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INTRODUCTION/AIMS: Heterogeneous nuclear ribonucleoprotein A1 is involved in nucleic acid homeostatic functions. The encoding gene HNRNPA1 has been associated with several neuromuscular disorders including an amyotrophic lateral sclerosis-like phenotype, distal hereditary motor neuropathy, multisystem proteinopathy, and various myopathies. We report two unrelated individuals with monoallelic stop loss variants affecting the same codon of HNRNPA1. METHODS: Two individuals with unsolved juvenile-onset myopathy were enrolled under approved institutional protocols. Phenotype data were collected and genetic analyses were performed, including whole-exome sequencing (WES). RESULTS: The two probands (MNOT002-01 and K1440-01) showed a similar onset of slowly progressive extremity and facial weakness in early adolescence. K1440-01 presented with facial weakness, winged scapula, elevated serum creatine kinase (CK) levels, and mild neck weakness. MNOT002-01 also exhibited elevated CK levels along with facial weakness, cardiomyopathy, respiratory dysfunction, pectus excavatum, a mildly rigid spine, and loss of ambulation. On quadriceps muscle biopsy, K1440-01 displayed rounded myofibers, mild variation in fiber diameter, and type 2 fiber hypertrophy, while MNOT002-01 displayed rimmed vacuoles. Monoallelic stop-loss variants in HNRNPA1 were identified for both probands: c.1119A>C p.*373Tyrext*6 (K1440-01) and c.1118A>C p.*373Serext*6 (MNOT002-01) affect the same codon and are both predicted to lead to the addition of six amino acids before termination at an alternative stop codon. DISCUSSION: Both stop-loss variants in our probands are likely pathogenic. Our findings contribute to the disease characterization of pathogenic variants in HNRNPA1. This gene should be screened in clinical diagnostic testing of unsolved cases of sporadic or dominant juvenile-onset myopathy.
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BACKGROUND: Preterm preeclampsia, a product of vascular dysfunction, is associated with prolonged hospital admission and proteinuria, significant risk factors for thromboembolism in pregnancy. The risk of thromboembolism in preterm preeclampsia warrants further investigation. OBJECTIVE: To determine the relationship between preterm preeclampsia and thromboembolic risk. We hypothesize that preterm preeclampsia is an independent risk factor for thromboembolism in pregnancy. STUDY DESIGN: This is a retrospective cohort study using the National Inpatient Sample database via Healthcare Cost and Utilization Project-Agency for Healthcare Cost and Utilization Project from 2017-2019. All subjects with an International Classification of Diseases, Tenth Revision code for pregnancy or peripartum encounter were included. Subjects were excluded if the gestational age at delivery was <20 weeks or if they had a history of thromboembolism, inherited thrombophilia, or antiphospholipid syndrome. Patients with preterm (delivered <37 weeks) preeclampsia and term (delivered ≥37 weeks) preeclampsia were compared with those without preeclampsia. The primary outcome was a composite of any thromboembolic event, including pulmonary embolism, deep vein thrombosis, cerebral thrombosis or transient ischemic attack, or other thromboses. The secondary outcomes were rates of each type of thromboembolic event. The groups were compared via variance analysis, chi-square, and logistic regression analyses. The logistic regression included those variables that differed between groups with P<.05. RESULTS: Of individuals in the database, >2.2 million met the inclusion criteria. A total of 56,446 (2.7%) had preterm preeclampsia, and 86,152 (6.7%) had term preeclampsia. Those with preterm preeclampsia were more likely to be older, identify as non-Hispanic black, have obesity, have chronic hypertension among other chronic diseases, and be in the lowest quartile of income (P<.001). Among patients with preterm preeclampsia, 0.32% experienced thromboembolism, whereas those with term preeclampsia and without preeclampsia experienced thromboembolism at 0.10% and 0.09%, respectively. After controlling for confounders that differed between groups with P<.05, preterm preeclampsia remained independently associated with any thromboembolic event (adjusted odds ratio, 2.21 [95% confidence interval, 1.84-2.65]), and each type of thromboembolism. Term preeclampsia was not associated with an increased risk of thromboembolism (adjusted odds ratio, 1.18 [95% confidence interval, 0.94-1.48]). CONCLUSION: Preterm preeclampsia is independently associated with an increased risk of thromboembolic events.
