The suspected link between infection by Zika virus (ZIKV), a re-emerging flavivirus, and microcephaly is an urgent global health concern. The direct target cells of ZIKV in the developing human fetus ...are not clear. Here we show that a strain of the ZIKV, MR766, serially passaged in monkey and mosquito cells efficiently infects human neural progenitor cells (hNPCs) derived from induced pluripotent stem cells. Infected hNPCs further release infectious ZIKV particles. Importantly, ZIKV infection increases cell death and dysregulates cell-cycle progression, resulting in attenuated hNPC growth. Global gene expression analysis of infected hNPCs reveals transcriptional dysregulation, notably of cell-cycle-related pathways. Our results identify hNPCs as a direct ZIKV target. In addition, we establish a tractable experimental model system to investigate the impact and mechanism of ZIKV on human brain development and provide a platform to screen therapeutic compounds.
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•Zika virus (ZIKV) infects human embryonic cortical neural progenitor cells (hNPCs)•ZIKV-infected hNPCs produce infectious ZIKV particles•ZIKV infection leads to increased cell death of hNPCs•ZIKV infection dysregulates cell cycle and transcription in hNPCs
The suspected link between ZIKV infection and microcephaly is an urgent global health concern. Tang et al. report that ZIKV virus directly infects human cortical neural progenitor cells with high efficiency, resulting in stunted growth of this cell population and transcriptional dysregulation.
Depression occurs frequently in individuals with coronary artery disease (CAD) and is associated with a poor prognosis.
To determine the effects of psychological and pharmacological interventions for ...depression in CAD patients with comorbid depression.
We searched the CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL databases up to August 2020. We also searched three clinical trials registers in September 2021. We examined reference lists of included randomised controlled trials (RCTs) and contacted primary authors. We applied no language restrictions.
We included RCTs investigating psychological and pharmacological interventions for depression in adults with CAD and comorbid depression. Our primary outcomes included depression, mortality, and cardiac events. Secondary outcomes were healthcare costs and utilisation, health-related quality of life, cardiovascular vital signs, biomarkers of platelet activation, electrocardiogram wave parameters, non-cardiac adverse events, and pharmacological side effects.
Two review authors independently examined the identified papers for inclusion and extracted data from the included studies. We performed random-effects model meta-analyses to compute overall estimates of treatment outcomes.
Thirty-seven trials fulfilled our inclusion criteria. Psychological interventions may result in a reduction in end-of-treatment depression symptoms compared to controls (standardised mean difference (SMD) -0.55, 95% confidence interval (CI) -0.92 to -0.19, I
= 88%; low certainty evidence; 10 trials; n = 1226). No effect was evident on medium-term depression symptoms one to six months after the end of treatment (SMD -0.20, 95% CI -0.42 to 0.01, I
= 69%; 7 trials; n = 2654). The evidence for long-term depression symptoms and depression response was sparse for this comparison. There is low certainty evidence that psychological interventions may result in little to no difference in end-of-treatment depression remission (odds ratio (OR) 2.02, 95% CI 0.78 to 5.19, I
= 87%; low certainty evidence; 3 trials; n = 862). Based on one to two trials per outcome, no beneficial effects on mortality and cardiac events of psychological interventions versus control were consistently found. The evidence was very uncertain for end-of-treatment effects on all-cause mortality, and data were not reported for end-of-treatment cardiovascular mortality and occurrence of myocardial infarction for this comparison. In the trials examining a head-to-head comparison of varying psychological interventions or clinical management, the evidence regarding the effect on end-of-treatment depression symptoms is very uncertain for: cognitive behavioural therapy compared to supportive stress management; behaviour therapy compared to person-centred therapy; cognitive behavioural therapy and well-being therapy compared to clinical management. There is low certainty evidence from one trial that cognitive behavioural therapy may result in little to no difference in end-of-treatment depression remission compared to supportive stress management (OR 1.81, 95% CI 0.73 to 4.50; low certainty evidence; n = 83). Based on one to two trials per outcome, no beneficial effects on depression remission, depression response, mortality rates, and cardiac events were consistently found in head-to-head comparisons between psychological interventions or clinical management. The review suggests that pharmacological intervention may have a large effect on end-of-treatment depression symptoms (SMD -0.83, 95% CI -1.33 to -0.32, I
= 90%; low certainty evidence; 8 trials; n = 750). Pharmacological interventions probably result in a moderate to large increase in depression remission (OR 2.06, 95% CI 1.47 to 2.89, I
= 0%; moderate certainty evidence; 4 trials; n = 646). We found an effect favouring pharmacological intervention versus placebo on depression response at the end of treatment, though strength of evidence was not rated (OR 2.73, 95% CI 1.65 to 4.54, I
= 62%; 5 trials; n = 891). Based on one to four trials per outcome, no beneficial effects regarding mortality and cardiac events were consistently found for pharmacological versus placebo trials, and the evidence was very uncertain for end-of-treatment effects on all-cause mortality and myocardial infarction. In the trials examining a head-to-head comparison of varying pharmacological agents, the evidence was very uncertain for end-of-treatment effects on depression symptoms. The evidence regarding the effects of different pharmacological agents on depression symptoms at end of treatment is very uncertain for: simvastatin versus atorvastatin; paroxetine versus fluoxetine; and escitalopram versus Bu Xin Qi. No trials were eligible for the comparison of a psychological intervention with a pharmacological intervention.
