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Can you do the accounting according to UK GAAP?
What are the rules about how an invoice needs to look?
Does my Spanish company always need to include VAT tax when billing our clients?
What tax forms need to be filed for a Spanish company?
With an SL, when do I get a refund of the VAT tax I've paid?
Why choose Strong Abogados to do my accounting in Spain?
Get a tax ID number for your business, if you don't already have one.
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Register the company for VAT purposes.
Register the company for social security.
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Legalize the official books of accountancy at the Mercantile Registry, as well as the notarised year-end annual accounts. This includes the libro de actas, libro de socios, memoria anual, cuentas anuales, balance de situación, cuenta de perdidas y ganancias, and libro diario, as well as the certificate of the annual meeting of shareholders to approve the accounting.
We provide information to the client regarding the Spanish rules on invoice creation, as well as general information on tracking expenses and charges.
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We are members of the Bar Association of Barcelona (Ilustre Colegio de Abogados de Barcelona) and the Association of Accounting and Tax Experts of Spain (AECE). You as a client can ask for referrals and complaints about us in both institutions.


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Home » Website » International » Inspired By Mother, Kamala Harris Says She Had To Do Something When 'So Much Is On The Line'
Inspired By Mother, Kamala Harris Says She Had To Do Something When 'So Much Is On The Line'
Kamala Harris has helped not only enthused the party's base, but also helped the campaign raise record amount of money.
PTI	10 September 2020
PTI	2020-09-10T08:29:20+05:30 Inspired By Mother, Kamala Harris Says She Had To Do Something When 'So Much Is On The Line'
Democratic vice-presidential candidate Kamala Harris has said her mother Shyamala Gopalan was her source of inspiration who had guided her throughout her entire life.
"My mother always used to say, 'Don't just sit around and complain about things. Do something'," Harris, 55, wrote in a fundraising email to her supporters on Wednesday. "Her words have guided me through my entire life, pushing me to take action, solve problems and fight for solutions."
The Indian-origin senator said it was not a hard decision when Democratic presidential candidate Joe Biden called her to be his running mate.
"I knew I had to do exactly what my mother would have wanted me to do. With so much on the line, I had to do something," said Harris, the the first Black woman on a major party vice-presidential ticket.
"I couldn't be more grateful to be a part of this ticket, or more humbled by the outpouring of support Joe and I have received over these past few weeks on the trail. And honestly, we're going to need every ounce of it," she said, urging her supporters to chip in with their contribution.
Harris has helped not only enthused the party's base, but also helped the campaign raise record amount of money.
During a virtual fundraiser a day earlier, which was hosted by Indian-American and 'Top Chef' host Padma Lakshmi and actor Billy Porter, Harris spoke about her parents' involvement in civil rights marches when she was growing up in Oakland.
Harris also said she still finds time to cook Sunday dinners for her family despite her hectic schedule and nationwide campaigning as. The Senator also spoke about her mother's cooking, noting that she was an "extraordinary cook".
According to Politico, Harris is an enthusiastic cook who bookmarks recipes from the New York Times' cooking section and had tried almost all the recipes from Alice Waters' 'The Art of Simple Food'.
Donald Trump Deliberately Wanted To Play Down Coronavirus, Says Bob Woodward's Book
PTI	Kamala Harris	Washington	US Presidential Elections	International
Covid-19 Vaccination Drive Begins In Several States; Check Details Here

redpajama_set_name: RedPajamaCommonCrawl


text:
Q: synchronized(this) blocks whole object?
Possible Duplicate:
synchronized block vs synchronized method?

From accepted answer to this question: In Java critical sections, what should I synchronize on?
I learn that
public synchronized void foo() {
    // do something thread-safe
}

and:
public void foo() {
    synchronized (this) {
        // do something thread-safe
    }
}

do exactly the same thing. But in first case we make synchronized only one method of object, and in second case we make inaccessible Whole object. So why this two code snippests do same things?

A: You seem to be mixing things.
Firstly
public synchronized void method() {
}

is equivalent, from a synchronization perspective, to:
public void method() {
    synchronized (this) {
    }
}

The pros / cons have already been mentioned and the various duplicates give more information.
Secondly,
synchronized(someObject) {
    //some instructions
}

means that the instructions in the synchronized block can't be executed simultaneously by 2 threads because they need to acquire the monitor on someObject to do so. (That assumes that someObject is a final reference that does not change).
In your case, someObject happens to be this.
Any code in your object that is not synchronized, can still be executed concurrently, even if the monitor on this is held by a thread because it is running the synchronized block. In other words, synchronized(this) does NOT "lock the whole object". It only prevents 2 threads from executing the synchronized block at the same time.
Finally, if you have two synchronized methods (both using this as a lock), if one thread (T1) acquires a lock on this to execute one of those 2 methods, no other thread is allowed to execute any of the two methods, because they would need to acquire the lock on this, which is already held by T1.
That situation can create contention in critical sections, in which case a more fine grained locking strategy must be used (for example, using multiple locks).

A: We don't synchronize an object, instead we synchronize a block of code. In the first that block of code is the method itself, while in the second it's the synchronized block.
The object only provides the lock so as to prevent multiple threads from simultaneously entering that block of code. In the first case, the this object (the one on which the method is invoked) will be used implicitly as the lock, while in the second case it doesn't always have to be this object, it could be some other object also.

A: They do the same thing. The first form is a short-hand for the second form.
One minor difference between the two constructs is this - synchronized blocks are compiled into monitorenter (op-code 0xC2) and monitorexit (op-code 0xC3) instructions.
A synchronized method, when compiled, is distinguished in the runtime constant pool by
the ACC_SYNCHRONIZED flag, which is checked by JVM's the method invocation instructions. This difference does not have much significance in practice though.

A: They dont do same things. First part being synched from beginning to end. Second is just synching the block(not whole method). Second one has some flexibility.

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text:
Q: Corollaries to the inversion formula (Durrett) In Durrett's §3.3, he proves:

Theorem 3.3.11: the inversion formula. Let $\varphi(t)=\int e^{itx}\mu(dx)$ where $\mu$ is a probability measure. If $a<b$ then $\frac{1}{2\pi}\lim\limits_{T\to\infty}\int_{-T}^T\frac{e^{-ita}-e^{-itb}}{it}\varphi(t)dt=\mu((a,b))+\frac{\mu(\{a,b\})}{2}$.

He then states two corollaries:

Corollary 3.3.12. If $\varphi$ is real then $X$ and $-X$ have the same distribution. [it is implicit that $\varphi(t)=\mathbb{E}[e^{itX}]$ is $X$'s characteristic function]
Corollary 3.3.13. If $X_1$ and $X_2$ are independent with distributions $N(0,\sigma_1)$ and $N(0,\sigma_2)$, then $X_1+X_2$ has distribution $N\left(0,\sqrt{\sigma_1^2+\sigma_2^2}\right)$.

I'm at a loss to see how these corollaries follow. For the first, would it be using $\mu(A):=\mathbb{P}[X\in A]$? For the second, I suspect it somehow uses $\varphi=\varphi_1\varphi_2$ where these are the characteristic functions for (resp.) $X_1+X_2$, $X_1$, and $X_2$, but I'm not really seeing the big picture here. Thanks in advance.

