Clinical and laboratory parameters associated with cycle outcomes in patients undergoing euploid frozen blastocyst transfer.

RESEARCH QUESTION: Which factors impact on clinical pregnancy rate (CPR) and live birth rates (LBR) in euploid frozen embryo transfer (eFET) cycles? DESIGN: Retrospective observational study including 1660 eFET cycles with 2439 euploid blastocysts, from November 2016 to December 2020. The impact of clinical and laboratory parameters on CPR, biochemical miscarriage rate (BMR), clinical miscarriage rate (CMR) and LBR was evaluated. RESULTS: CPR per transfer was 63.4%, LBR per transfer 51.6%. CPR and LBR were significantly higher when double embryo transfer (DET) was performed (71.6% versus 57.7%, P < 0.001; 55.2% versus 49.1%, P = 0.016, respectively). However, pregnancy loss was significantly higher in the DET group (28.8% versus 22.8%, P = 0.02). When patients were classified by body mass index (BMI), no differences were observed for CPR, but CMR was lower (P < 0.001) and LBR higher (p = 0.031) for the normal BMI group. The natural cycle protocol revealed lower CMR (P < 0.001) and lower pregnancy loss (P < 0.001); subsequently, higher LBR (57.6%, 48.8%, 45.0%, P = 0.001) compared with hormonal replacement protocol and stimulated cycle. Day of trophectoderm biopsy affected CPR (P < 0.001) and LBR (P < 0.001), yet no differences were observed for BMR, CMR or pregnancy loss. The multivariate analysis showed that day 6/7 embryos had lower probabilities for pregnancy; overweight and obesity had a negative impact on LBR, and natural cycle improved LBR (adjusted odds ratio 1.445, 95% confidence interval 0.519-0.806). CONCLUSIONS: Day of biopsy affected CPR, while BMI and endometrial preparation protocol were associated with LBR in eFET. DET should be discouraged as it will increase the risk of pregnancy loss. Women with higher BMI should be aware of the higher risk of pregnancy loss and lower LBR even though a euploid blastocyst is transferred.

First babies conceived with Automated Intracytoplasmic Sperm Injection.

RESEARCH QUESTION: Can an automated sperm injection robot perform Automated Intracytoplasmic Sperm Injection (ICSIA) for use in human IVF? DESIGN: The ICSIA robot automated the sperm injection procedure, including injection pipette advancement, zona pellucida and oolemma penetration with piezo pulses, and pipette removal after sperm release. The robot was first tested in mouse, hamster and rabbit oocytes, and subsequently using discarded human oocytes injected with microbeads. A small clinical pilot trial was conducted with donor oocytes to study the feasibility of the robot in a clinical setting. The ICSIA robot was controlled by engineers with no micromanipulation experience. Results were compared with those obtained with manual ICSI conducted by experienced embryologists. RESULTS: The ICSIA robot demonstrated similar results to the manual procedure in the different animal models tested as well as in the pre-clinical validations conducted in discarded human oocytes. In the clinical validation, 13 out of 14 oocytes injected with ICSIA fertilized correctly versus 16 out of 18 in the manual control; eight developed into good-quality blastocysts versus 12 in the manual control; and four were diagnosed as chromosomally normal versus 10 euploid in the manual control. Three euploid blastocysts from the ICSIA robot group have been transferred into two recipients, which resulted in two singleton pregnancies and two babies born. CONCLUSIONS: The ICSIA robot showed high proficiency in injecting animal and human oocytes when operated by inexperienced personnel. The preliminary results obtained in this first clinical pilot trial are within key performance indicators.

Children living with HIV in Europe: do migrants have worse treatment outcomes?