In individuals with CAD and depression, there is low certainty evidence that psychological intervention may result in a reduction in depression symptoms at the end of treatment. There was also low certainty evidence that pharmacological interventions may result in a large reduction of depression symptoms at the end of treatment. Moderate certainty evidence suggests that pharmacological intervention probably results in a moderate to large increase in depression remission at the end of treatment. Evidence on maintenance effects and the durability of these short-term findings is still missing. The evidence for our primary and secondary outcomes, apart from depression symptoms at end of treatment, is still sparse due to the low number of trials per outcome and the heterogeneity of examined populations and interventions. As psychological and pharmacological interventions can seemingly have a large to only a small or no effect on depression, there is a need for research focusing on extracting those approaches able to substantially improve depression in individuals with CAD and depression.
This article examines banks' de-risking practices inside Hong Kong's Anti-Money Laundering / Countering the Financing of Terrorism (AML/CFT) regime, a problem that has created considerable tension ...between the demands of AML/CFT prevention and those of financial inclusion. It unravels the public policy tensions stemming from a multitude of financial reform causes, namely the facilitation of AML/CFT regulatory compliance, the promotion of financial technology (FinTech) innovation and an ultimate expansion in financial inclusion. The article argues that tiered account services are an important first step towards financial inclusion, culminating in the introduction of simple bank accounts by some banks to mitigate the effect of de-risking. While proposed solutions such as the know-your-client utility system and central data repository may contribute to a digital financial inclusion framework, they are not tailored to solve a specific problem (de-risking). The article therefore proposes and evaluates whether FinTech and blockchain-based smart contracts qualify as alternative solutions to de-risking. The article aims to address those policy tensions and contribute to the regulatory policy formulation and the rule-making for financial law and regulation intended to facilitate financial inclusion.
In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ...∼6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.
Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivating mutations in GNAS. Patients with maternally-inherited mutations develop pseudohypoparathyroidism type 1A (PHP1A) with ...multi-hormone resistance and aberrant craniofacial and skeletal development among other abnormalities. Chiari malformation type 1 (CM1), a condition in which brain tissue extends into the spinal canal when the skull is too small, has been reported in isolated cases of PHP1A. It has been hypothesized to be associated with growth hormone (GH) deficiency. Given the adverse clinical sequelae that can occur if CM1 goes unrecognized, we investigated the previously undetermined prevalence of CM1, as well as any potential correlations with GH status, given the known increased prevalence of GH deficiency in PHP1A. We also investigated these metrics for low lying cerebellar tonsils (LLCT), defined as tonsillar descent less than 5 mm below the foramen magnum. In addition, we investigated possible correlations of CM1/LLCT with advanced hand/wrist bone ages and craniofacial abnormalities known to occur in PHP1A to determine whether premature chondrocyte differentiation and/or aberrant craniofacial development could be potential etiologies of CM1/LLCT through both human studies and investigations of our AHO mouse model.
We examined patients with PHP1A in our clinic and noticed CM1 more frequently than expected. Therefore, we set out to determine the true prevalence of CM1 and LLCT in a cohort of 54 mutation-confirmed PHP1A participants who had clinically-indicated brain imaging. We examined potential correlations with GH status, clinical features, biological sex, genotype, and hand/wrist bone age determinations. In addition, we investigated the craniofacial development in our mouse model of AHO (Gnas E1+/-m) by histologic analyses, dynamic histomorphometry, and micro-computerized tomographic imaging (MCT) in order to determine potential etiologies of CM1/LLCT in PHP1A.