A: Inversion Theorem tells us, in particular, that if two probability measures have the same characteristic function then they are identical: Suppose $\mu ((a,b))+\frac {\mu (\{a,b\})} 2=\nu ((a,b))+\frac {\nu (\{a,b\})} 2$ whenever $a<b$. Then $\mu ([a,b))=\nu ([a,b))$ except for countably many values of $a, b$. [ Because $\mu (\{a\})=0=\nu (\{a\})$ except for countably many values of $a$]. Now it follows by a  standard measure theoretic argument that $\mu (E)=\nu (E)$ for all Borel sets $E$.
For the first corollary just check that $X$ and $-X$ have the same characteristic function. [$\mathbb E e^{-itX} $ is the complex conjugate of $\mathbb E e^{itX} $].
For the second corollary use the fact that characteristic function of $X_1+X_2$ is the product of the characteristic functions of $X_1$ and $X_2$. It follows that the characteristic function of $X_1+X_2$ is same as that of $N(0,\sqrt {\sigma_1^{2}+\sigma_2^{2}})$ which implies that $X_1+X_2$ has this normal distribution.


text:
Famous first words.
Posted on Tuesday, December 31, 2013 by Tzivia
How to start a story? The words you pick are important, and to prove it, let's see if you can match up these famous first words with the story they're taken from.
I'll let you know the answers in a few days, but I think you'll be able to figure it out on your own. ;-)
(By the way, I started out trying to pick only ten, but the list gradually bulged to 11, then 12, where I put my foot down and left it the way it is now.)
1 Once there were four children whose names were Peter, Susan, Edmund and Lucy. The Tale of Despereaux,
by Kate DiCamillo
2 Once upon a time there were four little Rabbits, and their names were - Flopsy, Mopsy, Cotton-tail, and Peter. The Jungle Book,
by Rudyard Kipling
"'Where's Papa going with that axe?' said Fern to her mother as they were setting the table for breakfast."
The Very Hungry Caterpillar,
4 This story begins within the walls of a castle, with the birth of a mouse. The Phantom Tollbooth,
by Norton Juster
5 Mr. and Mrs. Dursley, of number four, Privet Drive, were proud to say that they were perfectly normal, thank you very much. The Tale of Peter Rabbit,
by Beatrix Potter.
6 These two very old people are the father and mother of Mr. Bucket. Murmel Murmel Murmel,
by Robert Munsch (got to throw in a Canadian!)
7 It was seven o'clock of a very warm evening in the Seeonee hills when Father Wolf woke up from his day's rest, scratched himself, yawned, and spread out his paws one after the other to get rid of the sleepy feeling in their tips. Where the Wild Things Are,
by Maurice Sendak
8 There was once a boy named Milo who didn't know what to do with himself—not just sometimes, but always. The Lion, the Witch and the Wardrobe,
by C.S. Lewis
9 Here is Edward Bear, coming downstairs now, bump, bump, bump, on the back of his head, behind Christopher Robin. Charlotte's Web,
by E.B. White
10 The night Max wore his wolf suit and made mischief of one kind and another his mother called him "WILD THING!" and Max said "I'LL EAT YOU UP!" so he was sent to bed without eating anything. Harry Potter and the Philosopher's Stone (Sorceror's Stone in the U.S.),
11 When Robin went out into her backyard, there was a big hole right in the middle of her sandbox. Winnie the Pooh,
by A. A. Milne
12 In the light of the moon, a little egg lay on a leaf. Charlie and the Chocolate Factory,
by Roald Dahl
I can think of so many more great ones, but I will stop at 12.
This probably isn't that hard a test, because a great opening line, followed up with great writing and great characters, sticks in our memory… in many cases, forever. So most of these matches should be obvious.
I've included this not just to trigger your memory of wonderful children's-book opening lines, but because I think all these lines (in different ways) make a terrific point: the story gets going RIGHT AWAY, right off the bat.
As a children's book author, you can't fiddle about and take ten pages to introduce your characters and their daily life. You have to start in with something exciting almost right away. You have to get kids asking questions, like:
What? A hole? How did it get there?
Who is Winnie the Pooh and why is he bumping on the back of his head?
What's Max going to do with no supper?
What the heck kind of wolves can tell time?
What IS papa doing with that axe?
It's also interesting to see that the older a kids' book is, generally the longer the author takes to warm up. That's true in adult writing as well. Modern audiences are not known for their patience, and a long warm-up line like Kipling's probably couldn't make the cut in modern children's writing (in some cases, Kipling's writing seems more aimed at adults in any event).
The older kid's books also start out in a way that everybody tells you not to today. I put two of them together to show it off deliberately: "Once [upon a time] there were four _____ (children, rabbits) whose names were ________ (Peter, Susan, Edmund and Lucy; Flopsy, Mopsy, Cottontail, Peter)."
Modern books of all kinds don't generally introduce characters in this kind of up-front way.
In a film course, I once learned that in old movies, a character at home might say, "I'm going to the store." Then, the director would show the character driving to the store, getting out and going inside to pick up some milk. Today, if the scene is included at all, it's about ten seconds – a guy tells someone he's buying milk, and flash – he's back home with the milk (unless something happens at the store that you need to show!).
So why did they make them clunky like that? They had to! Viewers 100 years ago would have found it confusing if the milk just appeared in the character's hands. And now that movies have been around for a while, we know the conventions and would find that sort of storytelling deathly dull.
Ditto with children's books. It's deathly dull to start out "This is Veronica and she is six years old."
What would your kids do if you showed them a new child and announced, "This is Veronica and she's six years old"? If they're anything like mine, they would probably ignore her.
But what if you start with, "This is Veronica and she's going bump bump bump down the stairs by the back of her head"? "This is Veronica and she found a big strange hole in her sandbox." "This is Veronica and she's heading out with an axe."
That last one, at least, might get them to look up from their book.
(Oh, yeah, did I mention that all 4 of my kids are big readers? Wonder where they got that from!)
So these books are some of my favourites. What opening lines or first words of kids' books stand out in your memory???
Posted under beginnings, bookshelf, classics, kids, posts, words
Are you a contender?
Interview with author / illustrator Ann D. Koffsky.
Basics, Part 1: What is a children's book?
Quick tip to double your odds: read it out loud.
Avoiding the #1 mistake: tossing in values.
Writer vs Author?
Two kinds of authors.
So you want to write kids' books?


text:
Q: Spring Boot with XML based security configuration doesn't seem to use correct authentication manager? We're trying to upgrade our old, mostly XML-based Spring web application, to Spring Boot (2.5.4). We've almost managed to do so but there's one thing that is still nagging us. Even after using Spring Boot we (still for now) have our Spring Security configuration defined like this in XML:
<http pattern="/api/something/v1/**" use-expressions="true" create-session="stateless" authentication-manager-ref="somethingAuthenticationManager">
    <http-basic/>

    <custom-filter ref="queryParamAuthFilter" before="BASIC_AUTH_FILTER" />

    <intercept-url pattern="/api/something/v1/**" access="hasRole('ROLE_SOMETHING')" />
    <csrf disabled="true"/>
</http>

The authentication managers are defined like this:
<authentication-manager alias="somethingAuthenticationManager">
    <authentication-provider user-service-ref="somethingUserDetailsService">
    </authentication-provider>
</authentication-manager>

<authentication-manager id="authenticationManager">
    <authentication-provider user-service-ref="customUserDetailsService">
    </authentication-provider>
</authentication-manager>

The problem is that when I make a GET request to /api/something/v1 it seems like it's using the wrong authentication manager (the one with id authenticationManager) and not the somethingAuthenticationManager. This used to work before Spring Boot. Why is this and how can we resolve it?
Note that we're not using @EnableWebSecurity or any Java configuration related to Spring Security (afaik), everything is defined in our XML file.
Update
We start the application like this:
@EnableRabbit
@EnableRetry
@SpringBootApplication
@EnableAsync
@EnableAspectJAutoProxy(proxyTargetClass = true)
@ImportResource(locations = {"classpath*:META-INF/spring/applicationContext*.xml", "classpath:spring/webflow-config.xml"})
public class OurApplication {

    public static void main(String[] args) {
        SpringApplication.run(OurApplication.class, args);
    }
}

which finds the WebappConfiguration that contains some additional configuration:
@Configuration
@ImportResource("classpath:spring/webmvc-config.xml")
public class WebappConfiguration implements WebMvcConfigurer {

@Bean
    public TilesConfigurer tilesConfigurer() {
        TilesConfigurer tilesConfigurer = new TilesConfigurer();
        String[] defs = {
                "classpath:WEB-INF/layouts/layouts.xml",
                "WEB-INF/views/**/views.xml"
        };
        // Scan views directory for Tiles configurations
        tilesConfigurer.setDefinitions(defs);
        return tilesConfigurer;
    }

