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PURPOSE: Investigate patient preferences in embryo selection for transfer regarding quality versus sex in IVF/ICSI cycles with PGT-A and assess associated clinical implications. METHODS: Retrospective cohort study at a university fertility practice from January 2012 to December 2021. Included were patients undergoing single frozen euploid transfers with at least one embryo of each sex available. Primary outcomes were preference for embryo selection (quality vs. sex) and sex preference (male vs. female). Trends over 10 years were evaluated and clinical outcomes, including clinical pregnancy rate (CPR), sustained implantation rate (SIR), and live birth rate (LBR), were compared. RESULTS: A total of 5,145 embryo transfer cycles were included; 54.5% chose the best-quality embryo, while 45.5% selected based on sex. Among those choosing based on sex, 56.5% chose male embryos and 43.5% chose female. Preference for quality remained consistent over the decade (p = 0.30), while male embryos were consistently favored (p = 0.64). Best-quality embryos had higher grades (p < 0.001). Clinical outcomes were similar between groups (CPR: 74.4% vs. 71.9%, p = 0.05; SIR: 64.9% vs. 63.4%, p = 0.26; LBR: 58.8% vs. 56.7%, p = 0.13), and between male and female embryo selections. CONCLUSIONS: Sex selection remains common, with 45.5% selecting embryos based on sex, predominantly favoring males. This trend persisted over 10 years, with comparable clinical outcomes regardless of selection criteria.
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Aneuploidia , Transferencia de Embrión , Fertilización In Vitro , Índice de Embarazo , Diagnóstico Preimplantación , Preselección del Sexo , Humanos , Femenino , Masculino , Embarazo , Adulto , Transferencia de Embrión/métodos , Pruebas Genéticas , Estudios Retrospectivos , Implantación del Embrión/genética , Tasa de Natalidad , Inyecciones de Esperma Intracitoplasmáticas/métodos , Blastocisto/fisiología , Nacimiento Vivo/epidemiología , Nacimiento Vivo/genéticaRESUMEN
BACKGROUND AND IMPORTANCE: Occurrence of mydriasis during the prehospital management of traumatic brain injury (TBI) may suggest severe intracranial hypertension (ICH) subsequent to brain herniation. The initiation of hyperosmolar therapy to reduce ICH and brain herniation is recommended. Whether mannitol or hypertonic saline solution (HSS) should be preferred is unknown. OBJECTIVES: The objective of this study is to assess whether HSS, compared with mannitol, is associated with improved survival in adult trauma patients with TBI and mydriasis. DESIGN/SETTING AND PARTICIPANTS: A retrospective observational cohort study using the French Traumabase national registry to compare the ICU mortality of patients receiving either HSS or mannitol. Patients aged 16â years or older with moderate to severe TBI who presented with mydriasis during prehospital management were included. OUTCOME MEASURES AND ANALYSIS: We performed propensity score matching on a priori selected variables [i.e. age, sex and initial Coma Glasgow Scale (GCS)] with a ratio of 1â :â 3 to ensure comparability between the two groups. The primary outcome was ICU mortality. The secondary outcomes were regression of pupillary abnormality during prehospital management, pulsatility index and diastolic velocity on transcranial Doppler within 24â h after TBI, early ICU mortality (within 48â h), ICU and hospital length of stay. RESULTS: Of 31â 579 patients recorded in the registry between 2011 and 2021, 1417 presented with prehospital mydriasis and were included: 1172 (82.7%) received mannitol and 245 (17.3%) received HSS. After propensity score matching, 720 in the mannitol group matched 240 patients in the HSS group. Median age was 41â years [interquartile ranges (IQR) 26-60], 1058 were men (73%) and median GCS was 4 (IQR 3-6). No significant difference was observed in terms of characteristics and prehospital management between the two groups. ICU mortality was lower in the HSS group (45%) than in the mannitol group (54%) after matching [odds ratio (OR) 0.68 (0.5-0.9), P â =â 0.014]. No differences were identified between the groups in terms of secondary outcomes. CONCLUSION: In this propensity-matched observational study, the prehospital osmotherapy with HSS in TBI patients with prehospital mydriasis was associated with a lower ICU mortality compared to osmotherapy with mannitol.