In our cohort of PHP1A, the prevalence of CM1 is 10.8%, which is at least 10-fold higher than in the general population. If LLCT is included, the prevalence increases to 21.7%. We found no correlation with GH status, biological sex, genotype, or hand/wrist bone age. Through investigations of our Gnas E1+/-m mice, the correlate to PHP1A, we identified a smaller cranial vault and increased cranial dome angle with evidence of hyperostosis due to increased osteogenesis. We also demonstrated that there was premature closure of the spheno-occipital synchondrosis (SOS), a cartilaginous structure essential to the development of the cranial base. These findings lead to craniofacial abnormalities and could contribute to CM1 and LLCT development in PHP1A.
The prevalence of CM1 is at least 10-fold higher in PHP1A compared to the general population and 20-fold higher when including LLCT. This is independent of the GH deficiency that is found in approximately two-thirds of patients with PHP1A. In light of potential serious consequences of CM1, clinicians should have a low threshold for brain imaging. Investigations of our AHO mouse model revealed aberrant cranial formation including a smaller cranium, increased cranial dome angle, hyperostosis, and premature SOS closure rates, providing a potential etiology for the increased prevalence of CM1 and LLCT in PHP1A.
Among the physiological consequences of extended spaceflight are loss of skeletal muscle and bone mass. One signaling pathway that plays an important role in maintaining muscle and bone homeostasis ...is that regulated by the secreted signaling proteins, myostatin (MSTN) and activin A. Here, we used both genetic and pharmacological approaches to investigate the effect of targeting MSTN/activin A signaling in mice that were sent to the International Space Station. Wild type mice lost significant muscle and bone mass during the 33 d spent in microgravity. Muscle weights of Mstn −/− mice, which are about twice those of wild type mice, were largely maintained during spaceflight. Systemic inhibition of MSTN/activin A signaling using a soluble form of the activin type IIB receptor (ACVR2B), which can bind each of these ligands, led to dramatic increases in both muscle and bone mass, with effects being comparable in ground and flight mice. Exposure to microgravity and treatment with the soluble receptor each led to alterations in numerous signaling pathways, which were reflected in changes in levels of key signaling components in the blood as well as their RNA expression levels in muscle and bone. These findings have implications for therapeutic strategies to combat the concomitant muscle and bone loss occurring in people afflicted with disuse atrophy on Earth as well as in astronauts in space, especially during prolonged missions
This review is timely given the 2018 publication of the first international Consensus Statement for the diagnosis and management of pseudohypoparathyroidism (PHP) and related disorders. The purpose ...of this review is to provide the knowledge needed to recognize and manage PHP1A, pseudopseudohypoparathyroidism (PPHP) and PHP1B - the most common of the subtypes - with an overview of the entire spectrum and to provide a concise summary of management for clinical use. This review will draw from recent literature as well as personal experience in evaluating hundreds of children and adults with PHP.
Progress is continually being made in understanding the mechanisms underlying the PHP spectrum. Every year, through clinical and laboratory studies, the phenotypes are elucidated in more detail, as are clinical issues such as short stature, brachydactyly, subcutaneous ossifications, cognitive/behavioural impairments, obesity and metabolic disturbances. Headed by a European PHP consortium, experts worldwide published the first international Consensus that provides detailed guidance in a systematic manner and will lead to exponential progress in understanding and managing these disorders.
As more knowledge is gained from clinical and laboratory investigations, the mechanisms underlying the abnormalities associated with PHP are being uncovered as are improvements in management.
Aim
To summarize current evidence for early identification and motor‐based intervention for children aged 5 years and younger of age with/at risk of developmental coordination disorder (DCD).
Method
...Using scoping review methodology, we independently screened over 11 000 articles and selected those that met inclusion criteria.
Results
Of the 103 included articles, 78 articles were related to early identification and are summarized in a companion article. Twenty‐two articles focused on early intervention, with an additional three articles covering both early identification and intervention. Most intervention studies were at a low level of evidence, but provide encouraging evidence that early intervention is beneficial for young children with/at risk of DCD. Direct intervention can be provided to whole classes, small groups, or individuals according to a tiers of service delivery model. Educating and building the capacity of parents and early childhood educators are also key elements of early intervention.
Interpretation
Evidence for early intervention for children with/at risk of DCD is emerging with promising results. Further studies are needed to determine best practice for early intervention and whether intervening early can prevent the negative developmental trajectory and secondary psychosocial consequences associated with DCD.
