Caracterización fenotípica y molecular de una familia colombiana con fenilcetonuria

Introduction: Phenylketonuria is a metabolic disorder characterized by severe neurological involvement and behavioral disorder, whose early diagnosis enables an effective treatment to avoid disease sequelae, thus changing the prognosis. Objective: To characterize a family with phenylketonuria in Colombia at clinical, biochemical and molecular levels. Materials and methods: The population consisted of seven individuals of a consanguineous family with four children with suggestive symptoms of phenylketonuria. After signing an informed consent, blood and urine samples were taken for colorimetric tests and high performance liquid and thin layer chromatographies. DNA extraction and sequencing of the 13 exons of the PAH gene were performed in all subjects. We designed primers for each exon with the Primer 3 software using automatic sequencing equipment Abiprism 3100 Avant. Sequences were analyzed using the SeqScape, v2.0, software. Results: We described the clinical and molecular characteristics of a Colombian family with phenylketonuria and confirmed the presence of the mutation c.398_401delATCA. We established a genotype-phenotype correlation, highlighting the interesting clinical variability found among the affected patients despite having the same mutation in all of them. Conclusions: Early recognition of this disease is very important to prevent its neurological and psychological sequelae, given that patients reach old age without diagnosis or proper management.Introducción. La fenilcetonuria es un trastorno metabólico caracterizado por un compromiso neurológico grave y por alteraciones del comportamiento. Su diagnóstico temprano permite establecer un tratamiento efectivo que evita las secuelas y modifica el pronóstico. Objetivo. Caracterizar a una familia con fenilcetonuria en Colombia, a nivel clínico, bioquímico y molecular. Materiales y métodos. Se estudió una población de siete individuos de una familia consanguínea en la que cuatro hijos presentaban signos clínicos sugestivos de fenilcetonuria. Una vez firmado el consentimiento informado, se tomaron muestras de sangre y orina para las pruebas colorimétricas, la cromatografía de capa fina y la cromatografía líquida de alta eficacia. Se extrajo el ADN y se secuenciaron los 13 exones del gen PAH de todos los sujetos estudiados. Se diseñaron iniciadores para cada exón con el programa Primer 3; la secuenciación automática se hizo con el equipo Abiprism 3100 Avant y, el análisis de las secuencias, con el programa SeqScape v2.0. Resultados. Se describieron las características clínicas y moleculares de una familia colombiana con fenilcetonuria en la que se identificó la mutación c.398_401delATCA; se presentó una correlación fenotipo-genotipo con una interesante variabilidad clínica entre los afectados, a pesar de tener la misma mutación. Conclusiones. Es importante el reconocimiento temprano de esta enfermedad para evitar sus secuelas neurológicas y psicológicas, pues los pacientes llegan a edades avanzadas sin diagnóstico ni tratamiento adecuados

Manual lymphatic drainage therapy in patients with breast cancer related lymphoedema

<p>Abstract</p> <p>Background</p> <p>Lymphoedema is a common and troublesome condition that develops following breast cancer treatment. The aim of this study is to analyze the effectiveness of Manual Lymphatic Drainage in the treatment of postmastectomy lymphoedema in order to reduce the volume of lymphoedema and evaluate the improvement of the concomitant symptomatology.</p> <p>Methods</p> <p>A randomized, controlled clinical trial in 58 women with post-mastectomy lymphoedema. The control group includes 29 patients with standard treatment (skin care, exercise and compression measures, bandages for one month and, subsequently, compression garnments). The experimental group includes 29 patients with standard treatment plus Manual Lymphatic Drainage. The therapy will be administered daily for four weeks and the patient's condition will be assessed one, three and six months after treatment.</p> <p>The primary outcome parameter is volume reduction of the affected arm after treatment, expressed as a percentage. Secondary outcome parameters include: duration of lymphoedema reduction and improvement of the concomitant symptomatology (degree of pain, sensation of swelling and functional limitation in the affected extremity, subjective feeling of being physically less atractive and less feminine, difficulty looking at oneself naked and dissatisfaction with the corporal image).</p> <p>Discussion</p> <p>The results of this study will provide information on the effectiveness of Manual Lymphatic Drainage and its impact on the quality of life and physical limitations of these patients.</p> <p>Trial registration</p> <p>ClinicalTrials (NCT): <a href="http://www.clinicaltrials.gov/ct2/show/NCT01152099">NCT01152099</a></p

Allele-Specific Impairment of GJB2 Expression by GJB6 Deletion del(GJB6-D13S1854)

Mutations in the GJB2 gene, which encodes connexin 26, are a frequent cause of congenital non-syndromic sensorineural hearing loss. Two large deletions, del(GJB6-D13S1830) and del(GJB6-D13S1854), which truncate GJB6 (connexin 30), cause hearing loss in individuals homozygous, or compound heterozygous for these deletions or one such deletion and a mutation in GJB2. Recently, we have demonstrated that the del(GJB6-D13S1830) deletion contributes to hearing loss due to an allele-specific lack of GJB2 mRNA expression and not as a result of digenic inheritance, as was postulated earlier. In the current study we investigated the smaller del(GJB6-D13S1854) deletion, which disrupts the expression of GJB2 at the transcriptional level in a manner similar to the more common del(GJB6-D13S1830) deletion. Interestingly, in the presence of this deletion, GJB2 expression remains minimally but reproducibly present. The relative allele-specific expression of GJB2 was assessed by reverse-transcriptase PCR and restriction digestions in three probands who were compound heterozygous for a GJB2 mutation and del(GJB6-D13S1854). Each individual carried a different sequence variant in GJB2. All three individuals expressed the mutated GJB2 allele in trans with del(GJB6-D13S1854), but expression of the GJB2 allele in cis with the deletion was almost absent. Our study clearly corroborates the hypothesis that the del(GJB6-D13S1854), similar to the larger and more common del(GJB6-D13S1830), removes (a) putative cis-regulatory element(s) upstream of GJB6 and narrows down the region of location