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Lesiones Traumáticas del Encéfalo , Servicios Médicos de Urgencia , Manitol , Humanos , Manitol/uso terapéutico , Manitol/administración & dosificación , Solución Salina Hipertónica/uso terapéutico , Solución Salina Hipertónica/administración & dosificación , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/mortalidad , Lesiones Traumáticas del Encéfalo/terapia , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Servicios Médicos de Urgencia/métodos , Francia , Escala de Coma de Glasgow , Sistema de Registros , Puntaje de Propensión , Estudios de Cohortes , Hipertensión Intracraneal/etiología , Hipertensión Intracraneal/tratamiento farmacológico , Hipertensión Intracraneal/terapia , Anciano , Diuréticos Osmóticos/uso terapéuticoRESUMEN
Intrapersonal parental factors play a significant role in the development of problematic gaming in children. However, few studies have explored parental perspectives on their relationship with a child engaged in problematic gaming, as well as the need for support parents perceive in relation to the child's gaming. We conducted semi-structured interviews with 12 parents (83.3% women) of 11 children (81.8% boys, Mage = 15 ± 2) to examine how parents of children with problematic gaming behavior perceive the parent-child relationship and their need for additional support. We analyzed qualitative accounts using thematic analysis to identify themes and subthemes while drawing on the theoretical frameworks of Aaron Antonovsky's theory of sense of coherence (SOC) and Jürgen Habermas' theory of logic. Participants described difficulties regarding all three components of SOC (meaningfulness, comprehensibility, and manageability) in relation to their child's gaming, with the most significant challenge being manageability. Parents primarily sought assistance from institutions and organizations, such as mental health services, to enhance manageability. The findings emphasize parents' need for relational and practical support tailored to their unique context, as well as their wish to be more involved in the treatment of their children.
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PURPOSE: To investigate whether leukocytospermia (defined as the presence of ≥ 1 × 106 white blood cells/mL) affects clinical and embryologic outcomes in in vitro fertilization (IVF) cycles with intracytoplasmic sperm injection (ICSI) and preimplantation genetic testing for aneuploidy (PGT-A). METHODS: This was a retrospective cohort study including 5425 cycles between January 2012 to December 2021 at a single large university-affiliated fertility clinic. The primary outcome was live birth rate (LBR). RESULTS: The prevalence of leukocytospermia was 33.9% (n = 1843). Baseline characteristics including female age, BMI, AMH, Day 3 FSH, and male partner's age were similar in cycles with and without leukocytospermia. The LBR after the first euploid embryo transfer was similar in those with and without leukocytospermia (62.3% vs. 63% p = 0.625). Secondary outcomes including clinical pregnancy rate (CPR), sustained implantation rate (SIR), fertilization (2PN) rate, blastulation rate, and aneuploidy rate were also evaluated. The CPR (73.3% vs 74.9%, p = 0.213) and SIR (64.6% vs. 66%, p = 0.305) were similar in both groups. The 2PN rate was also similar in both groups (85.7% vs. 85.8%, p = 0.791), as was the blastulation rate per 2PN (56.7% vs. 57.5%, p = 0.116). The aneuploidy rate was not significantly different between groups (25.7% vs 24.4%, p = 0.053). A generalized estimation equation with logistic regression demonstrated that the presence leukocytospermia did not influence the LBR (adjusted OR 0.878; 95% CI, 0.680-1.138). CONCLUSION: Leukocytospermia diagnosed just prior to an IVF cycle with PGT-A does not negatively impact clinical or embryologic outcomes.