OBJECTIVES: To assess the effect of migrant status on treatment outcomes among children living with HIV in Europe. METHODS: Children aged < 18 years at the start of antiretroviral therapy (ART) in European paediatric HIV observational cohorts where ≥ 5% of children were migrants (defined as born abroad) were included. Three outcomes were considered: (i) severe immunosuppression-for-age; (ii) viraemic viral load (≥ 400 copies/mL) at 1 year after ART initiation; and (iii) AIDS/death after ART initiation. The effect of migrant status was assessed using univariable and multivariable logistic and Cox models. RESULTS: Of 2620 children included across 12 European countries, 56% were migrants. At ART initiation, migrant children were older than domestic-born children (median 6.1 vs. 0.9 years, p < 0.001), with slightly higher proportions being severely immunocompromised (35% vs. 33%) and with active tuberculosis (2% vs. 1%), but a lower proportion with an AIDS diagnosis (14% vs. 19%) (all p < 0.001). At 1 year after beginning ART, a lower proportion of migrant children were viraemic (18% vs. 24%) but there was no difference in multivariable analysis (p = 0.702), and no difference in severe immunosuppression (p = 0.409). However, there was a trend towards higher risk of AIDS/death in migrant children (adjusted hazard ratio = 1.51, 95% confidence interval: 0.96-2.38, p = 0.072). CONCLUSIONS: After adjusting for characteristics at ART initiation, migrant children have virological and immunological outcomes at 1 year of ART that are comparable to those who are domestic-born, possibly indicating equity in access to healthcare in Europe. However, there was some evidence of a difference in AIDS-free survival, which warrants further monitoring.

Stem cell transplantation as treatment for major histocompatibility class I deficiency.

Major histocompatibility class I deficiency, due to genetic lesions in TAP1, TAP2, TAPBP, or B2M, manifests with recurrent sinopulmonary infections and granulomatous skin ulceration, and is predominately treated with antimicrobial prophylaxis and chest physiotherapy. One previous report of hematopoietic stem cell transplantation has been described in the literature, demonstrating cure of the immune defect without significant graft-versus-host disease. In this report, we expand the literature on HSCT in MHC-I deficiency with follow-up of the original patient, demonstrating maintained resolution of normal immune function and regression of the granulomatous rash 15 years post-transplant, and describe a further patient with mycobacterial disease whose transplant course was complicated by severe graft-versus-host disease.

Inherited GATA2 Deficiency Is Dominant by Haploinsufficiency and Displays Incomplete Clinical Penetrance.

PURPOSE: Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown. METHODS: We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives. RESULTS: We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic. CONCLUSION: Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.

Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia.

Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978).

Net contribution and predictive ability of the CUN-BAE body fatness index in relation to cardiometabolic conditions.

BACKGROUND: The CUN-BAE (Clínica Universidad de Navarra-Body adiposity estimator) index is an anthropometric index based on age, sex and body mass index (BMI) for a refined prediction of body fatness in adults. CUN-BAE may help detect metabolically unhealthy individuals with otherwise normal weight according to BMI or waist circumference (WC). The aim of this study was to evaluate whether CUN-BAE, independent of its components (BMI, age and sex), was associated with cardiometabolic conditions including arterial hypertension, diabetes mellitus and metabolic syndrome (MetS). METHODS: The ENRICA study was based on a cross-sectional sample of non-institutionalized men and women representative of the adult Spanish population. Body weight, height, and WC were measured in all participants. The residual of CUN-BAE (rCUN-BAE), i.e. the part of the index not explained by its components, was calculated. The associations of CUN-BAE, rCUN-BAE, BMI and WC with hypertension, diabetes and MetS were analysed by multivariate logistic regression, and the Akaike information criterion (AIC) was calculated. RESULTS: The sample included 12,122 individuals. rCUN-BAE was associated with hypertension (OR 1.14, 95% CI 1.07-1.21) and MetS (OR 1.48, 1.37-1.60), but not with diabetes (OR 1.05, 0.94-1.16). In subjects with a BMI < 25 kg/m2, CUN-BAE was significantly associated with all three outcome variables. CUN-BAE was more strongly associated with the cardiometabolic conditions than BMI and WC and fit similar AICs. CONCLUSIONS: The CUN-BAE index for body fatness was positively associated with hypertension, diabetes and MetS in adults independent of BMI or WC. CUN-BAE may help to identify individuals with cardiometabolic conditions beyond BMI, but this needs to be confirmed in prospective settings.

Long-term trends in mortality and AIDS-defining events after combination ART initiation among children and adolescents with perinatal HIV infection in 17 middle- and high-income countries in Europe and Thailand: A cohort study.