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Orthotopic transcatheter tricuspid valve replacement (TTVR) devices have been shown to be highly effective in reducing tricuspid regurgitation (TR), and interest in this therapy is growing with the recent commercial approval of the first orthotopic TTVR. Recent TTVR studies report preexisting cardiac implantable electronic device (CIED) transvalvular leads in â¼35% of patients, with entrapment during valve implantation. Concerns have been raised regarding the safety of entrapping leads and counterbalanced against the risks of transvenous lead extraction (TLE) when indicated. This Heart Valve Collaboratory consensus document attempts to define the patient population with CIED lead-associated or lead-induced TR, describe the risks of lead entrapment during TTVR, delineate the risks and benefits of TLE in this setting, and develop a management algorithm for patients considered for TTVR. An electrophysiologist experienced in CIED management should be part of the multidisciplinary heart team and involved in shared decision making.
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Desfibriladores Implantáveis , Marca-Passo Artificial , Insuficiência da Valva Tricúspide , Humanos , Insuficiência da Valva Tricúspide/cirurgia , Desfibriladores Implantáveis/efeitos adversos , Marca-Passo Artificial/efeitos adversos , Implante de Prótese de Valva Cardíaca/métodos , Implante de Prótese de Valva Cardíaca/efeitos adversos , Índice de Gravidade de DoençaRESUMO
Theoretical and empirical scholars of cultural evolution have traditionally studied social learning strategies, such as conformity, as adaptive strategies to obtain accurate information about the environment, whereas within social psychology there has been a greater focus upon the social consequences of such strategies. Although these two approaches are often used in concert when studying human social learning, we believe the potential social benefits of conformity, and of social learning more broadly, have been overlooked in studies of non-humans. We review evidence from studies of homophily, imitation, and rapid facial mimicry that suggests that behaving like others affords social benefits to non-human animals and that behaviour matching may be deployed strategically to increase affiliation. Furthermore, we review studies of conformity in dispersers, and suggest that forgoing personal information or preferences in favour of those of the new group during immigration may be a strategy to facilitate social integration. We therefore propose that the informational and social functions of conformity apply to humans and animals alike. We use this perspective to generate several interesting research questions to inspire work in this field. For example, under what conditions do animals use informational or social conformity and what role does uncertainty play in social learning in immigrant individuals?
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BACKGROUND: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline pathogenic variants in TP53. Individuals with LFS have a 70-100% lifetime risk of developing cancer. The current standard of care involves annual surveillance with whole-body and brain MRI (WB-MRI) and clinical review; however, there are no chemoprevention agents licensed for individuals with LFS. Preclinical studies in LFS murine models show that the anti-diabetic drug metformin is chemopreventive and, in a pilot intervention trial, short-term use of metformin was well-tolerated in adults with LFS. However, metformin's mechanism of anticancer activity in this context is unclear. METHODS: Metformin in adults with Li-Fraumeni syndrome (MILI) is a Precision-Prevention phase II open-labelled unblinded randomised clinical trial in which 224 adults aged ≥ 16 years with LFS are randomised 1:1 to oral metformin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years. The primary endpoint is to compare cumulative cancer-free survival up to 5 years (60 months) from randomisation between the intervention (metformin) and control (no metformin) arms. Secondary endpoints include a comparison of cumulative tumour-free survival at 5 years, overall survival at 5 years and clinical characteristics of emerging cancers between trial arms. Safety, toxicity and acceptability of metformin; impact of metformin on quality of life; and impact of baseline lifestyle risk factors on cancer incidence will be assessed. Exploratory end-points will evaluate the mechanism of action of metformin as a cancer preventative, identify biomarkers of response or carcinogenesis and assess WB-MRI performance as a diagnostic tool for detecting cancers in participants with LFS by assessing yield and diagnostic accuracy of WB-MRI. DISCUSSION: Alongside a parallel MILI study being conducted by collaborators at the National Cancer Institute (NCI), MILI is the first prevention trial to be conducted in this high-risk group. The MILI study provides a unique opportunity to evaluate the efficacy of metformin as a chemopreventive alongside exploring its mechanism of anticancer action and the biological process of mutated P53-driven tumourigenesis. TRIAL REGISTRATION: ISRCTN16699730. Registered on 28 November 2022. URL: https://www.isrctn.com/ EudraCT/CTIS number 2022-000165-41.