Intervención temprana para niños con (o en riesgo de) trastorno del desarrollo de la coordinación: una revisión de alcance
Objetivo
Recapitular la evidencia actual acerca de la identificación temprana y la intervención motora para niños de hasta 5 años inclusive con/ en riesgo de trastorno del desarrollo de la coordinación (TDC).
Método
Utilizando la metodología de revisión del alcance, examinamos de forma independiente más de 11.000 artículos y seleccionamos aquellos que cumplían con los criterios de inclusión.
Resultados
De los 103 artículos incluidos, 78 artículos estaban relacionados con la identificación temprana y se resumen en un artículo aparte. Veintidós artículos se centraron en la intervención temprana, y otros tres artículos abordan tanto la identificación temprana como la intervención temprana. La mayoría de los estudios de intervención muestran todavía un nivel de evidencia bajo, pero brindan evidencia alentadora de que la intervención temprana es beneficiosa para los niños pequeños con TDC o en riesgo de padecer TDC. La intervención directa se puede brindar a clases completas, grupos pequeños o individuos de acuerdo con un modelo de prestación de servicios por niveles. Educar y desarrollar la capacidad de los padres y los educadores también son elementos clave de la intervención temprana.
Interpretación
Están surgiendo pruebas acerca de la intervención temprana para niños con (o en riesgo de) TDC con resultados prometedores. Se necesitan más estudios para determinar las mejores prácticas para la intervención temprana y si la intervención temprana puede prevenir la trayectoria de desarrollo negativa y las consecuencias psicosociales secundarias asociadas con el TDC.
Intervenção precoce para crianças com (em risco para) transtorno do desenvolvimento da coordenação: uma revisão de escopo
Objetivo
Sintetizar a evidência disponível atualmente sobre a identificação precoce e intervenção motora para crianças com idade de até 5 anos de vida com/em risco para transtorno do desenvolvimento da coordenação (TDC).
Método
Usando metodologia de revisão de escopo, avaliamos de forma independente 11.000 artigos e selecionamos os que atenderam os critérios de inclusão.
Resultados
Dos 103 artigos incluídos, 78 se relacionaram com identificação precoce e são sintetizados em um artigo paralelo. Vinte e dois artigos foracam em intervenção precoce, com três artigos adicionais cobrindo tanto identificação quanto intervenção precoces. A maior parte dos estudos de intervenção tiveram baixo nível de evidência, mas fornecem evidências encorajadoras de que a intervenção precoce é benéfica para crianças pequenas com (em risco para) TDC. A intervenção direta pode ser fornecida para a sala toda, pequenos grupos, ou indivíduos, de acordo com as características do modelo de prestação de serviços. Educar e fomentar a capacidade dos pais e educadores infantis também são elementos‐chave da intervenção precoce.
Interpretação
A evidência para intervenção precoce voltada para crianças com (em risco para) TDC é emergente, com resultados promissores. Mais estudos são necessários para determinar as melhores práticas de intervenção precoce e se intervir precocemente pode evitar uma trajetória desenvolvimental negative e consequências psicossociais secundárias associadas com TDC.
This article is commented on by Damiano on page 630 of this issue.
This article's has been translated into Spanish and Portuguese.
Follow the links from the to view the translations.
Aim
To summarize current evidence for early identification and motor‐based intervention for children aged 5 years and younger with/at risk of developmental coordination disorder (DCD).
Method
Using ...scoping review methodology and after duplicates were removed, 11 115 peer‐reviewed articles and grey literature were independently screened by two authors. Data from 103 included records were extracted and synthesized by both assessors. One author entered the relevant data into tables, while the other author double‐checked the entries.
Results
Records included peer‐reviewed studies, guidelines, conference presentations, and theses/dissertations. Most literature pertained to early identification (n=78), with fewer studies targeting intervention (n=22) or covering both topics (n=3). Literature was summarized in two main categories: (1) assessments for diagnostic criteria A and B; and (2) motor‐based interventions for young children with/at risk of DCD. This article highlights the findings related to assessments, while a companion article summarizes the intervention literature.
Interpretation
Emerging evidence shows that children, especially those at greatest risk of DCD, may be identified before formal school entry. Earlier identification will allow for earlier intervention, which may help to improve the developmental trajectories of children with/at risk of DCD and prevent secondary consequences of the disorder. It is recommended that health care providers explicitly use the term ‘at risk of DCD’.
This article is commented on by Damiano on page 630 of this issue.
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