    @Bean
    public TomcatServletWebServerFactory tomcatFactory() {
        return new TomcatServletWebServerFactory() {
            @Override
            protected void postProcessContext(Context context) {
                ((StandardJarScanner) context.getJarScanner()).setScanManifest(false);
                context.setResources(new ExtractingRoot());
            }
        };
    }

    @Bean
    public WebServerFactoryCustomizer<TomcatServletWebServerFactory> servletContainerCustomizer() {
        return container -> container.addContextCustomizers(context -> context.setReloadable(false));
    }

    @Override
    public void addResourceHandlers(ResourceHandlerRegistry registry) {
        registry.addResourceHandler("/web-resources/**").addResourceLocations("classpath:/META-INF/web-resources/");
    }

    @Bean
    public TilesViewResolver tilesViewResolver() {
        TilesViewResolver tilesViewResolver = new TilesViewResolver();
        tilesViewResolver.setRequestContextAttribute("requestContext");
        tilesViewResolver.setExposedContextBeanNames("ownerLogoUrlFinder");
        return tilesViewResolver;
    }

    @Bean
    public DispatcherServletRegistrationBean dispatcherServletRegistrationBean() {
        DispatcherServlet servlet = new DispatcherServlet();
        servlet.setApplicationContext(new AnnotationConfigWebApplicationContext());
        return new DispatcherServletRegistrationBean(servlet, "/");
    }

    @Bean
    public FilterRegistrationBean<OpenEntityManagerInViewFilter> openEntityManagerInViewFilterRegistrationBean(OpenEntityManagerInViewFilter openEntityManagerInViewFilter) {
        FilterRegistrationBean<OpenEntityManagerInViewFilter> registration = new FilterRegistrationBean<>();
        registration.setFilter(openEntityManagerInViewFilter);
        registration.addUrlPatterns("/*");
        registration.setName("openEntityManagerInViewFilter");
        registration.setOrder(1);
        return registration;
    }

    @Bean
    public OpenEntityManagerInViewFilter openEntityManagerInViewFilter() {
        return new OpenEntityManagerInViewFilter();
    }

}

Update 2
I get this when starting up:
2021-09-21 13:46:33.933  WARN 46673 --- [           main] o.s.b.f.parsing.FailFastProblemReporter  : Configuration problem: Overriding globally registered AuthenticationManager
Offending resource: file [/Users/johan/myproject/target/classes/META-INF/spring/applicationContext-security.xml]

A: I have seen something similar and solved it by changing alias to id on my authentication-manager after reading this: https://github.com/spring-projects/spring-security/issues/2163


text:
Anna and Joe Greene and their kids and grandchildren love Christmas.
Each year the family transforms the U.S. 161 Flea Market into a winter wonderland. The decorating starts early and if it doesn't move, it gets a bow, wreath or gift wrap on it.
Vendors and customers get in on the action buying up raffle tickets to help the Salvation Army with its Christmas outreach.
The Greenes do all this because when Joe was a child his parents got help one Christmas from the Salvation Army. He's never forgotten that. Joe, who has an uncanny resemblance to the guy in the red suit, even dresses up as Santa Claus during the holiday season to greet children who visit the flea market.
This year the Greenes make a $1,525 donation to The Gazette Empty Stocking Fund. Steve White, the winner of the raffle, took home a 50-inch Vizio TV.
Santa (getting some help from Joe) will be making appearances each Saturday and Sunday from 10 a.m. to noon, at the flea market on Bessemer City Kings Mountain Highway.
Kids can also catch a ride on the own Santa Express train from 1 to 3 p.m. Dec. 10. The rain date is Saturday Dec. 17. The train rides and Santa visits are free.
Donations to the Empty Stocking Fund campaign have also been made:
In honor of our children and grandchildren, from Meurice and Bob Smith, $100
In honor of Helen Farris, from Wanda M. Clark, $20
In honor of Gregory and in memory of Michael, from Bill Carpenter, $100.
The campaign kicked off on Thanksgiving Day and continues through Christmas Eve. The goal is to raise $100,000.
Each year the Salvation Army uses that money to help those who have hit hard times at Christmas. Thanks to your generosity children will receive toys and warm clothes for winter, families will receive food boxes and seniors and shut-ins will get gifts.
Giving is easy:
Donations will be accepted at The Gazette, 1893 Remount Road, Gastonia. Lobby hours are 9 a.m. to noon and 1 to 4 p.m. Monday through Friday.
Donations can also be made to The Gazette, P.O. Box 1538, Gastonia, NC, 28053, attention Empty Stocking Fund campaign.
Giving is a great way to honor or remember someone special in your life. Each day during the campaign The Gazette will run a list of donors and the names of those they'd like honored with their gift. Contributions may also be made anonymously.
This year, 478 families applied for help. Other numbers provided by the Salvation Army paint a picture of the need that's out there:
947 youth under the age of 15 will be helped this year, as will 87 seniors.
2,400 nursing home residents will be visited by the Salvation Army and receive gifts
225 homeless will get a hot meal, some warm clothes and other basics to survive life on the streets.
Will MacDonald is The Gazette's Community Editor. You can reach him at 704-869-1838 or email him at wmacdonald@gastongazette.com.
TODAY'S TOTAL: $1,745
GOAL: $100,000
CAMPAIGN UPDATE