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Síndrome de Li-Fraumeni , Metformina , Adulto , Humanos , Camundongos , Animais , Síndrome de Li-Fraumeni/diagnóstico por imagem , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/prevenção & controle , Metformina/efeitos adversos , Qualidade de Vida , Mutação em Linhagem Germinativa , Imageamento por Ressonância Magnética , Predisposição Genética para Doença , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase II como AssuntoRESUMO
BACKGROUND: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3 ) receptor type 1 (IP3 R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. OBJECTIVES: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. METHODS: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. RESULTS: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3 -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. CONCLUSIONS: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Aniridia , Anidrases Carbônicas , Ataxia Cerebelar , Deficiência Intelectual , Transtornos dos Movimentos , Degenerações Espinocerebelares , Humanos , Ataxia Cerebelar/genética , Mutação de Sentido Incorreto/genética , Transtornos dos Movimentos/complicações , Atrofia , Receptores de Inositol 1,4,5-Trifosfato/química , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Anidrases Carbônicas/genética , Anidrases Carbônicas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genéticaRESUMO
The incidence of placenta accreta spectrum, the deeply adherent placenta with associated increased risk of maternal morbidity and mortality, has seen a significant rise in recent years. Therefore, there has been a rise in clinical and research focus on this complex diagnosis. There is international consensus that a multidisciplinary coordinated approach optimizes outcomes. The composition of the team will vary from center to center; however, central themes of complex surgical experts, specialists in prenatal diagnosis, critical care specialists, neonatology specialists, obstetrics anesthesiology specialists, blood bank specialists, and dedicated mental health experts are universal throughout. Regionalization of care is a growing trend for complex medical needs, but the location of care alone is just a starting point. The goal of this article is to provide an evidence-based framework for the crucial infrastructure needed to address the unique antepartum, delivery, and postpartum needs of the patient with placenta accreta spectrum. Rather than a clinical checklist, we describe the personnel, clinical unit characteristics, and breadth of contributing clinical roles that make up a team. Screening protocols, diagnostic imaging, surgical and potential need for critical care, and trauma-informed interaction are the basis for comprehensive care. The vision from the author group is that this publication provides a semblance of infrastructure standardization as a means to ensure proper preparation and readiness.
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Obstetrícia , Placenta Acreta , Hemorragia Pós-Parto , Gravidez , Feminino , Humanos , Placenta Acreta/diagnóstico , Placenta Acreta/epidemiologia , Placenta Acreta/terapia , Cesárea/métodosRESUMO
BACKGROUND: Obesity and prescription opioid misuse are important public health concerns in the United States. A common intersection occurs when women with obesity undergo cesarean birth and receive narcotic medications for postpartum pain. OBJECTIVE: To examine the association between obesity and inpatient opioid use after cesarean birth. METHODS: A retrospective cohort study of patients that underwent cesarean birth in 2015-2018. Primary outcome was post-cesarean delivery opioid consumption starting 24 h after delivery measured as morphine milliequivalents per hour (MME/h). Secondary outcome was MME/h consumption in the highest quartile of all subjects. Opioid consumption was compared between three BMI groups: non-obese BMI 18.5-29.9 kg/m2; obese BMI 30.0-39.9 kg/m2; and morbidly obese BMI ≥ 40.0 kg/m2 using univariable and multivariable analyses. RESULTS: Of 1620 patients meeting inclusion criteria, 496 (30.6%) were in the non-obese group, 753 (46.5%) were in the obese group, and 371 (22.9%) were in the morbidly obese group. In the univariate analysis, patients with obesity and morbid obesity required higher MME/h than patients in the non-obese group [1.3 MME/h (IQR 0.1, 2.4) vs. 1.6 MME/h (IQR 0.5, 2.8) vs. 1.8 MME/h (IQR 0.8, 2.9), for non-obese, obese, and morbidly obese groups respectively, p < 0.001]. In the multivariable analysis, this association did not persist. In contrast, subjects in the obese and morbidly obese groups were more likely to be in the highest quartile of MME/h opioid consumption compared with those in the non-obese group (23.5% vs. 48.1% vs. 28.4%, p < 0.001, respectively); with aOR 1.42 (95% CI 1.07-1.89, p = 0.016) and aOR 1.60 (95% CI 1.16-2.22, p = 0.005) for patients with obesity and morbid obesity, respectively. CONCLUSION: Maternal obesity was not associated with higher hourly MME consumption during inpatient stay after cesarean birth. However, patients with obesity and morbid obesity were significantly more likely to be in the top quartile of MME hourly consumption.
