.63; 1.44-4.81, respectively), while post-menopause increased the likelihood of having psychological (2.16; 1.13-4.14) and urogenital symptoms (2.54; 1.42-4.85). By other hand, post-menopausal women had a statistically significant five-fold increase in the likelihood of presenting severe urogenital symptoms than pre-menopausal women (4.90; 1.74-13.84). No significant differences by menopausal status were found for anxiety/depression. Joint/muscle problems, exhaustion and sleeping disorders were the most commonly reported symptoms among all women. Differences in the prevalences of vaginal dryness (p = 0.002), joint/muscle complaints (p = 0.032), and sweating/flush (p = 0.032) were found among the three groups. Conclusions: Women living with HIV experienced a wide variety of menopausal symptoms, some of them initiated before women had any menstrual irregularity. We found a higher likelihood of somatic symptoms in peri- and post-menopausal women, while a higher likelihood of psychological and urogenital symptoms was found in post-menopausal women. Most somatic symptoms were of low or moderate severity, probably due to the good clinical and immunological situation of these women

COVID-19 in hospitalized HIV-positive and HIV-negative patients : A matched study

CatedresObjectives: We compared the characteristics and clinical outcomes of hospitalized individuals with COVID-19 with [people with HIV (PWH)] and without (non-PWH) HIV co-infection in Spain during the first wave of the pandemic. Methods: This was a retrospective matched cohort study. People with HIV were identified by reviewing clinical records and laboratory registries of 10 922 patients in active-follow-up within the Spanish HIV Research Network (CoRIS) up to 30 June 2020. Each hospitalized PWH was matched with five non-PWH of the same age and sex randomly selected from COVID-19@Spain, a multicentre cohort of 4035 patients hospitalized with confirmed COVID-19. The main outcome was all-cause in-hospital mortality. Results: Forty-five PWH with PCR-confirmed COVID-19 were identified in CoRIS, 21 of whom were hospitalized. A total of 105 age/sex-matched controls were selected from the COVID-19@Spain cohort. The median age in both groups was 53 (Q1-Q3, 46-56) years, and 90.5% were men. In PWH, 19.1% were injecting drug users, 95.2% were on antiretroviral therapy, 94.4% had HIV-RNA < 50 copies/mL, and the median (Q1-Q3) CD4 count was 595 (349-798) cells/μL. No statistically significant differences were found between PWH and non-PWH in number of comorbidities, presenting signs and symptoms, laboratory parameters, radiology findings and severity scores on admission. Corticosteroids were administered to 33.3% and 27.4% of PWH and non-PWH, respectively (P = 0.580). Deaths during admission were documented in two (9.5%) PWH and 12 (11.4%) non-PWH (P = 0.800). Conclusions: Our findings suggest that well-controlled HIV infection does not modify the clinical presentation or worsen clinical outcomes of COVID-19 hospitalization