BACKGROUND: Published estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and AIDS-defining events in children and adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle- and high-income countries, including some in Western and Central Europe (W&CE), Eastern Europe (Russia and Ukraine), and Thailand. METHODS AND FINDINGS: Children with perinatal HIV aged <18 years initiating cART were followed until their 21st birthday, transfer to adult care, death, loss to follow-up, or last visit up until 31 December 2013. Rates of death and first AIDS-defining events were calculated. Baseline and time-updated risk factors for early/late (≤/>6 months of cART) death and progression to AIDS were assessed. Of 3,526 children included, 32% were from the United Kingdom or Ireland, 30% from elsewhere in W&CE, 18% from Russia or Ukraine, and 20% from Thailand. At cART initiation, median age was 5.2 (IQR 1.4-9.3) years; 35% of children aged <5 years had a CD4 lymphocyte percentage <15% in 1997-2003, which fell to 15% of children in 2011 onwards (p < 0.001). Similarly, 53% and 18% of children ≥5 years had a CD4 count <200 cells/mm3 in 1997-2003 and in 2011 onwards, respectively (p < 0.001). Median follow-up was 5.6 (2.9-8.7) years. Of 94 deaths and 237 first AIDS-defining events, 43 (46%) and 100 (42%) were within 6 months of initiating cART, respectively. Multivariable predictors of early death were: being in the first year of life; residence in Russia, Ukraine, or Thailand; AIDS at cART start; initiating cART on a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen; severe immune suppression; and low BMI-for-age z-score. Current severe immune suppression, low current BMI-for-age z-score, and current viral load >400 c/mL predicted late death. Predictors of early and late progression to AIDS were similar. Study limitations include incomplete recording of US Centers for Disease Control (CDC) disease stage B events and serious adverse events in some countries; events that were distributed over a long time period, and that we lacked power to analyse trends in patterns and causes of death over time. CONCLUSIONS: In our study, 3,526 children and adolescents with perinatal HIV infection initiated antiretroviral therapy (ART) in countries in Europe and Thailand. We observed that over 40% of deaths occurred ≤6 months after cART initiation. Greater early mortality risk in infants, as compared to older children, and in Russia, Ukraine, or Thailand as compared to W&CE, raises concern. Current severe immune suppression, being underweight, and unsuppressed viral load were associated with a higher risk of death at >6 months after initiation of cART.

The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis.

BACKGROUND: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. METHODS AND FINDINGS: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. CONCLUSION: To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.

Last-century forest productivity in a managed dry-edge Scots pine population: the two sides of climate warming.

Climate change in the Mediterranean, associated with warmer temperatures and more frequent droughts, is expected to impact forest productivity and the functioning of forests ecosystems as carbon reservoirs in the region. Climate warming can positively affect forest growth by extending the growing season, whereas increasing summer drought generally reduces forest productivity and may cause growth decline, trigger dieback, hamper regeneration, and increase mortality. Forest management could potentially counteract such negative effects by reducing stand density and thereby competition for water. The effectiveness of such interventions, however, has so far mostly been evaluated for short time periods at the tree and stand levels, which limits our confidence regarding the efficacy of thinning interventions over longer time scales under the complex interplay between climate, stand structure, and forest management. In this study, we use a century-long historical data set to assess the effects of climate and management on forest productivity. We consider rear-edge Scots pine (Pinus sylvestris) populations covering continental and Mediterranean conditions along an altitudinal gradient in Central Spain. We use linear mixed-effects models to disentangle the effects of altitude, climate, and stand volume on forest growth and ingrowth (recruitment and young trees' growth). We find that warming tends to benefit these tree populations, warmer winter temperature has a significant positive effect on both forest growth and ingrowth, and the effect is more pronounced at low elevations. However, drought conditions severely reduce growth and ingrowth, in particular when competition (stand volume) is high. We conclude that summer droughts are the main threat to Scots pine populations in the region, and that a reduction of stand volume can partially mitigate the negative impacts of more arid conditions. Mitigation and adaptation measures could therefore manage stand structure to adopt for the anticipated impacts of climate change in Mediterranean forest ecosystems.