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Analgésicos Opioides , Endrin/análogos & derivados , Obesidade Mórbida , Gravidez , Humanos , Feminino , Estados Unidos/epidemiologia , Analgésicos Opioides/uso terapêutico , Estudos Retrospectivos , Obesidade Mórbida/complicações , Obesidade Mórbida/epidemiologia , Pacientes InternadosRESUMO
OBJECTIVE: Cesarean hysterectomy is generally presumed to decrease maternal morbidity and mortality secondary to placenta accreta spectrum disorder. Recently, uterine-sparing techniques have been introduced in conservative management of placenta accreta spectrum disorder to preserve fertility and potentially reduce surgical complications. However, despite patients often expressing the intention for future conception, few data are available regarding the subsequent pregnancy outcomes after conservative management of placenta accreta spectrum disorder. Thus, we aimed to perform a systematic review and meta-analysis to assess these outcomes. DATA SOURCES: PubMed, Scopus, and Web of Science databases were searched from inception to September 2022. STUDY ELIGIBILITY CRITERIA: We included all studies, with the exception of case studies, that reported the first subsequent pregnancy outcomes in individuals with a history of placenta accreta spectrum disorder who underwent any type of conservative management. METHODS: The R programming language with the "meta" package was used. The random-effects model and inverse variance method were used to pool the proportion of pregnancy outcomes. RESULTS: We identified 5 studies involving 1458 participants that were eligible for quantitative synthesis. The type of conservative management included placenta left in situ (n=1) and resection surgery (n=1), and was not reported in 3 studies. The rate of placenta accreta spectrum disorder recurrence in the subsequent pregnancy was 11.8% (95% confidence interval, 1.1-60.3; I2=86.4%), and 1.9% (95% confidence interval, 0.0-34.1; I2=82.4%) of participants underwent cesarean hysterectomy. Postpartum hemorrhage occurred in 10.3% (95% confidence interval, 0.3-81.4; I2=96.7%). A composite adverse maternal outcome was reported in 22.7% of participants (95% confidence interval, 0.0-99.4; I2=56.3%). CONCLUSION: Favorable pregnancy outcome is possible following successful conservation of the uterus in a placenta accreta spectrum disorder pregnancy. Approximately 1 out of 4 subsequent pregnancies following conservative management of placenta accreta spectrum disorder had considerable adverse maternal outcomes. Given such high incidence of adverse outcomes and morbidity, patient and provider preparation is vital when managing this population.