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Background: Graves's disease (GD) is the most common cause of hyperthyroidism. Maximal 30% of pediatric GD patients achieve remission with antithyroid drugs. The majority of patients therefore require definitive treatment. Both thyroidectomy and radioactive iodine (RAI) are often used as definitive treatment for GD. However, data on efficacy and short- and long-term side effects of RAI treatment for pediatric GD are relatively scarce. Methods: A systematic review of the literature (PubMed and Embase) was performed to identify studies reporting the efficacy or short- and long-term side effects of RAI treatment in pediatric GD. Results: Twenty-three studies evaluating 1,283 children and adolescents treated with RAI for GD were included. The treatment goal of RAI treatment changed over time, from trying to achieve euthyroidism in the past to aiming at complete thyroid destruction and subsequent hypothyroidism in the last 3 decades. The reported efficacy of a first RAI treatment when aiming at hypothyroidism ranged from 42.8 to 97.5%, depending on the activity administered. The efficacy seems to increase with higher RAI activities. When aiming at hypothyroidism, both short- and long-term side effects of treatment are very rare. Long-term side effects were mainly seen in patients in whom treatment aimed at achieving euthyroidism. Conclusion: RAI is a safe definitive treatment option for pediatric GD when aiming at complete thyroid destruction. When aiming at hypothyroidism, the efficacy of treatment seems to increase with a higher RAI activity. Prospective studies are needed to determine the optimal RAI dosing regimen in pediatric GD.
Keywords: Graves' disease; Pediatric Graves' disease; Radioactive iodine; Side effects
In adults and children, hyperthyroidism is mostly caused by Graves' disease (GD) [1, 2]. Treatment options for GD include antithyroid drugs (ATDs), thyroidectomy, and radioactive iodine (RAI). In Europe, ATDs are the preferred first-line treatment modality in newly diagnosed pediatric GD patients [3-5]. Unfortunately, the relapse frequency of hyperthyroidism is high in this age group, with only 20–30% reaching long-lasting remission after 2 years of ATD treatment [5]. Therefore, most pediatric GD patients eventually require definitive treatment.
Both thyroidectomy and RAI are proven effective therapeutic measures for hyperthyroidism. The choice between RAI and total thyroidectomy is a contentious topic and will reflect local expertise and opinion. The final decision on what option to follow will involve shared decision-making including the patient and parents, focusing on the (dis)advantages of each option and local expertise. Total thyroidectomy is a safe treatment option in pediatric GD patients, especially if performed by high-volume surgeons [6]. Only in a minority of pediatric patients, irreversible complications of surgery like permanent hypocalcemia (2.5%) or recurrent laryngeal nerve injury (0.4%) have been reported [6]. Furthermore, thyroidectomy is potentially associated with general surgical risks and consequences, like postoperative bleeding, infections, and a permanent scar. RAI treatment using iodine-131 has been carried out for 80 years. RAI is taken up by thyrocytes and stored within the thyroid follicle. The radioactive isotope decays by emitting β-radiation, causing DNA damage leading to thyrocyte apoptosis and necrosis. In the past, in many areas of the world, the aim of RAI treatment for GD was to achieve euthyroidism; hypothyroidism was considered a side effect. The current American Thyroid Association and European Thyroid Association treatment guidelines both state that in pediatric GD patients, the RAI treatment goal is to achieve hypothyroidism (ablative RAI treatment) [4, 7]. The main reason to aim for complete thyroid destruction in pediatric patients is to prevent the need for additional RAI therapy (and thus extra radiation exposure) as low RAI activity has been associated with poor remission rates. In addition, the current guidelines state that aiming at hypothyroidism will minimize the future risk of malignant transformation of viable but radiation-damaged thyrocytes [7]. RAI treatment should be avoided in cases with active Graves' orbitopathy as it can result in exacerbation, and specific preparatory measures prior to RAI administration have to be taken in patients with inactive Graves' orbitopathy [8].
Data on the efficacy of RAI treatment, the optimal RAI activity, and its short- and long-term side effects in pediatric GD patients are scarce. However, such data are necessary to aid in deciding on the modality of definitive treatment. Several approaches are used to determine the RAI activity to be used in pediatric GD patients. RAI activity may be calculated based on estimated thyroid weight or based on full dosimetry using the result of a RAI uptake, either probe or scan based [9, 10]. Alternatively, administration of a fixed amount of RAI activity has been reported [9]. In adult patients undergoing RAI treatment for GD, radiation thyroiditis is reported as a short-term side effect in 1.2% of the patients [11]. With respect to long-term side effects, there are some worries that RAI treatment at a younger age may increase the risk of other malignancies later in life [12]. In this study, we performed the first systematic review on the efficacy and short- and long-term side effects of RAI treatment in pediatric GD patients. Ideally, the results of this systematic review should be helpful in formulating an evidence-based advice on the optimal ablative RAI activity, preferably without short- or long-term side effects. An overview of available data on both the efficacy and side effects of RAI treatment may be helpful when counseling young patients and their parents who require definitive treatment for GD.
This systematic review was performed following the PRISMA 2009 guidelines [13].
The literature search for this review, using the electronic databases PubMed and Embase, was performed in July 2020 and was further not limited to a specific period. The following search terms were used: Graves' disease, RAI, and efficacy or side effects. For all main terms, synonyms were inserted. MeSH and tiab terms were combined to find a wide range of articles. The exact search strategy used for both the PubMed and Embase database is available in online suppl. data (see online Supplementary Materials). The search was limited to studies in pediatric patients (age limit <18 years). Additional articles were searched by scanning the references of relevant articles and using the "related article" function of the databases.
Study Selection and Quality Assessment
Title and abstract screening was performed independently and blinded by S.L.L. and C.F.M. Full-text screening was performed by S.L.L. and discussed with C.F.M.; in case of disagreement, a third reviewer (A.S.P.v.T.) was consulted. Original studies reporting on the efficacy or on short- and long-term side effects of RAI treatment in a minimum of 10 pediatric GD patients were included. When a study reported data on pediatric patients separate from adult patients, the study was also included. Full-text availability was the last inclusion criterion. Exclusion criteria were conference abstracts, review articles, and articles published in other languages than English, Dutch, German, French, Italian, or Spanish. Part of the full-text screening was a critical appraisal to evaluate the quality per study using the Critical Appraisal Skills Program checklist. The used checklist is designed for cohort studies and is therefore applicable to all of the included articles.
Data extraction was performed by S.L.L. and was double-checked by C.F.M. Data on the treatment goal, efficacy, used RAI activity, and side effects of treatment were collected. The side effects were classified as either long- or short-term side effects. For efficacy, we mainly focused on studies using ablative RAI treatment. For side effects, studies on RAI treatment that aimed at either ablation or euthyroidism were analyzed. Short-term side effects were defined as side effects that occurred within 3 months of RAI treatment, while long-term side effects occurred >3 months after RAI treatment.
The PubMed and Embase searches were performed on July 16, 2020, and yielded 208 unique articles. Ten additional articles were identified via references reading. A total of 154 articles were excluded after title and abstract screening, and an additional 41 articles were excluded after full-text screening. Twenty-three retrospective observational cohort studies were included in this review (Fig. 1). Based on the quality assessment, the quality of 2 of the included studies was rated as good [14, 15], 18 studies as fair [16-33], and 3 studies as reasonable [34-36]. As reported RAI treatment protocols differed between studies or changed over time (including the treatment goal: aiming for eu- or hypothyroidism) and individual patient data were lacking, we were unable to perform a meta-analysis calculating the optimal iodine-131 activity aiming for hypothyroidism.
Flowchart illustrating the results of the literature search on studies evaluating the efficacy and/or short- and long-term side effects of RAI treatment in pediatric GD patients. GD, Graves' disease; RAI, radioactive iodine.
Citation: European Thyroid Journal 10, 5; 10.1159/000517174
Study Characteristics
The 23 included studies reported on RAI treatment of 1,283 children and adolescents with GD. Study characteristics of the included studies regarding the study period, number of patients, gender of included patients, age at RAI treatment, and the indication for RAI treatment are shown in online suppl. Table 1. Extracted data on the applied iodine-131 activity (converted to megabecquerel [MBq]), the efficacy of RAI treatment, and the short- and long-term side effects are shown in Table 1. Seventeen studies used a calculated activity of RAI [17, 19-33, 36], and 2 studies a fixed activity of RAI [14, 15]. In 4 studies, it was not clear how the activity of RAI was determined [16, 18, 34, 35]. The way in which the efficacy of RAI treatment was evaluated differed between studies. In 13 of the 23 included studies, data on short-term side effects of RAI treatment are reported, and data on long-term side effects are reported in 15 studies. In most studies, the majority of patients was treated with ATDs prior to RAI treatment.