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Aneuploidia , Transferencia de Embrión , Fertilización In Vitro , Pruebas Genéticas , Índice de Embarazo , Diagnóstico Preimplantación , Inyecciones de Esperma Intracitoplasmáticas , Humanos , Femenino , Inyecciones de Esperma Intracitoplasmáticas/métodos , Embarazo , Masculino , Adulto , Transferencia de Embrión/métodos , Estudios Retrospectivos , Nacimiento Vivo/epidemiología , Nacimiento Vivo/genética , Tasa de Natalidad , Leucocitos/patología , Infertilidad Masculina/genética , Infertilidad Masculina/patología , Infertilidad Masculina/terapia , Infertilidad Masculina/diagnóstico , Implantación del Embrión/genéticaRESUMEN
PURPOSE OF REVIEW: This article reviews recent advances in ultrasound elastography in diagnosing and evaluating the normal nongravid uterus and the infertile uterus in the gynecologic patient. RECENT FINDINGS: Focusing on the most recent primary literature, studies have demonstrated new findings among a breadth of gynecologic clinical settings. Studies in the nongravid uterus have found that menopausal status, age, and menstrual phase have not been associated with changes in uterine tissue stiffness. Focusing on myometrial disease, there have been conflicting data regarding the ability to distinguish uterine fibroids from adenomyosis. One area of expanding research surrounding uterine elastography includes the infertile population, where ongoing studies attempt to provide a predictive model using shear wave elastography (SWE) in patients undergoing in-vitro fertilization. SUMMARY: Ultrasound elastography has become an increasingly studied and utilized tool in assessing physiologic and pathologic processes in the field of gynecology. Evaluating tissue stiffness through strain and SWE can serve to improve diagnosis of various uterine and cervical lesions, as well as prognosticate outcomes after fertility treatments. This growing area of research will continue to establish the role and application of ultrasound elastography into clinical practice.
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Diagnóstico por Imagen de Elasticidad , Infertilidad Femenina , Útero , Humanos , Femenino , Diagnóstico por Imagen de Elasticidad/métodos , Útero/diagnóstico por imagen , Infertilidad Femenina/diagnóstico por imagen , Leiomioma/diagnóstico por imagen , Enfermedades Uterinas/diagnóstico por imagen , Neoplasias Uterinas/diagnóstico por imagen , Adenomiosis/diagnóstico por imagenRESUMEN
Peat is the most common used substrate in horticultural seedling production. To reduce peat in horticultural potted plant cultivation systems in general is an obstacle, even within the highly specialized horticultural industry. Next to soil-less cultivation systems as e.g. hydroponics, the horticultural industry is eagerly looking for suitable peat substitutes. The demands on these compounds are high, basically mimicking the physical properties of peat. A 100% replacement of peat for press-pots used in seedling production has not yet been found, and only mixes of peat and substrates exist. Several suitable peat substitutes with different properties are known, that usually are used as a share of a mixed peat-substitute substrate. A constrained mixture design was used to test substrates containing 50% v/v and 25% v/v peat and four peat substitutes (two composts and two wood fibers) for vegetable seedling production. By limiting the maximum quantities of each material to be added, there was no negative effect on the growth of Chinese cabbage (Brassica rapa subsp. pekinensis). This means a reduction in of peat to 25% v/v is possible without a change in substrate quality. The mixture design allowed a quick decision to be made regarding the most suitable peat-reduced mixtures. The surface response approach enabled the experimental results to be easily transferred to horticultural practices, additionally. This flexible and efficient method also allows the predictions to be used to meet specific crop management needs.