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Polarized (sub)millimetre emission from dust grains in circumstellar disks was initially thought to be because of grains aligned with the magnetic field1,2. However, higher-resolution multi-wavelength observations3-5 and improved models6-10 found that this polarization is dominated by self-scattering at shorter wavelengths (for example, 870 µm) and by grains aligned with something other than magnetic fields at longer wavelengths (for example, 3 mm). Nevertheless, the polarization signal is expected to depend on the underlying substructure11-13, and observations until now have been unable to resolve polarization in multiple rings and gaps. HL Tau, a protoplanetary disk located 147.3 ± 0.5 pc away14, is the brightest class I or class II disk at millimetre-submillimetre wavelengths. Here we show deep, high-resolution polarization observations of HL Tau at 870 µm, resolving polarization in both the rings and the gaps. We find that the gaps have polarization angles with a notable azimuthal component and a higher polarization fraction than the rings. Our models show that the disk polarization is due to both scattering and emission from the aligned effectively prolate grains. The intrinsic polarization of aligned dust grains is probably more than 10%, which is much higher than that expected in low-resolution observations (about 1%). Asymmetries and dust features that are not seen in non-polarimetric observations are seen in the polarization observations.
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Remedial investigations of sites contaminated with legacy pollutants like polychlorinated biphenyls (PCBs) have traditionally focused on mapping sediment contamination to develop a site conceptual model and select remedy options. Ignoring dissolved concentrations that drive transport and bioaccumulation often leads to an incomplete assessment of ongoing inputs to the water column and overestimation of potential effectiveness of sediment remediation. Here, we demonstrate the utility of codeployment of passive equilibrium samplers and freshwater mussels as dual lines of evidence to identify ongoing sources of PCBs from eight main tributaries of the Anacostia River in Washington, DC, that has been historically polluted from industrial and other human activities. The freely dissolved PCB concentrations measured using passive samplers tracked well with the accumulation in mussels and allowed predictions of biouptake within a factor of 2 for total PCBs and a factor of 4 for most congeners. One tributary was identified as the primary source of PCBs to the water column and became a focus of additional ongoing investigations. Codeployment of passive samplers and mussels provides strong lines of evidence to refine site conceptual models and identify ongoing sources critical to control to achieve river water quality standards and reduce bioaccumulation in the aquatic food web.
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Touchscreen technology has provided researchers with opportunities to conduct well-controlled cognitive tests with captive animals, allowing researchers to isolate individuals, select participants based on specific traits, and control aspects of the environment. In this study, we aimed to investigate the potential utility of touchscreen technology for the study of cognition in wild vervet monkeys. We assessed the viability of touchscreen testing by comparing rates of participation between wild and sanctuary-housed vervets. Additionally, we compared performance on a simple associative learning task in order to verify that wild participants are able to engage meaningfully with a touchscreen task presented in their natural environment. We presented eight groups of vervet monkeys (four wild and four sanctuary groups, totalling 240 individuals) with a portable touchscreen device. The touchscreen displayed tasks in which food rewards could be gained by touching a stimulus displayed on the screen. We assessed individuals' likelihood of interacting with the touchscreen, their frequency of participation, and their performance on a simple associative learning task. We found that sanctuary-housed monkeys were more likely to interact with the touchscreen. Participation in wild vervet monkeys was influenced by sex and age. However, monkeys in the two contexts (sanctuary vs. wild) did not differ in their performance on a simple associative learning task. This study demonstrates that touchscreen technology can be successfully deployed in a population of wild primates. This gives us a starting point to test animal cognition under natural conditions that include varying group composition, environmental challenges and ongoing activities such as foraging, which are challenging to recreate in captivity. While rates of participation were lower than those found in captivity, reasonable sample sizes can be achieved, and wild primates can successfully learn touchscreen tasks in a manner comparable to their captive counterparts.
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Cognição , Primatas , Animais , Chlorocebus aethiops , Fenótipo , HaplorrinosRESUMO
The association between vascular Ehlers-Danlos Syndrome (vEDS) and amniotic band sequence (ABS) has been previously reported in the literature, mostly in single patient case reports. Here, we aim to extend the current knowledge of this association through a case series of five unrelated individuals with ABS in association with molecularly confirmed vEDS, in addition to undertaking a comprehensive literature review. All the individuals were recruited through the EDS national diagnostic service in the UK following appropriate history, physical examination and genetic investigations. Clinical presentation ranged from a single constriction ring to complex craniofacial clefts to limb reduction deformities, reflecting the spectrum of ABS presentation. vEDS was inherited paternally (n = 2), maternally (n = 2) and de novo (n = 1). Previously, maternal vEDS was considered the risk factor for ABS, but our findings suggest that it may be the disease status of the fetus which poses the main risk. It is established that amniotic membrane is derived from fetal tissue, which supports our conclusions. Our observations suggest the increased risk of ABS in fetuses with vEDS. Therefore, exploring family history and features that may suggest vEDS diagnosis in patients with ABS might be useful. We also recommend that a collaborative international study would be useful to help gain a better insight into this association.