Characteristics and outcomes of included studies reporting on the efficacy and side effects of RAI treatment in pediatric GD
The Efficacy of RAI Treatment in Pediatric GD
The goal of RAI treatment – hypothyroidism or euthyroidism – differed between and even within included studies. Based on the current treatment goal of aiming at destruction of the thyroid gland, we analyzed data on studies using ablative RAI treatment. This, however, was the specific treatment goal in only 5 of the included studies, reporting on a combined total of 278 patients [14, 25, 27, 28, 36]. In these 5 studies, the reported efficacy after a first RAI treatment aiming at hypothyroidism ranged from 42.8 to 97.5%, depending on the activity administered. When aiming at hypothyroidism, the efficacy appears to increase with a higher iodine-131 activity. The study by Nebesio et al. [14] was the only one aiming at hypothyroidism using a fixed RAI activity (555 MBq; equals 15,000 microcurie [µCi]) resulting in hypothyroidism in 97.5% of the studied patients after 1 course of RAI. This fixed RAI activity is far more than used in the other studies based on the average thyroid weight in children. Pinto et al. [27] reported hypothyroidism in 73% of the patients after a first activity of 3.7 MBq/g thyroid tissue adjusted for RAI uptake. Azizi and Amouzegar [36] aimed for hypothyroidism using an RAI activity of 7.4 MBq/g thyroid tissue and reported that 14.7% of the patients required a second cycle of RAI therapy, but did not specify the percentage of patients becoming hypothyroid after the first RAI activity (eventually 66.2% of the RAI-treated patients were classified as hypothyroid). The studies by Nakatake et al. [28] and Rivkees and Cornelius [25] are the only 2 studies that retrospectively evaluated the efficacy of different RAI activities aiming at hypothyroidism. Nakatake et al. [28] reported hypothyroidism in 48% of the patients who received 4.44 MBq (120 μCi) of iodine-131 per gram of thyroid tissue. However, 85% of the patients who received 11.1 MBq (300 μCi) of iodine-131 per gram of thyroid tissue became hypothyroid [28]. In line with these findings, Rivkees and Cornelius [25] reported similar results: hypothyroidism was achieved in 42.8% of the patients receiving an activity of 2.96–4.44 MBq (80–120 μCi) of iodine-131 per gram of thyroid tissue, while 93.75% of the patients who received 11.1–14.99 MBq (300–405 μCi) of iodine-131 per gram of thyroid tissue became hypothyroid. Based on these last 2 studies, administering a minimum activity of 11 MBq but possibly a little >15 MBq of iodine-131 per gram of thyroid tissue seems necessary to achieve thyroid destruction in the vast majority of pediatric GD patients.
Several of the other included studies aimed at either euthyroidism or euthyroidism/hypothyroidism and are therefore not usable for formulating an evidence-based advice on the optimal RAI activity that aims at thyroid destruction. However, overall, the studies show that the efficacy seems to increase with a higher iodine-131 activity. All studies reported patients requiring additional RAI treatment because of persistent or recurrent hyperthyroidism. A detailed presentation of the reported efficacy of RAI treatment in all included studies is presented in Table 1.
Short- and Long-Term Side Effects of RAI Treatment in Pediatric GD
To evaluate the presence of side effects after RAI treatment, studies aiming at both euthyroidism and hypothyroidism were included. Short-term side effects of RAI treatment in pediatric GD patients were only rarely reported. Among them were vomiting (n = 4), radiation thyroiditis (n = 1), local inflammation (n = 1), palpitations (n = 1), and myxedema (n = 6). Reported long-term side effects included benign thyroid nodules (n = 6), multinodular benign goiter (n = 1), hyperparathyroidism (n = 1), and papillary thyroid carcinoma (n = 1). No additional cases of thyroid cancer, no cases of leukemia, and no impaired reproductive capacity were reported in the patients who received RAI treatment for pediatric GD, nor was there a reported increased frequency of congenital abnormalities in their offspring in studies with a long enough follow-up period. The cases of thyroid nodules, multinodular goiter, and thyroid carcinoma after RAI treatment were all reported in patients with RAI treatment not exclusively aiming at hypothyroidism. However, in these studies, a causal relation between RAI treatment and the development of thyroid nodules was not proven. Detailed information on the reported side effects of RAI treatment in the included studies is shown in Table 1.
In this systematic review, we report the efficacy and short- and long-term side effects of RAI treatment in pediatric patients with GD. Twenty-three studies evaluating 1,283 children and adolescents with GD were included. In 5 studies, the specific treatment goal of RAI was hypothyroidism (including a total of 278 patients). In these studies, the reported efficacy of the first RAI treatment in achieving hypothyroidism ranged from 42.8 to 97.5%, depending on the applied activity. Unfortunately, prospective studies evaluating the effect of different iodine-131 activities in the treatment of pediatric GD are lacking, hampering evidence-based activity advice. Yet, in the few retrospective studies in which RAI treatment aimed at hypothyroidism, a minimal activity of 11.1–14.99 MBq of iodine-131 per gram of thyroid tissue seemed to result in hypothyroidism in 85–94% of pediatric GD patients. Short- and long-term side effects of RAI treatment in pediatric GD were very rare. Reported long-term side effects were benign thyroid nodules, multinodular benign goiter, hyperparathyroidism, and papillary thyroid carcinoma. These side effects affecting thyroid tissue were only reported in cases in which the RAI treatment aim was euthyroidism. However, it has not been proven that the abovementioned long-term side effects are caused by low-level thyroid irradiation. Overall, the data in this systematic review show that RAI aiming at hypothyroidism of the thyroid seems a safe definitive treatment option for pediatric GD. Evidence for the best dosing strategy to reach hypothyroidism after RAI treatment is still weak as only 2 retrospective studies evaluated the efficacy of different RAI activities [25, 28].
Ideally, the optimal RAI activity should result in 100% efficacy without significant short- or long-term side effects. Based on the 2 studies reporting the effects of different RAI activities aiming at hypothyroidism, an activity of 11 MBq but possibly a little >15 MBq per gram of thyroid tissue leads to an efficacy of 85–94% [25, 28]. In addition, Kaplowitz et al. [33] stated that a higher RAI activity was associated with a higher likelihood of hypothyroidism (8.95 vs. 7.84 MBq per gram of thyroid tissue; p = 0.013). Interestingly, none of the studies aiming at hypothyroidism reached 100% efficacy, meaning that a minority of patients may require a second RAI treatment to achieve hypothyroidism. However, one may be reluctant to prescribe higher RAI activities for treatment of a benign thyroid disorder like GD as RAI has, at least theoretically, been associated with an increased risk of development of malignancies in other tissues than the thyroid later in life.
Recently, an association was reported between RAI treatment for benign adult thyroid disease and an increased risk of death from breast or gastric cancer many years later [37]. However, these results have been heavily criticized, and studies on this association in children are lacking [38]. Nevertheless, one should be prudent using higher RAI activities in the treatment of pediatric GD because of the (theoretical) risk of RAI-induced cancers later in life. None of the studies included in this review reported nonthyroidal malignancies or leukemia later in life, despite long-term follow-up after RAI treatment, up to 27 years in some studies [17, 19-21, 26]. Since all patients included in these 5 studies were treated with RAI between 1941 and 1973, new studies with a long follow-up are needed to determine the exact risk of secondary malignancies later in life after RAI treatment with dosing according to current treatment guidelines. The only reported case of malignancy was papillary thyroid carcinoma in a patient in whom RAI treatment aimed at euthyroidism [18]. Hypothetically, this side effect might not have occurred if treatment had aimed at thyroid destruction. Pediatric patients with differentiated thyroid carcinoma receive much higher activities of iodine-131 for remnant ablation after thyroidectomy [39], varying from 1,100 MBq (29,729 μCi) up to 7,400 MBq (200,000 μCi) in case of lung metastases. Even after the use of such high activities of RAI in pediatric differentiated thyroid carcinoma, an increased risk of secondary malignancies has thus far not been reported [40-42]. Therefore, one may assume that it is safe to apply somewhat higher activities than currently used for complete thyroid ablation in pediatric GD.