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Brassica , Suelo , Suelo/química , Plantones , Verduras , HorticulturaRESUMEN
BACKGROUND: Veno-arterial carbon dioxide tension difference (ΔPCO2) and mixed venous oxygen saturation (SvO2) have been shown to be markers of the adequacy between cardiac output and metabolic needs in critical care patients. However, they have hardly been assessed in trauma patients. We hypothesized that femoral ΔPCO2 (ΔPCO2 fem) and SvO2 (SvO2 fem) could predict the need for red blood cell (RBC) transfusion following severe trauma. METHODS: We conducted a prospective and observational study in a French level I trauma center. Patients admitted to the trauma room following severe trauma with an Injury Severity Score (ISS) > 15, who had arterial and venous femoral catheters inserted were included. ΔPCO2 fem, SvO2 fem and arterial blood lactate were measured over the first 24 h of admission. Their abilities to predict the transfusion of at least one pack of RBC (pRBCH6) or hemostatic procedure during the first six hours of admission were assessed using receiver operating characteristics curve. RESULTS: 59 trauma patients were included in the study. Median ISS was 26 (22-32). 28 patients (47%) received at least one pRBCH6 and 21 patients (35,6%) had a hemostatic procedure performed during the first six hours of admission. At admission, ΔPCO2 fem was 9.1 ± 6.0 mmHg, SvO2 fem 61.5 ± 21.6% and blood lactate was 2.7 ± 1.9 mmol/l. ΔPCO2 fem was significantly higher (11.6 ± 7.1 mmHg vs. 6.8 ± 3.7 mmHg, P = 0.003) and SvO2 fem was significantly lower (50 ± 23 mmHg vs. 71.8 ± 14.1 mmHg, P < 0.001) in patients who were transfused than in those who were not transfused. Best thresholds to predict pRBCH6 were 8.1 mmHg for ΔPCO2 fem and 63% for SvO2 fem. Best thresholds to predict the need for a hemostatic procedure were 5.9 mmHg for ΔPCO2 fem and 63% for SvO2 fem. Blood lactate was not predictive of pRBCH6 or the need for a hemostatic procedure. CONCLUSION: In severe trauma patients, ΔPCO2 fem and SvO2 fem at admission were predictive for the need of RBC transfusion and hemostatic procedures during the first six hours of management while admission lactate was not. ΔPCO2 fem and SvO2 fem appear thus to be more sensitive to blood loss than blood lactate in trauma patients, which might be of importance to early assess the adequation of tissue blood flow with metabolic needs.
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Arteria Femoral , Vena Femoral , Hemorragia , Heridas y Lesiones , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de los Gases de la Sangre , Dióxido de Carbono/sangre , Arteria Femoral/química , Vena Femoral/química , Hemorragia/sangre , Hemorragia/diagnóstico , Hemorragia/etiología , Hemorragia/terapia , Hemostáticos , Puntaje de Gravedad del Traumatismo , Ácido Láctico/sangre , Oxígeno/sangre , Estudios Prospectivos , Heridas y Lesiones/complicaciones , Valor Predictivo de las PruebasRESUMEN
BACKGROUND: Although gaming is a common arena where children socialize, an increasing number of children are exhibiting signs of problem gaming or internet gaming disorder. An important factor to the development of problem gaming is parent-child relationships. A cognitive behavioral therapy-based form of treatment, labeled relapse prevention, has been developed as a treatment for child and adolescent problem gaming or internet gaming disorder. However, no study has evaluated the effect of this treatment among Swedish children and youth nor the role of the parent-child relationships in this treatment. OBJECTIVE: This study aims (1) to evaluate a relapse prevention treatment for patients showing signs of problem gaming or internet gaming disorder recruited from child and youth psychiatric clinics and (2) to test whether the quality of parent-child relationships plays a role in the effect of relapse prevention treatment and vice versa-whether the relapse prevention treatment has a spillover effect on the quality of parent-child relationships. Moreover, we explore the carer's attitudes about parent-child relationships and child gaming, as well as experiences of the treatment among the children, their carers, and the clinicians who carried out the treatment. METHODS: This study is a 2-arm, parallel-group, early-stage randomized controlled trial with embedded qualitative components. Children aged 12-18 years who meet the criteria for problem gaming or internet gaming disorder will be randomized in a 1:1 ratio to either intervention (relapse prevention treatment) or control (treatment as usual), with a total of 160 (80 + 80) participants. The primary outcomes are measures of gaming and gambling behavior before and after intervention, and the secondary outcomes include child ratings of parent-child communication and family functioning. The study is supplemented with a qualitative component with semistructured interviews to capture participants' and clinicians' experiences of the relapse prevention, as well as attitudes about parent-child relationships and parenting needs in carers whose children completed the treatment. RESULTS: The trial started in January 2022 and is expected to end in December 2023. The first results are expected in March 2023. CONCLUSIONS: This study will be the first randomized controlled trial evaluating relapse prevention as a treatment for child and adolescent problem gaming and internet gaming disorder in Sweden. Since problem behaviors in children interact with the family context, investigating parent-child relationships adjacent to the treatment of child problem gaming and internet gaming disorder is an important strength of the study. Further, different parties, ie, children, carers, and clinicians, will be directly or indirectly involved in the evaluation of the treatment, providing more knowledge of the treatment and its effect. Limitations include comorbidity in children with problem gaming and internet gaming disorder and challenges with the recruitment of participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT05506384 (retrospectively registered); https://clinicaltrials.gov/ct2/show/NCT05506384. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/44318.