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Síndrome de Ehlers-Danlos , Síndrome de Bandas Amnióticas , Colágeno Tipo III/genética , Serviços de Diagnóstico , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Humanos , Reino UnidoRESUMO
Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, UBA2, and USP9X. The role of these genes in diaphragm development was supported by their expression in the developing mouse diaphragm, their similarity to known CDH genes using data from a previously published and validated machine learning algorithm, and/or the presence of CDH in other individuals with their associated genetic disorders. Our results demonstrate how data from DECIPHER, and other public databases, can be used to identify new phenotypic expansions and suggest that CREBBP, SMARCA4, UBA2, and USP9X play a role in diaphragm development.
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Hérnias Diafragmáticas Congênitas , Animais , Variações do Número de Cópias de DNA , Diafragma , Hérnias Diafragmáticas Congênitas/genética , CamundongosRESUMO
Children with osteogenesis imperfecta (OI) are commonly treated with bisphosphonates. We investigated the skeletal response to mechanical stimulation in children with OI before and after bisphosphonate treatment. Twelve children with OI, naïve to bisphosphonate treatment, stood on a high-frequency (30 Hz), low-amplitude (50 to 200 µ) vibrating platform (Marodyne LivMD) for 10 minutes daily (2.5 minutes × 4 with interspersed 1-minute rest periods) for 7 days (whole body vibration [WBV] 1; day (D) 1-7), followed successively by 5 weeks' monitoring without intervention, 6 weeks' risedronate treatment, 1 week of WBV (WBV2; D85-91), and 1 week without intervention (D92-98). Procollagen type I N-terminal propeptide (P1NP), bone-specific alkaline phosphatase (BSALP), and carboxy-terminal telopeptide of type I collagen cross-link (CTX) were measured at baseline and intervals bracketing periods of vibration and risedronate treatment. Both P1NP and CTX rose to D8 (18.4%, 13.8%, p < 0.05, respectively), plateaued, then rose again at D43 (19.8%, 19.2%, respectively, p < 0.05 versus baseline). At D85 (after risedronate) both P1NP and CTX had fallen to pre-WBV1 levels. A significantly smaller increase in P1NP was found after WBV2 (D85-91) at D92 (3.5%, 9.2%, respectively) and D99 versus after WBV1 (both p < 0.05). BSALP changed little after WBV1, fell during risedronate, and rose toward baseline after WBV2. We thus showed that WBV increased bone formation and resorption; that increase was attenuated after risedronate. The early increase in P1NP and CTX (D8) after WBV1 suggests increased osteoid formation within existing remodeling units but not increased mineralization. Later increases in P1NP/CTX (D42) suggest increased remodeling cycle initiation after WBV. Risedronate suppressed both biomarkers. The lower increase in P1NP/CTX after WBV2 suggests limited capacity to increase osteoid formation from existing "early stage" osteoblasts and a possible "hangover" effect of risedronate on remodeling activation. These results provide insights into both the response to WBV, ie, mechanical stimulation, and the effect of antiresorptive therapy in children with OI. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
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OBJECTIVE: To examine the prevalence of antenatal maternal hypoglycemia after initiation of pharmacotherapy for gestational diabetes mellitus (GDMA2) and its association with pregnancy outcomes. STUDY DESIGN: Retrospective cohort of GDMA2 women receiving either insulin or oral hypoglycemic agents. Composite neonatal outcome included macrosomia, jaundice, respiratory distress syndrome, large for gestational age, shoulder dystocia, birth trauma, 5-minute Apgar < 7, and neonatal hypoglycemia, and was compared between women with and without hypoglycemia using bivariate and multivariate analyses. RESULTS: Of 489 women included in the study, 95 (19.4%) had at least one episode of hypoglycemia, most often in the setting of glyburide. Newborns exposed to maternal hypoglycemia had higher rates of the composite neonatal outcome (54.7% vs. 38.3%, p = 0.004). After controlling for confounding factors, maternal hypoglycemia remained independently associated with the composite neonatal outcome (aOR = 1.69, 95% CI 1.04-2.72). CONCLUSION: Maternal hypoglycemia in GDMA2 was associated with higher rates of adverse neonatal outcomes.