Disseminated Granulomatous Perifollicular Dermatosis With Comedones: A Follicular Variant of Lichen Nitidus or a New Entity?

The presence of acquired generalized keratotic follicular papules and comedones developing in adulthood constitute an uncommon clinical situation. Although this clinical presentation has been described in several noninflammatory, inflammatory, and neoplastic skin disorders, its association with an exclusive perifollicular epitheliod or granulomatous inflammatory reaction represents an exceedingly rare phenomenon. We report a case of a 57-year-old male patient presenting clinically numerous acquired disseminated follicular papules and comedones, showing isolated perifollicular sarcoid-like granulomatous inflammatory infiltrates at the histological examination. These lesions experienced a complete spontaneous resolution after several months. The possibility that this disseminated, epithelioid, granulomatous, perifollicular dermatosis may represent an isolated follicular variant of lichen nitidus or a previously nonreported skin disorder is discussed.

Alterations in PGC1α expression levels are involved in colorectal cancer risk: a qualitative systematic review.

BACKGROUND: Colorectal cancer (CRC) is a major global public health problem and the second leading cause of cancer-related death. Mitochondrial dysfunction has long been suspected to be involved in this type of tumorigenesis, as supported by an accumulating body of research evidence. However, little is known about how mitochondrial alterations contribute to tumorigenesis. Mitochondrial biogenesis is a fundamental cellular process required to maintain functional mitochondria and as an adaptive mechanism in response to changing energy requirements. Mitochondrial biogenesis is regulated by peroxisome proliferator-activated receptor gamma coactivator 1-α (PPARGC1A or PGC1α). In this paper, we report a systematic review to summarize current evidence on the role of PGC1α in the initiation and progression of CRC. The aim is to provide a basis for more comprehensive research. METHODS: The literature search, data extraction and quality assessment were performed according to the document Guidance on the Conduct of Narrative Synthesis in Systematic Reviews and the PRISMA declaration. RESULTS: The studies included in this review aimed to evaluate whether increased or decreased PGC1α expression affects the development of CRC. Each article proposes a possible molecular mechanism of action and we create two concept maps. CONCLUSION: Our systematic review indicates that altered expression of PGC1α modifies CRC risk. Most studies showed that overexpression of this gene increases CRC risk, while some studies indicated that lower than normal expression levels could increase CRC risk. Thus, various authors propose PGC1α as a good candidate molecular target for cancer therapy. Reducing expression of this gene could help to reduce risk or progression of CRC.

Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD).

Mutations in genes encoding proteins that are involved in mitochondrial heme synthesis, iron-sulfur cluster biogenesis, and mitochondrial protein synthesis have previously been implicated in the pathogenesis of the congenital sideroblastic anemias (CSAs). We recently described a syndromic form of CSA associated with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Here we demonstrate that SIFD is caused by biallelic mutations in TRNT1, the gene encoding the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs. Using budding yeast lacking the TRNT1 homolog, CCA1, we confirm that the patient-associated TRNT1 mutations result in partial loss of function of TRNT1 and lead to metabolic defects in both the mitochondria and cytosol, which can account for the phenotypic pleiotropy.

A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD).

Congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders identified by pathological erythroid precursors with perinuclear mitochondrial iron deposition in bone marrow. An international collaborative group of physicians and laboratory scientists collated clinical information on cases of CSA lacking known causative mutations, identifying a clinical subgroup of CSA associated with B immunodeficiency, periodic fevers, and development delay. Twelve cases from 10 families were identified. Median age at presentation was 2 months. Anemia at diagnosis was sideroblastic, typically severe (median hemoglobin, 7.1 g/dL) and markedly microcytic (median mean corpuscular volume, 62.0 fL). Clinical course involved recurrent febrile illness and gastrointestinal disturbance, lacking an infective cause. Investigation revealed B-cell lymphopenia (CD19⁺ range, 0.016-0.22 × 109/L) and panhypogammaglobulinemia in most cases. Children displayed developmental delay alongside variable neurodegeneration, seizures, cerebellar abnormalities, sensorineural deafness, and other multisystem features. Most required regular blood transfusion, iron chelation, and intravenous immunoglobulin replacement. Median survival was 48 months, with 7 deaths caused by cardiac or multiorgan failure. One child underwent bone marrow transplantation aged 9 months, with apparent cure of the hematologic and immunologic manifestations. We describe and define a novel CSA and B-cell immunodeficiency syndrome with additional features resembling a mitochondrial cytopathy. The molecular etiology is under investigation.