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BACKGROUND: During the SARS-CoV-2 pandemic, the French Government imposed various containment strategies, such as severe lockdown (SL) or moderate lockdown (ML). The aim of this study was to evaluate the effect of both strategies on severe trauma admissions and ICU capacity in Ile-de-France region (Paris Area). MAIN TEXT: We conducted a multicenter cohort-based observational study from 1stJanuary 2017 to 31th December 2020, including all consecutive trauma patients admitted to the trauma centers of Ile-de-France region participating in the national registry (Traumabase®). Two periods were defined, the "non-pandemic period" (NPP) from 2017 to 2019, and the "pandemic period" (PP) concerning those admitted in 2020. The number of ICU beds released during 2020 pandemic period (overall period, SL and ML) was estimated by multiplying difference in trauma admissions by the median length of stay during the same week of pandemic period (ICU day-beds in 2020). A 15% yearly reduction of trauma patients was observed during the PP, associated with the release of 6422 ICU day-beds in 2020. During SL and ML, the observed decrease in trauma admission was respectively 49 and 39% compared with similar dates of the NPP. The number of beds released was 1531 days-beds in SL and 679 day-beds in ML. Those reductions respectively accounted for 4.5 and 6.0% of the overall ICU admission for COVID-19 in Ile-de-France. CONCLUSION: The lockdown strategies during pandemic resulted in a reduction of severe trauma admissions. In addition to the social distancing effect, lockdown strategies freed up an important number of ICU beds in trauma centers, available for severe COVID-19 patients.
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COVID-19 , Control de Enfermedades Transmisibles , Humanos , Pandemias/prevención & control , SARS-CoV-2 , Flujo de TrabajoRESUMEN
BACKGROUND: Emerging evidence suggests that the reallocation of health care resources during the COVID-19 pandemic negatively impacts health care system. This study describes the epidemiology and the outcome of major trauma patients admitted to centers in France during the first wave of the COVID-19 outbreak. METHODS: This retrospective observational study included all consecutive trauma patients aged 15 years and older admitted into 15 centers contributing to the TraumaBase® registry during the first wave of the SARS-CoV-2 pandemic in France. This COVID-19 trauma cohort was compared to historical cohorts (2017-2019). RESULTS: Over a 4 years-study period, 5762 patients were admitted between the first week of February and mid-June. This cohort was split between patients admitted during the first 2020 pandemic wave in France (pandemic period, 1314 patients) and those admitted during the corresponding period in the three previous years (2017-2019, 4448 patients). Trauma patient demographics changed substantially during the pandemic especially during the lockdown period, with an observed reduction in both the absolute numbers and proportion exposed to road traffic accidents and subsequently admitted to traumacenters (348 annually 2017-2019 [55.4% of trauma admissions] vs 143 [36.8%] in 2020 p < 0.005). The in-hospital observed mortality and predicted mortality during the pandemic period were not different compared to the non-pandemic years. CONCLUSIONS: During this first wave of COVID-19 in France, and more specifically during lockdown there was a significant reduction of patients admitted to designated trauma centers. Despite the reallocation and reorganization of medical resources this reduction prevented the saturation of the trauma rescue chain and has allowed maintaining a high quality of care for trauma patients.