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Diabetes Gestacional , Hipoglicemia , Doenças do Recém-Nascido , Diabetes Gestacional/tratamento farmacológico , Diabetes Gestacional/epidemiologia , Feminino , Macrossomia Fetal/epidemiologia , Glibureto/efeitos adversos , Humanos , Hipoglicemia/tratamento farmacológico , Hipoglicemia/epidemiologia , Hipoglicemiantes/efeitos adversos , Recém-Nascido , Doenças do Recém-Nascido/epidemiologia , Doenças do Recém-Nascido/etiologia , Gravidez , Resultado da Gravidez/epidemiologia , Estudos Retrospectivos , Aumento de PesoRESUMO
BACKGROUND: Von Hippel-Lindau (VHL) disease is an inherited tumour predisposition syndrome and a paradigm for the importance of early diagnosis and surveillance. However, there is limited information on the "real world" management of VHL disease. METHODS: A national audit of VHL disease in the United Kingdom. RESULTS: VHL disease was managed mostly via specialist clinics coordinated through regional clinical genetics services (but frequently involving additional specialties). Over the study period, 19 genetic centres saw 842 individuals (393 males, 449 females) with a clinical and/or molecular diagnosis of VHL disease and 74 individuals (35 male, 39 female) with a prior risk of 50% (affected parent). All centres offered retinal, central nervous system and abdominal surveillance to affected individuals and at-risk relatives though surveillance details differed between centres (but complied with international recommendations). Renal lesions detected on the first surveillance scan were, on average, larger than those detected during subsequent scans and the larger the diameter at detection the greater the likelihood of early intervention. CONCLUSIONS: In a state-funded health care system individuals with a rare inherited cancer predisposition syndrome are generally able to access appropriate surveillance and patient management is improved compared to historical data. The "real world" data from this study will inform the future development of VHL management protocols.
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Neoplasias , Doença de von Hippel-Lindau , Feminino , Genótipo , Humanos , Masculino , Medicina Estatal , Reino Unido/epidemiologia , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/genéticaRESUMO
Social learning in non-human primates has been studied experimentally for over 120 years, yet until the present century this was limited to what one individual learns from a single other. Evidence of group-wide traditions in the wild then highlighted the collective context for social learning, and broader 'diffusion experiments' have since demonstrated transmission at the community level. In the present article, we describe and set in comparative perspective three strands of our recent research that further explore the collective dimensions of culture and cumulative culture in chimpanzees. First, exposing small communities of chimpanzees to contexts incorporating increasingly challenging, but more rewarding tool use opportunities revealed solutions arising through the combination of different individuals' discoveries, spreading to become shared innovations. The second series of experiments yielded evidence of conformist changes from habitual techniques to alternatives displayed by a unanimous majority of others but implicating a form of quorum decision-making. Third, we found that between-group differences in social tolerance were associated with differential success in developing more complex tool use to exploit an increasingly inaccessible resource. We discuss the implications of this array of findings in the wider context of related studies of humans, other primates and non-primate species. This article is part of a discussion meeting issue 'The emergence of collective knowledge and cumulative culture in animals, humans and machines'.