Topical rapamycin combined with pulsed dye laser in the treatment of capillary vascular malformations in Sturge-Weber syndrome: phase II, randomized, double-blind, intraindividual placebo-controlled clinical trial.

BACKGROUND: Sturge-Weber syndrome (SWS) is characterized by port-wine stains (PWS) affecting the face, eyes, and central nervous system. Pulsed dye laser (PDL) is the standard treatment for PWS. Unfortunately, recurrence is frequent because of reformation and reperfusion of blood vessels. OBJECTIVE: We sought to assess the clinical efficacy of topical rapamycin combined with PDL in PWS of patients with SWS. METHODS: We conducted a phase II, randomized, double-blind, intraindividual placebo-controlled, clinical trial. We recruited 23 patients with SWS and facial PWS (12 women; median age 33 years, age range 17-65 years) from the University Clinic of Navarra, Spain. Four interventions were evaluated: placebo, PDL + placebo, rapamycin, and PDL + rapamycin. Clinical and histologic responses were evaluated using a chromatographic computerized system, spectrometry, and histologic analyses at 6, 12, and 18 weeks after the intervention. RESULTS: PDL + rapamycin yielded the lowest digital photographic image score and the lowest percentage of vessels in histologic analysis, and showed a statistically significant improvement compared with the other interventions. The treatment was generally well tolerated. LIMITATIONS: PDL was only applied to the lateral parts of the PWS area. CONCLUSION: Topical rapamycin associated with PDL seems to be an effective treatment for PWS in patients with SWS.

BK virus nephropathy complicated with meningoencephalitis after kidney transplantation.

BK disease is an opportunistic infection in organ transplant recipients and patients with other cellular immunodeficiencies. To the best of our knowledge, we report the second case of BK meningoencephalitis associated with nephropathy in a kidney transplant recipient. A 15-yr-old boy underwent a cadaveric kidney transplant without complications; however, 11 wk after the transplantation, he was admitted to the hospital for graft dysfunction and cytopenia, which were confirmed by BK nephropathy (plasma viral replication and histological evidence). Four days after his hospital admission, he developed a high-grade fever and headache. CSF analysis revealed pleocytosis with a positive PCR for BK virus. Reduction in immunosuppression and supportive care conducting cycles of immunoglobulin and cidofovir were successful in treating the patient. BK meningoencephalitis should be considered in kidney transplant recipients who present with signs and symptoms of meningoencephalitis.

Acclimation of phenology relieves leaf longevity constraints in deciduous forests.

Leaf phenology is key for regulating total growing-season mass and energy fluxes. Long-term temporal trends towards earlier leaf unfolding are observed across Northern Hemisphere forests. Phenological dates also vary between years, whereby end-of-season (EOS) dates correlate positively with start-of-season (SOS) dates and negatively with growing-season total net CO2 assimilation (Anet). These associations have been interpreted as the effect of a constrained leaf longevity or of premature carbon (C) sink saturation-with far-reaching consequences for long-term phenology projections under climate change and rising CO2. Here, we use multidecadal ground and remote-sensing observations to show that the relationships between Anet and EOS are opposite at the interannual and the decadal time scales. A decadal trend towards later EOS persists in parallel with a trend towards increasing Anet-in spite of the negative Anet-EOS relationship at the interannual scale. This finding is robust against the use of diverse observations and models. Results indicate that acclimation of phenology has enabled plants to transcend a constrained leaf longevity or premature C sink saturation over the course of several decades, leading to a more effective use of available light and a sustained extension of the vegetation CO2 uptake season over time.

Long COVID in Children and Adolescents: A Retrospective Study in a Pediatric Cohort.