To our knowledge, this is the most extensive systematic review on the efficacy and short- and long-term side effects of RAI treatment in pediatric GD and therefore gives a good overview of the available data on outcome of RAI treatment in children and adolescents with GD. It is remarkable that in spite of the long history of RAI treatment in pediatric GD, the available studies only focused on activities administered and not on dosimetric parameters related to the actual radiation dose delivered to the thyroid. It is very well possible that individualization of administered RAI activity through more extensive dosimetry may not only increase efficacy but also minimize unnecessary exposure of other tissues than the thyroid. In many of the included studies, the procedure on determining or estimating thyroid weight was not fully explained. It is well known that in healthy children, thyroid size increases with age [43, 44], and that in pediatric GD patients, the thyroid is frequently symmetrically enlarged. In our opinion, when dosing RAI per gram of thyroid tissue, thyroid ultrasound by an operator experienced in thyroid ultrasound is the most reliable way to determine thyroid size in pediatric GD patients and should be performed prior to RAI treatment to calculate the desired RAI activity. A major limitation of our study is that we were unable to perform a meta-analysis on the efficacy of RAI treatment in pediatric GD patients as treatment goals changed over time, dosing regimens differed between and changed within studies, and original data were lacking. Endpoints for efficacy were not consistently defined across the included studies. As a result, it is difficult to compare efficacy between studies. Only 5 retrospective studies reported efficacy data on ablative RAI dose of which only 2 studies evaluated the efficacy of different RAI doses [25, 28]. Future prospective studies evaluating different RAI treatment strategies (fixed activity, calculated activity based on estimated thyroid weight, or activity based on full dosimetry) are needed to determine the best evidence-based RAI strategy for the treatment of pediatric GD. From the 5 studies in which RAI treatment specifically aimed at hypothyroidism [14, 25, 27, 28, 36], only the study by Azizi and Amouzegar [36] reported on long-term side effects of RAI treatment. In this study, the follow-up duration after RAI treatment was not fully specified, but was probably between 1 and 3 years. In the other 4 studies, the follow-up duration was not specified or reported to be <5 years, and authors did not mention long-term side effects. Although this does not mean that their presence or absence was not assessed, this may point to reporting bias.
In conclusion, based on the results of this review, RAI treatment is a safe definitive treatment option in pediatric GD. Both short- and long-term side effects of RAI treatment are very rare. However, new studies focusing on the long-term risk of RAI-induced malignancies are needed to evaluate risks associated with current treatment guidelines. Also, new well-designed prospective studies are essential to come to a well-founded RAI dosing strategy in pediatric GD patients. Yet, based on the few retrospective studies on this subject, RAI treatment seems to be effective in achieving hypothyroidism in the majority of treated patients when 11–15 MBq (approximately 300–400 μCi) iodine-131 per gram of thyroid tissue is administered.
For this type of study (systematic review), formal consent is not required.
The authors report that they have no conflicts of interest to disclose.
The authors did not receive any funding for the present work.
All authors conceived the idea of evaluating the efficacy and short- and long-term side effects of RAI treatment in pediatric GD patients. S.L.L. and C.F.M., and if necessary A.S.P.v.T., performed the literature search including title and abstract screening, full-text screening, and data abstraction. S.L.L., C.F.M., and A.S.P.v.T. discussed the abstracted data and took the lead in writing this review. All authors discussed previous versions of the manuscript and agreed to the submission of the final version.
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Hamburger JI . Management of hyperthyroidism in children and adolescents. J Clin Endocrinol Metab. 1985 May;60(5):1019–24.http://dx.doi.org/10.1210/jcem-60-5-1019.
Hamburger JI . Management of hyperthyroidism in children and adolescents. J Clin Endocrinol Metab. 1985 May;60(5):1019–24.http://dx.doi.org/10.1210/jcem-60-5-1019.)| false
Clark JD , Gelfand MJ, Elgazzar AH. Iodine-131 therapy of hyperthyroidism in pediatric patients. J Nucl Med. 1995 Mar;36(3):442–5.
Clark JD , GelfandMJ, ElgazzarAH. Iodine-131 therapy of hyperthyroidism in pediatric patients. J Nucl Med. 1995 Mar;36(3):442–5.)| false
Moll GW Jr , Patel BR. Pediatric Graves' disease: therapeutic options and experience with radioiodine at the University of Mississippi Medical Center. South Med J. 1997 Oct;90(10):1017–22.http://dx.doi.org/10.1097/00007611-199710000-00008.
Moll GW Jr , PatelBR. Pediatric Graves' disease: therapeutic options and experience with radioiodine at the University of Mississippi Medical Center. South Med J. 1997 Oct;90(10):1017–22.http://dx.doi.org/10.1097/00007611-199710000-00008.)| false
Rivkees SA , Cornelius EA. Influence of iodine-131 dose on the outcome of hyperthyroidism in children. Pediatrics. 2003 Apr;111(4 Pt 1):745–9.http://dx.doi.org/10.1542/peds.111.4.745.
Rivkees SA , CorneliusEA. Influence of iodine-131 dose on the outcome of hyperthyroidism in children. Pediatrics. 2003 Apr;111(4 Pt 1):745–9.http://dx.doi.org/10.1542/peds.111.4.745.)| false
Read CH Jr , Tansey MJ, Menda Y. A 36-year retrospective analysis of the efficacy and safety of radioactive iodine in treating young Graves' patients. J Clin Endocrinol Metab. 2004 Sep;89(9):4229–33.http://dx.doi.org/10.1210/jc.2003-031223.
Read CH Jr , TanseyMJ, MendaY. A 36-year retrospective analysis of the efficacy and safety of radioactive iodine in treating young Graves' patients. J Clin Endocrinol Metab. 2004 Sep;89(9):4229–33.http://dx.doi.org/10.1210/jc.2003-031223.)| false
Pinto T , Cummings EA, Barnes D, Salisbury S. Clinical course of pediatric and adolescent Graves' disease treated with radioactive iodine. J Pediatr Endocrinol Metab. 2007 Sep;20(9):973–80.http://dx.doi.org/10.1515/jpem.2007.20.9.973.
Pinto T , CummingsEA, BarnesD, SalisburyS. Clinical course of pediatric and adolescent Graves' disease treated with radioactive iodine. J Pediatr Endocrinol Metab. 2007 Sep;20(9):973–80.http://dx.doi.org/10.1515/jpem.2007.20.9.973.)| false
Nakatake N , Fukata S, Tajiri J. Prediction of post-treatment hypothyroidism using changes in thyroid volume after radioactive iodine therapy in adolescent patients with Graves' disease. Int J Pediatr Endocrinol. 2011 Nov 7;2011:14.http://dx.doi.org/10.1186/1687-9856-2011-14.
Nakatake N , FukataS, TajiriJ. Prediction of post-treatment hypothyroidism using changes in thyroid volume after radioactive iodine therapy in adolescent patients with Graves' disease. Int J Pediatr Endocrinol. 2011 Nov 7;2011:14.http://dx.doi.org/10.1186/1687-9856-2011-14.)| false
Enes Romero P , Martín-Frías M, de Jesús M, Caballero Loscos C, Alonso Blanco M, Barrio Castellanos R. [Efficacy of treatment with I(131) in paediatric Graves disease]. An Pediatr. 2014 Jan;80(1):16–20.http://dx.doi.org/10.1016/j.anpedi.2013.01.023.
Enes Romero P , Martín-FríasM, de JesúsM, Caballero LoscosC, Alonso BlancoM, Barrio CastellanosR. [Efficacy of treatment with I(131) in paediatric Graves disease]. An Pediatr. 2014 Jan;80(1):16–20.http://dx.doi.org/10.1016/j.anpedi.2013.01.023.)| false
Cohen RZ , Felner EI, Heiss KF, Wyly JB, Muir AB. Outcomes analysis of radioactive iodine and total thyroidectomy for pediatric Graves' disease. J Pediatr Endocrinol Metab. 2016 Mar;29(3):319–25.http://dx.doi.org/10.1515/jpem-2015-0333.
Cohen RZ , FelnerEI, HeissKF, WylyJB, MuirAB. Outcomes analysis of radioactive iodine and total thyroidectomy for pediatric Graves' disease. J Pediatr Endocrinol Metab. 2016 Mar;29(3):319–25.http://dx.doi.org/10.1515/jpem-2015-0333.)| false
Getsuwan S , Wiromrat P, Panamonta O, Panamonta M, Paireepinas S. Effectiveness and safety of radioactive iodine therapy in childhood Graves' disease in Khon Kaen, Thailand. J Med Assoc Thai. 2016 Aug;99(Suppl 5):S112–9.
Getsuwan S , WiromratP, PanamontaO, PanamontaM, PaireepinasS. Effectiveness and safety of radioactive iodine therapy in childhood Graves' disease in Khon Kaen, Thailand. J Med Assoc Thai. 2016 Aug;99(Suppl 5):S112–9.)| false
Wu VT , Lorenzen AW, Beck AC, Reid VJ, Sugg SL, Howe JR, et al.. Comparative analysis of radioactive iodine versus thyroidectomy for definitive treatment of Graves disease. Surgery. 2017 Jan;161(1):147–55.http://dx.doi.org/10.1016/j.surg.2016.06.066.
Wu VT , LorenzenAW, BeckAC, ReidVJ, SuggSL, HoweJR, . Comparative analysis of radioactive iodine versus thyroidectomy for definitive treatment of Graves disease. Surgery. 2017 Jan;161(1):147–55.http://dx.doi.org/10.1016/j.surg.2016.06.066.)| false
Kaplowitz PB , Jiang J, Vaidyanathan P. Radioactive iodine therapy for pediatric Graves' disease: a single-center experience over a 10-year period. J Pediatr Endocrinol Metab. 2020 Mar 26;33(3):383–9.http://dx.doi.org/10.1515/jpem-2019-0316.
Kaplowitz PB , JiangJ, VaidyanathanP. Radioactive iodine therapy for pediatric Graves' disease: a single-center experience over a 10-year period. J Pediatr Endocrinol Metab. 2020 Mar 26;33(3):383–9.http://dx.doi.org/10.1515/jpem-2019-0316.)| false
Sheline GE , Lindsay S, Mccormack KR, Galante M. Thyroid nodules occurring late after treatment of thyrotoxicosis with radioiodine. J Clin Endocrinol Metab. 1962 Jan;22:8–18.http://dx.doi.org/10.1210/jcem-22-1-8.
Sheline GE , LindsayS, MccormackKR, GalanteM. Thyroid nodules occurring late after treatment of thyrotoxicosis with radioiodine. J Clin Endocrinol Metab. 1962 Jan;22:8–18.http://dx.doi.org/10.1210/jcem-22-1-8.)| false
Pavia C , Villanueva J, Valls C, Mane S, Cedo J. Radioiodine therapy for Graves disease in adolescents: analysis of 11 patients. Endocrinologist. 2002 Jan–Feb;12(1):17–9.
Pavia C , VillanuevaJ, VallsC, ManeS, CedoJ. Radioiodine therapy for Graves disease in adolescents: analysis of 11 patients. Endocrinologist. 2002 Jan–Feb;12(1):17–9.)| false
Azizi F , Amouzegar A. Management of thyrotoxicosis in children and adolescents: 35 years' experience in 304 patients. J Pediatr Endocrinol Metab. 2018 Jan 26;31(2):159–65.http://dx.doi.org/10.1515/jpem-2017-0394.
Azizi F , AmouzegarA. Management of thyrotoxicosis in children and adolescents: 35 years' experience in 304 patients. J Pediatr Endocrinol Metab. 2018 Jan 26;31(2):159–65.http://dx.doi.org/10.1515/jpem-2017-0394.)| false
Kitahara CM , Berrington de Gonzalez A, Bouville A, Brill AB, Doody MM, Melo DR, et al.. Association of radioactive iodine treatment with cancer mortality in patients with hyperthyroidism. JAMA Intern Med. 2019 Aug 1;179(8):1034–42.