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Hominidae , Aprendizado Social , Animais , Cultura , Aprendizagem , Pan troglodytes , Primatas , Comportamento SocialRESUMO
OBJECTIVE: To compare the glycemic threshold for pharmacotherapy initiation in women with gestational diabetes (GDM) based on maternal race/ethnicity. METHODS: A retrospective cohort study of women with GDM who received pharmacotherapy during pregnancy, in addition to diet and exercise, between 2015 and 2019 in a university center. The primary outcome was percent of elevated capillary blood glucoses (CBGs) prior to pharmacotherapy initiation. This was compared between four maternal racial and ethnic groups: non-Hispanic white (NHW), non-Hispanic black (NHB), Hispanic and other race and ethnicity group that included Asian, American Indian and Alaskan Native. Univariable and multivariable analyses were done to estimate whether there was an independent association between maternal race and ethnicity and the percent of elevated CBGs prior to pharmacotherapy initiation. RESULTS: A total of 440 women met inclusion criteria. In univariable analysis, NHB women, Hispanic, and women of other race and ethnicity had higher percent of elevated CBGs prior to pharmacotherapy initiation, compared to NHW women (45.5 ± 22.5% for NHW, 65.2 ± 25.4% for NHB, 58.3 ± 21.7% for Hispanic and 51.6 ± 26.8% for other race and ethnicity, respectively, p < .001). After the adjustment for maternal demographic and clinical factors, maternal race and ethnicity remained to be significantly associated with timing of pharmacotherapy initiation, with women of racial and ethnic minority having a higher percent of elevated CBGs prior to pharmacotherapy initiation (adjusted linear regression coefficient 18.1, 95% CI 11.3-25.0 for NHB, adjusted linear regression coefficient 13.2, 95% CI 5.0-21.4 for Hispanic, and adjusted linear regression coefficient 9.8, 95% CI 2.6-16.9 for women of other race and ethnicity). CONCLUSION: A significant variation was identified in glycemic threshold for pharmacotherapy initiation in women with GDM across different maternal racial and ethnic groups with minority women starting pharmacotherapy at higher percent of elevated CBGs.
Assuntos
Diabetes Gestacional , Etnicidade , Diabetes Gestacional/tratamento farmacológico , Minorias Étnicas e Raciais , Feminino , Humanos , Grupos Minoritários , Gravidez , Estudos Retrospectivos , Estados UnidosRESUMO
OBJECTIVE: Phaeochromocytomas and paragangliomas (PPGL) are rare, but strongly heritable tumours. Variants in succinate dehydrogenase (SDH) subunits are identified in approximately 25% of cases. However, clinical and genetic information of patients with SDHC variants are underreported. DESIGN: This retrospective case series collated data from 18 UK Genetics and Endocrinology departments. PATIENTS: Both asymptomatic and disease-affected patients with confirmed SDHC germline variants are included. MEASUREMENTS: Clinical data including tumour type and location, surveillance outcomes and interventions, SDHC genetic variant assessment, interpretation, and tumour risk calculation. RESULTS: We report 91 SDHC cases, 46 probands and 45 non-probands. Fifty-one cases were disease-affected. Median age at genetic diagnosis was 43 years (range: 11-79). Twenty-four SDHC germline variants were identified including six novel variants. Head and neck paraganglioma (HNPGL, n = 30, 65.2%), extra-adrenal paraganglioma (EAPGL, n = 13, 28.2%) and phaeochromocytomas (PCC) (n = 3, 6.5%) were present. One case had multiple PPGLs. Malignant disease was reported in 19.6% (9/46). Eight cases had non-PPGL SDHC-associated tumours, six gastrointestinal stromal tumours (GIST) and two renal cell cancers (RCC). Cumulative tumour risk (95% CI) at age 60 years was 0.94 (CI: 0.79-0.99) in probands, and 0.16 (CI: 0-0.31) in non-probands, respectively. CONCLUSIONS: This study describes the largest cohort of 91 SDHC patients worldwide. We confirm disease-affected SDHC variant cases develop isolated HNPGL disease in nearly 2/3 of patients, EAPGL and PCC in 1/3, with an increased risk of GIST and RCC. One fifth developed malignant disease, requiring comprehensive lifelong tumour screening and surveillance.