Studies on long coronavirus disease (COVID) in children are scarce. We aimed to describe persistent symptoms and identify risk factors for its development. In our study population, 17.6% presented with long COVID, with respiratory symptoms more frequent in the first weeks and neuropsychiatric symptoms over time. Chronic conditions and obesity were risk factors, and adolescents were at a greater risk for long COVID.

Global patterns of tree density are contingent upon local determinants in the world's natural forests.

Previous attempts to quantify tree abundance at global scale have largely neglected the role of local competition in modulating the influence of climate and soils on tree density. Here, we evaluated whether mean tree size in the world's natural forests alters the effect of global productivity on tree density. In doing so, we gathered a vast set of forest inventories including >3000 sampling plots from 23 well-conserved areas worldwide to encompass (as much as possible) the main forest biomes on Earth. We evidence that latitudinal productivity patterns of tree density become evident as large trees become dominant. Global estimates of tree abundance should, therefore, consider dependencies of latitudinal sources of variability on local biotic influences to avoid underestimating the number of trees on Earth and to properly evaluate the functional and social consequences.

Nucleoside/nucleotide reverse transcriptase inhibitor sparing regimen with once daily integrase inhibitor plus boosted darunavir is non-inferior to standard of care in virologically-suppressed children and adolescents living with HIV - Week 48 results of the randomised SMILE Penta-17-ANRS 152 clinical trial.

Background: Integrase inhibitor (INSTI) with boosted darunavir (DRV/r), a regimen with a high-resistance barrier, avoiding NRTI toxicities, might be a switching option in children living with HIV (CLWHIV). Methods: SMILE is a randomised non-inferiority trial evaluating safety and antiviral efficacy of once-daily INSTI + DRV/r vs. continuing on current standard-of-care (SOC) triple ART (2NRTI + boosted PI/NNRTI) in virologically-suppressed CLWHIV aged 6-18 years. The primary outcome is the proportion with confirmed HIV-RNA ≥50 copies/mL by week 48, estimated by Kaplan-Meier method. Non-inferiority margin was 10%. Registration number for SMILE are: ISRCTN11193709, NCT #: NCT02383108. Findings: Between 10th June 2016 and 30th August 2019, 318 participants were enrolled from Africa 53%, Europe 24%, Thailand 15% and Latin America 8%, 158 INSTI + DRV/r [153 Dolutegravir (DTG); 5 Elvitegravir (EVG)], 160 SOC. Median (range) age was 14.7 years (7.6-18.0); CD4 count 782 cells/mm3 (227-1647); 61% female. Median follow-up was 64.3 weeks with no loss to follow-up. By 48 weeks, 8 INSTI + DRV/r vs. 12 SOC had confirmed HIV-RNA ≥50 copies/mL; difference (INSTI + DRV/r-SOC) -2.5% (95% CI: -7.6, 2.5%), showing non-inferiority. No major PI or INSTI resistance mutations were observed. There were no differences in safety between arms. By week 48, difference (INSTI + DRV/r-SOC) in mean CD4 count change from baseline was -48.3 cells/mm3 (95% CI: -93.4, -3.2; p = 0.036). Difference (INSTI + DRV/r-SOC) in mean HDL change from baseline was -4.1 mg/dL (95% CI: -6.7, -1.4; p = 0.003). Weight and Body Mass Index (BMI) increased more in INSTI + DRV/r than SOC [difference: 1.97 kg (95% CI: 1.1, 2.9; p < 0.001), 0.66 kg/m2 (95% CI: 0.3, 1.0; p < 0.001)]. Interpretation: In virologically-suppressed children, switching to INSTI + DRV/r was non-inferior virologically, with similar safety profile, to continuing SOC. Small but significant differences in CD4, HDL-cholesterol, weight and BMI were observed between INSTI + DRV/r vs. SOC although clinical relevance needs further investigation. SMILE data corroborate adult findings and provide evidence for this NRTI-sparing regimen for children and adolescents. Funding: Fondazione Penta Onlus, Gilead, Janssen, INSERM/ANRS and UK MRC. ViiV-Healthcare provided Dolutegravir.