Kitahara CM , Berrington de GonzalezA, BouvilleA, BrillAB, DoodyMM, MeloDR, . Association of radioactive iodine treatment with cancer mortality in patients with hyperthyroidism. JAMA Intern Med. 2019 Aug 1;179(8):1034–42.)| false
Greenspan BS , Siegel JA, Hassan A, Silberstein EB. There is no association of radioactive iodine treatment with cancer mortality in patients with hyperthyroidism. J Nucl Med. 2019 Nov;60(11):1500–1.http://dx.doi.org/10.2967/jnumed.119.235929.
Greenspan BS , SiegelJA, HassanA, SilbersteinEB. There is no association of radioactive iodine treatment with cancer mortality in patients with hyperthyroidism. J Nucl Med. 2019 Nov;60(11):1500–1.http://dx.doi.org/10.2967/jnumed.119.235929.)| false
Lebbink CA , Dekker BL, Bocca G, Braat AJAT, Derikx JPM, Dierselhuis MP, et al.. New national recommendations for the treatment of pediatric differentiated thyroid carcinoma in the Netherlands. Eur J Endocrinol. 2020 Oct;183(4):P11–18.http://dx.doi.org/10.1530/EJE-20-0191.
Lebbink CA , DekkerBL, BoccaG, BraatAJAT, DerikxJPM, DierselhuisMP, . New national recommendations for the treatment of pediatric differentiated thyroid carcinoma in the Netherlands. Eur J Endocrinol. 2020 Oct;183(4):P11–18.http://dx.doi.org/10.1530/EJE-20-0191.)| false
Chow SM , Law SC, Mendenhall WM, Au SK, Yau S, Mang O, et al.. Differentiated thyroid carcinoma in childhood and adolescence-clinical course and role of radioiodine. Pediatr Blood Cancer. 2004 Feb;42(2):176–83.http://dx.doi.org/10.1002/pbc.10410.
Chow SM , LawSC, MendenhallWM, AuSK, YauS, MangO, . Differentiated thyroid carcinoma in childhood and adolescence-clinical course and role of radioiodine. Pediatr Blood Cancer. 2004 Feb;42(2):176–83.http://dx.doi.org/10.1002/pbc.10410.)| false
Mihailovic J , Nikoletic K, Srbovan D. Recurrent disease in juvenile differentiated thyroid carcinoma: prognostic factors, treatments, and outcomes. J Nucl Med. 2014 May;55(5):710–7.http://dx.doi.org/10.2967/jnumed.113.130450.
Mihailovic J , NikoleticK, SrbovanD. Recurrent disease in juvenile differentiated thyroid carcinoma: prognostic factors, treatments, and outcomes. J Nucl Med. 2014 May;55(5):710–7.http://dx.doi.org/10.2967/jnumed.113.130450.)| false
Tamam M , Uyanik E, Edís N, Mulazimoglu M, Ozpacaci T. Differentiated thyroid carcinoma in children: clinical characteristics and long-term follow-up. World J Nucl Med. 2020 Jan–Mar;19(1):28–35.http://dx.doi.org/10.4103/wjnm.WJNM_15_19.
Tamam M , UyanikE, EdísN, MulazimogluM, OzpacaciT. Differentiated thyroid carcinoma in children: clinical characteristics and long-term follow-up. World J Nucl Med. 2020 Jan–Mar;19(1):28–35.http://dx.doi.org/10.4103/wjnm.WJNM_15_19.)| false
Ueda D . Normal volume of the thyroid gland in children. J Clin Ultrasound. 1990 Jul–Aug;18(6):455–62.http://dx.doi.org/10.1002/jcu.1870180602.
Ueda D . Normal volume of the thyroid gland in children. J Clin Ultrasound. 1990 Jul–Aug;18(6):455–62.http://dx.doi.org/10.1002/jcu.1870180602.)| false
Garcia-Ascaso MT , Ares Segura S, Ros Perez P, Pineiro Perez R, Alfageme Zubillaga M. Thyroid volume assessment in 3–14 year-old Spanish children from an iodine-replete area. Eur Thyroid J. 2019 Jul;8(4):196–201.
Garcia-Ascaso MT , Ares SeguraS, Ros PerezP, Pineiro PerezR, Alfageme ZubillagaM. Thyroid volume assessment in 3–14 year-old Spanish children from an iodine-replete area. Eur Thyroid J. 2019 Jul;8(4):196–201.)| false
A.S. Paul van Trotsenburg and Christiaan F. Mooij contributed equally.
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Graves' disease; Pediatric Graves' disease; Radioactive iodine; Side effects
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Emily D Ickinson Essay
Although Emily Dickinson is considered one of America's utmost poets, she was not regarded as a key force until the twentieth century when modern readers recognized Dickinson's work as groundbreaking and unprecedented by any of the time. Dickinson was not recognized in the nineteenth century because when she died at fifty-six years of age, only a few friends and relatives knew of the nearly two thousand, of which only 12 were published anonymously, poems that went unpublished. Dickinson did not base her writing style on writers who preceded her. However, her knowledge of the bible, classical myths, and Shakespeare aided Dickinson to create allusions and references in her poetry. She also transformed popular church hymns from standard rhythms to free-form hymn meters, a depiction of her inventive originality. Her originality has not always been understandable. Dickinson was noted as "the most paradoxical of poets: the very poet of paradox" (Johnson, 26).On December 10, 1830 Emily Elizabeth Dickinson was born in Amherst Massachusetts. She was the second child of Edward and Emily Norcross Dickinson; Emily had an older brother William Austin Dickinson and a younger sister Lavinia Norcross Dickinson. Dickinson's Mother was not a significant presence in her life, as she appeared to have been rather emotionally inaccessible. However, her father headed the quiet, reserved household. Donoghue states Edward Dickinson "was a dedicated Whig, and a resolute defender of temperance. As a parent, he was somewhat harsh, or at best remote" (6). Because of her parent's religious background, Dickinson's parents raised her to be a good Christian woman who would one day have a family of her own. In fact, her father sheltered her from books he viewed as harmful to her mind and religious faith. However, Dickinson did not conform to the society in which she was raised. At any rate, the Dickinson's were a prominent family in Amherst.Dickinson's grandfather Samuel Fowler Dickinson graduated from Dartmouth Law School in 1795 when he was twenty years old. And he went on to establish a law practice in Amherst, to found, in 1814, the Amherst Academy, and in 1821 co founded Amherst College. Her father received his law degree from Yale University and became one of Amherst's leading attorneys as well as a highly regarded community leader serving in the Massachusetts state senate, the United States House of Representatives, and as both attorney and treasurer of Amherst College. Dickinson's mother was rather quiet but active in the community of Amherst although she was not in a leadership role as was her husband (Donoghue, 6). Dickinson's family status, her father being a successful attorney as well as a local and state politician, likely attributed to her extensive formal education not usually granted to females of her time.Dickinson attended secondary school at Amherst Academy from the years 1840 to 1847; while there she excelled in botany and horticulture. Dickinson then went to...
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The cowboy "westerns" out of Hollywood left us with the narrative of the "man on a white horse" – the hero – riding into town to save the hapless citizens who'd been held at ransom by the "bad guy" – who, of course, rode a black horse! It was an update on the medieval "knight in shining armour" who would save the "damsel in distress" – held in captivity by the inevitable dastardly "bad guy".
You can take your pick, dear reader, in deciding which role President Granger was playing when he sat down with the Teachers Union at the eleventh hour of another strike that was being considered. After almost a year of playing "hold me; loose me" politics, was Granger's offer going to break the chains of subsistence wages that were keeping teachers imprisoned in penury? Your Eyewitness hardly thinks so…his 10 per cent for 2016 and eight per cent for 2018 is a far cry from the 40 per cent Granger's own task force had offered – and which was quite close to the 50 per cent demand of the teachers.
The teachers, of course, have a basis of comparison – the precedent set by the President when he awarded his Ministers that 50 per cent increase in salaries, just as they assumed office. And that was 50 per cent plus on hundreds of thousands of dollars – and not the measly fifty thousand of the average teacher!! But going back to the analogies cited above, the question arises: if Granger's trying to be the hero on the white horse, who was the villain on the black horse who'd held the teachers in Babylonian-like captivity??
The role had been played by Minister in the Social Protection Ministry responsible for the Department of Labour, Keith Scott, assisted by his sidekick, the taciturn Education Minister. He'd accused the teachers of being "selfish and uncaring", and generally treated them with contempt. The Education Minister was generally given to sneering ominously at the teachers across the table when negotiating with them!!
But let's get real, dear readers. Do any of you really believe Keith Scott was acting on his own? The man doesn't even sit in Cabinet, according to Granger, and is basically an errand boy. The position on teachers' salaries from the Government side was set by Granger himself when he rejected his task force recommendation as being "deficient"! And who do you think made the decision to reject the teachers' nominees for Arbitral Chair – all ex-PNC big wigs? Scott and Henry?? Pleeease!!
Granger's playing a "double role" and trying to ride two horses – white and black – simultaneously. The teachers shouldn't let him get away with it.
Nothing less than 40 per cent is acceptable!! Break those chains!!
Winston Jordan was a faceless bureaucrat toiling away in the backrooms of finance-related governmental institutions from 1981 when he was at State Planning Secretariat. He lucked out on the Finance Ministry job because Granger didn't want his competitor for the PNC leader position – Carl Greenidge – to occupy that critical job!
So Jordan stoutly accepted his charge. But from the beginning of his tenure, even well-wishers concluded he was clearly out of his depth. And as Guyana begins its transition to an oil-producing nation, this has become even more troubling. But don't tell Jordan that!! The Stabber tried and Jordan zinged right back at them!! Referring to the Stabber harping on his senior staff leaving, Jordan wrote, "Stabroek News itself is not immune to an exodus of skills, including competent editors and senior reporters, which is sadly apparent in the decline of its journalism over the past decade"!!!
But isn't this sly riposte exactly that?