Results of an early access treatment protocol of daratumumab monotherapy in spanish patients with relapsed or refractory multiple myeloma

Daratumumab is a human CD38-targeted monoclonal antibody approved as monotherapy for heavily pretreated relapsed and refractory multiple myeloma. We report findings for the Spanish cohort of an open-label treatment protocol that provided early access to daratumumab monotherapy and collected safety and patient-reported outcomes data for patients with relapsed or refractory multiple myeloma. At 15 centers across Spain, intravenous daratumumab (16mg/kg) was administered to 73 patients who had ≥3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double refractory to both. The median duration of daratumumab treatment was 3.3 (range: 0.03–13.17) months, with a median number of 12 (range: 1–25) infusions. Grade 3/4 treatment-emergent adverse events were reported in 74% of patients and included lymphopenia (28.8%), thrombocytopenia (27.4%), neutropenia (21.9%), leukopenia (19.2%), and anemia (15.1%). Common (>5%) serious treatmentemergent adverse events included respiratory tract infection (9.6%), general physical health deterioration (6.8%), and back pain (5.5%). Infusion-related reactions occurred in 45% of patients. The median change from baseline in all domains of the EQ-5D-5L and EORTC QLQ-C30 was mostly 0. A total of 18 (24.7%) patients achieved a partial response or better, with 10 (13.7%) patients achieving a very good partial response or better. Median progression-free survival was 3.98 months. The results of this early access treatment protocol are consistent with previously reported trials of daratumumab monotherapy and confirm its safety and antitumoral efficacy in Spanish patients with heavily treated relapsed or refractory multiple myeloma

Exploring Attitudes Toward “Sugar Relationships” Across 87 Countries: A Global Perspective on Exchanges of Resources for Sex and Companionship

The current study investigates attitudes toward one form of sex for resources: the so-called sugar relationships, which often involve exchanges of resources for sex and/or companionship. The present study examined associations among attitudes toward sugar relationships and relevant variables (e.g., sex, sociosexuality, gender inequality, parasitic exposure) in 69,924 participants across 87 countries. Two self-report measures of Acceptance of Sugar Relationships (ASR) developed for younger companion providers (ASR-YWMS) and older resource providers (ASR-OMWS) were translated into 37 languages. We tested cross-sex and cross-linguistic construct equivalence, cross-cultural invariance in sex differences, and the importance of the hypothetical predictors of ASR. Both measures showed adequate psychometric properties in all languages (except the Persian version of ASR-YWMS). Results partially supported our hypotheses and were consistent with previous theoretical considerations and empirical evidence on human mating. For example, at the individual level, sociosexual orientation, traditional gender roles, and pathogen prevalence were significant predictors of both ASR-YWMS and ASR-OMWS. At the country level, gender inequality and parasite stress positively predicted the ASR-YWMS. However, being a woman negatively predicted the ASR-OMWS, but positively predicted the ASR-YWMS. At country-level, ingroup favoritism and parasite stress positively predicted the ASR-OMWS. Furthermore, significant cross-subregional differences were found in the openness to sugar relationships (both ASR-YWMS and ASR-OMWS scores) across subregions. Finally, significant differences were found between ASR-YWMS and ASR-OMWS when compared in each subregion. The ASR-YWMS was significantly higher than the ASR-OMWS in all subregions, except for Northern Africa and Western Asia

Clustering COVID-19 ARDS patients through the first days of ICU admission. An analysis of the CIBERESUCICOVID Cohort

Background Acute respiratory distress syndrome (ARDS) can be classified into sub-phenotypes according to different inflammatory/clinical status. Prognostic enrichment was achieved by grouping patients into hypoinflammatory or hyperinflammatory sub-phenotypes, even though the time of analysis may change the classification according to treatment response or disease evolution. We aimed to evaluate when patients can be clustered in more than 1 group, and how they may change the clustering of patients using data of baseline or day 3, and the prognosis of patients according to their evolution by changing or not the cluster.Methods Multicenter, observational prospective, and retrospective study of patients admitted due to ARDS related to COVID-19 infection in Spain. Patients were grouped according to a clustering mixed-type data algorithm (k-prototypes) using continuous and categorical readily available variables at baseline and day 3.Results Of 6205 patients, 3743 (60%) were included in the study. According to silhouette analysis, patients were grouped in two clusters. At baseline, 1402 (37%) patients were included in cluster 1 and 2341(63%) in cluster 2. On day 3, 1557(42%) patients were included in cluster 1 and 2086 (57%) in cluster 2. The patients included in cluster 2 were older and more frequently hypertensive and had a higher prevalence of shock, organ dysfunction, inflammatory biomarkers, and worst respiratory indexes at both time points. The 90-day mortality was higher in cluster 2 at both clustering processes (43.8% [n = 1025] versus 27.3% [n = 383] at baseline, and 49% [n = 1023] versus 20.6% [n = 321] on day 3). Four hundred and fifty-eight (33%) patients clustered in the first group were clustered in the second group on day 3. In contrast, 638 (27%) patients clustered in the second group were clustered in the first group on day 3.Conclusions During the first days, patients can be clustered into two groups and the process of clustering patients may change as they continue to evolve. This means that despite a vast majority of patients remaining in the same cluster, a minority reaching 33% of patients analyzed may be re-categorized into different clusters based on their progress. Such changes can significantly impact their prognosis

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

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

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

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years