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COVID-19/epidemiología , Control de Enfermedades Transmisibles/organización & administración , Atención a la Salud/métodos , Manejo de la Enfermedad , Pandemias/prevención & control , Sistema de Registros , Centros Traumatológicos/estadística & datos numéricos , Adulto , COVID-19/terapia , Femenino , Francia/epidemiología , Hospitalización/tendencias , Humanos , Masculino , Estudios Retrospectivos , SARS-CoV-2RESUMEN
Reliable and comprehensive monitoring data are required to trace and counteract biodiversity loss. High-throughput metabarcoding using DNA extracted from community samples (bulk) or from water or sediment (environmental DNA) has revolutionized biomonitoring, given the capability to assess biodiversity across the tree of life rapidly with feasible effort and at a modest price. DNA metabarcoding can be upscaled to process hundreds of samples in parallel. However, while automated high-throughput analysis workflows are well-established in the medical sector, manual sample processing still predominates in biomonitoring laboratory workflows limiting the upscaling and standardization for routine monitoring applications. Here we present an automated, scalable, and reproducible metabarcoding workflow to extract DNA from bulk samples, perform PCR and library preparation on a liquid handler. Key features are the independent sample replication throughout the workflow and the use of many negative controls for quality assurance and quality control. We generated two datasets: i) a validation dataset consisting of 42 individual arthropod specimens of different species, and ii) a routine monitoring dataset consisting of 60 stream macroinvertebrate bulk samples. As a marker, we used the mitochondrial COI gene. Our results show that the developed single-deck workflow is free of laboratory-derived contamination and produces highly consistent results. Minor deviations between replicates are mostly due to stochastic differences for low abundant OTUs. Thus, we successfully demonstrated that robotic liquid handling can be used reliably from DNA extraction to final library preparation on a single deck, thereby substantially increasing throughput, reducing costs, and increasing data robustness for biodiversity assessments and monitoring.
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Worldwide, multiple stressors affect stream ecosystems and frequently lead to complex and non-linear biological responses. These combined stressor effects on ecologically diverse and functionally important macroinvertebrate communities are often difficult to assess, in particular species-specific responses across many species and effects of different stressors and stressor levels in concert. A central limitation in many studies is the taxonomic resolution applied for specimen identification. DNA metabarcoding can resolve taxonomy and provide greater insights into multiple stressor effects. This was detailed by results of a recent multiple stressor mesocosm experiment, where only for the dipteran family Chironomidae 183 Operational Taxonomic Units (OTUs) could be distinguished. Numerous OTUs showed very different response patterns to multiple stressors. In this study, we applied DNA metabarcoding to assess multiple stressor effects on all non-chironomid invertebrates from the same experiment. In the experiment, we applied three stressors (increased salinity, deposited fine sediment, reduced flow velocity) in a full-factorial design. We compared stressor responses inferred through DNA metabarcoding of the mitochondrial COI gene to responses based on morphotaxonomic taxa lists. We identified 435 OTUs, of which 122 OTUs were assigned to EPT (Ephemeroptera, Plecoptera, Trichoptera) taxa. The most common 35 OTUs alone showed 15 different response patterns to the experimental manipulation, ranging from insensitivity to any applied stressor to sensitivity to single and multiple stressors. These response patterns even comprised differences within one family. The species-specific taxonomic resolution and the inferred response patterns to stressors highlights the potential of DNA metabarcoding in the context of multiple stressor research, even for well-known taxa such as EPT species.
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Ríos , Salinidad , Animales , Código de Barras del ADN Taxonómico , Ecosistema , Monitoreo del Ambiente , Invertebrados/genéticaRESUMEN
Type 2 heparin-induced thrombocytopenia (HIT 2) is a rare pro-thrombotic disorder occurring in patients treated with heparin. It is defined as a clinical-biological syndrome associating the sudden onset of a thrombocytopenia, characterized by a drop of more than 50% of the initial platelet count, and thrombosis. We report two cases of HIT 2 occurring in patients with major bleeding tendency. The first HIT occurred in a patient whose management, in accordance with current guidelines, made it possible to control the thrombocytopenia and the anticoagulation despite the complexity of adapting and monitoring treatments in the context of recent cerebral hemorrhage. The second refers to an autoimmune HIT, which occurred in a patient whose management required the use of alternative therapies to the standard treatments suggested for HIT 2, to correct the severe refractory thrombocytopenia.
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Trastornos de la Coagulación Sanguínea/terapia , Hemorragia/prevención & control , Heparina/efectos adversos , Trombocitopenia/inducido químicamente , Trombocitopenia/terapia , 4-Hidroxicumarinas/administración & dosificación , Anciano , Anticoagulantes/efectos adversos , Arginina/administración & dosificación , Arginina/análogos & derivados , Trastornos de la Coagulación Sanguínea/complicaciones , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Hemorragia/etiología , Humanos , Indenos/administración & dosificación , Trombosis Intracraneal/tratamiento farmacológico , Trombosis Intracraneal/etiología , Trombosis Intracraneal/cirugía , Masculino , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos/métodos , Ácidos Pipecólicos/administración & dosificación , Sulfonamidas/administración & dosificación , Vitamina K/administración & dosificación , Vitamina K/antagonistas & inhibidoresRESUMEN
The mitochondrial electron transport chain (ETC) is necessary for tumour growth1-6 and its inhibition has demonstrated anti-tumour efficacy in combination with targeted therapies7-9. Furthermore, human brain and lung tumours display robust glucose oxidation by mitochondria10,11. However, it is unclear why a functional ETC is necessary for tumour growth in vivo. ETC function is coupled to the generation of ATP-that is, oxidative phosphorylation and the production of metabolites by the tricarboxylic acid (TCA) cycle. Mitochondrial complexes I and II donate electrons to ubiquinone, resulting in the generation of ubiquinol and the regeneration of the NAD+ and FAD cofactors, and complex III oxidizes ubiquinol back to ubiquinone, which also serves as an electron acceptor for dihydroorotate dehydrogenase (DHODH)-an enzyme necessary for de novo pyrimidine synthesis. Here we show impaired tumour growth in cancer cells that lack mitochondrial complex III. This phenotype was rescued by ectopic expression of Ciona intestinalis alternative oxidase (AOX)12, which also oxidizes ubiquinol to ubiquinone. Loss of mitochondrial complex I, II or DHODH diminished the tumour growth of AOX-expressing cancer cells deficient in mitochondrial complex III, which highlights the necessity of ubiquinone as an electron acceptor for tumour growth. Cancer cells that lack mitochondrial complex III but can regenerate NAD+ by expression of the NADH oxidase from Lactobacillus brevis (LbNOX)13 targeted to the mitochondria or cytosol were still unable to grow tumours. This suggests that regeneration of NAD+ is not sufficient to drive tumour growth in vivo. Collectively, our findings indicate that tumour growth requires the ETC to oxidize ubiquinol, which is essential to drive the oxidative TCA cycle and DHODH activity.
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Mitocondrias/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Ubiquinona/análogos & derivados , Animales , Línea Celular Tumoral , Proliferación Celular , Ciona intestinalis/enzimología , Ciclo del Ácido Cítrico , Citosol/metabolismo , Dihidroorotato Deshidrogenasa , Transporte de Electrón , Complejo I de Transporte de Electrón/metabolismo , Complejo II de Transporte de Electrones/metabolismo , Complejo III de Transporte de Electrones/deficiencia , Complejo III de Transporte de Electrones/metabolismo , Humanos , Levilactobacillus brevis/enzimología , Masculino , Ratones , Mitocondrias/enzimología , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Complejos Multienzimáticos/genética , Complejos Multienzimáticos/metabolismo , NAD/metabolismo , NADH NADPH Oxidorreductasas/genética , NADH NADPH Oxidorreductasas/metabolismo , Neoplasias/enzimología , Fosforilación Oxidativa , Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ubiquinona/metabolismoRESUMEN
Recent evidence in humans and mice supports the notion that mitochondrial metabolism is active and necessary for tumor growth. Mitochondrial metabolism supports tumor anabolism by providing key metabolites for macromolecule synthesis and generating oncometabolites to maintain the cancer phenotype. Moreover, there are multiple clinical trials testing the efficacy of inhibiting mitochondrial metabolism as a new cancer therapeutic treatment. In this review, we discuss the rationale of using these anti-cancer agents in clinical trials and highlight how to effectively utilize them in different tumor contexts.
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Antineoplásicos/farmacología , Mitocondrias/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/química , Humanos , Mitocondrias/metabolismo , Neoplasias/metabolismoRESUMEN
PURPOSE: To evaluate if sperm DNA fragmentation (SDF) in the sample used for intracytoplasmic sperm injection (ICSI) impacts outcomes after euploid blastocyst transfer. METHODS: Prospective cohort study of couples undergoing IVF with preimplantation genetic testing for aneuploidy from December 2014-June 2017. Sperm collected on the day of ICSI was analyzed for SDF using the sperm chromatin structure assay (SCSA®). Semen analysis parameters, embryologic outcomes, and clinical outcomes after euploid blastocyst transfer were compared between groups with DNA fragmentation index (DFI) ≤ 15% and DFI > 15% using Mann-Whitney U, t tests, and generalized linear mixed effects models. RESULTS: Two hundred thirty-four patients were included. One hundred seventy-nine men had DFI ≤ 15% (low DFI group) and 55 men had DFI > 15% group (high DFI group). Total motile sperm and sperm concentration were significantly lower in the group with DFI > 15% vs. DFI ≤ 15%. There was no difference in fertilization (86.3 vs. 84.2%, adjusted OR (95% CI) 0.86 (0.63-1.18)), blastulation (49.5 vs. 48.8%, adjusted OR 1.02 (0.75-1.36)), or euploidy (55.7 vs. 52.1%, adjusted OR 0.96 (0.7-1.31)) between the low and high DFI groups, respectively. Clinical outcomes were similar between low and high DFI groups, including implantation rate (68.8 vs. 79.8%), ongoing pregnancy rate (65.9 vs. 72.6%), and miscarriage rate (4.2 vs. 8.8%), respectively. CONCLUSION: Sperm DNA fragmentation on the day of ICSI is not associated with embryologic or clinical outcomes after euploid blastocyst transfer. Increasing levels of SDF are associated with low sperm concentration and total motile sperm count.
Asunto(s)
Fragmentación del ADN , ADN/metabolismo , Implantación del Embrión , Embrión de Mamíferos/fisiología , Fertilización In Vitro/métodos , Inyecciones de Esperma Intracitoplasmáticas/métodos , Espermatozoides/fisiología , Adulto , Apoptosis , ADN/química , Embrión de Mamíferos/citología , Femenino , Humanos , Masculino , Embarazo , Índice de Embarazo , Estudios ProspectivosRESUMEN
OBJECTIVE: To determine if natural selection and follicular stimulation produces a lower risk for embryonic aneuploidy than that attained following superovulation with exogenous gonadotropins. DESIGN: Prospective observational with historical control group. SETTING: Large academically affiliated private practice. PATIENT(S): All patients presenting for their evaluation for infertility were offered participation in the study. INTERVENTION(S): All participants in the natural cycle group underwent an unstimulated in vitro fertilization (IVF) cycle. A subsequent frozen embryo transfer was performed if a euploid blastocyst was attained. MAIN OUTCOME MEASURE(S): Rates of embryonic aneuploidy attained in unstimulated IVF cycles were compared to those observed in age-controlled historical cohort undergoing conventional stimulated IVF cycles with exogenous gonadotropins. RESULT(S): Aneuploidy rates were equivalent in unstimulated and stimulated IVF cycles. The prevalence of aneuploidy in natural cycles increased with the age of the female partner in a manner identical to that seen in stimulated IVF cycles. Finally, sustained implantation rates of euploid blastocysts were equivalent in natural and stimulated IVF cycles. CONCLUSION(S): Rates of embryonic aneuploidy are not impacted by follicular stimulation with exogenous gonadotropins. Prior concerns of inducing a higher risk of embryonic aneuploidy are not supported by this data. CLINICAL TRIAL REGISTRATION NUMBER: NCT01866618.