text:
Q: How do I prevent large horizontal gaps when aligning? The closest solution to what I'm looking for that I've been able to come up with so far is this
\[
\begin{align*}
A & = & B & C\\
& = & B & (D\\
& & + & E)
\end{align*}
\]

which produces this

Now that's fairly close to what I'm intending. D and E are fairly large expressions, so I have to put them on separate lines and having them aligned like this is aesthetically quite pleasing. But there's this mysterious gap between the equal signs and the B's. Is there a way to get rid of that? Or perhaps a wholly different approach to typesetting this?

A: I'm not sure I've understood what you want to do, but I'd go for something like this:
% My standard header for TeX.SX answers:
\documentclass[a4paper]{article} % To avoid confusion, let us explicitly
                                 % declare the paper format.

\usepackage[T1]{fontenc}         % Not always necessary, but recommended.
\usepackage[utf8]{inputenc}      % Not always necessary, but recommended.
% End of standard header.  What follows pertains to the problem at hand.

\usepackage{amsmath}

\begin{document}

An example:
\begin{equation}
    \begin{split}
        A &= \text{1st fairly large expr.}\cdot C \\
            &=\text{1st fairly large expr.} \cdot
            \begin{aligned}[t]
                & (\text{2nd fairly large expr.} \\
                & \quad + \text{3rd fairly large expr.})
            \end{aligned}
    \end{split}
\end{equation}
This assumes that you want to label the whole block with a single
equation number.

\end{document}

This is the output:

Another option
If you want each line to be numbered, use alignat:
% My standard header for TeX.SX answers:
\documentclass[a4paper]{article} % To avoid confusion, let us explicitly
                                 % declare the paper format.

\usepackage[T1]{fontenc}         % Not always necessary, but recommended.
\usepackage[utf8]{inputenc}      % Not always necessary, but recommended.
% End of standard header.  What follows pertains to the problem at hand.

\usepackage{amsmath}

\newcommand*{\myexpr}[1]{%
    \langle\text{#1 fairly large expr.}\rangle
}

\begin{document}

An example:
\begin{equation}
    \begin{split}
        A &= \myexpr{1st} \cdot C \\
            &= \myexpr{1st} \cdot
            \begin{aligned}[t]
                & (\myexpr{2nd} \\
                & \quad + \myexpr{3rd})
            \end{aligned}
    \end{split}
\end{equation}
This assumes you want to label the whole block with a single equation number.
Individual lines can be numbered with the help of the \texttt{alignat}
environment:

\begin{alignat}{2}
    A &= \myexpr{1st} && \cdot C \\
        &= \myexpr{1st}
            && \cdot (\myexpr{2nd} \notag \\ % no number on this line
        &   && \mathbin{\hphantom{\cdot}} \quad {} + \myexpr{3rd})
\end{alignat}
We've also shown how to suppress the equation number on a particular line.

\end{document}

Note how the nature of binary operator of the phantom \cdot is preserved, so that it is properly spaced.
The output is:

A: Here are two options:

\documentclass{article}

\usepackage{amsmath}

\begin{document}

Option 1:
\begin{align*}
  A = {} & B C \\
    = {} & B (D \\
         & \phantom{B} + E)
\end{align*}

Option 2:
\begin{align*}
  A &= B C \\
    &= B (D \\
    &\phantom{{}= B} + E)
\end{align*}

\end{document}

Since you're splitting the parentheses across multiple lines, you can't use \left-\right. For more on this, see How to make \left, \right pairs of delimiter work over multiple lines?


SRK and Aamir are caught in a candid and hilarious moment with Gulshan Grover.
Memories are always to cherish and this hilarious throwback picture of Bollywood's superstars Shah Rukh Khan and Aamir Khan will sure bring a smile on your face. A photo of Aamir, SRK and Bollywood's bad boy Gulshan Grover has surfaced over the internet and gone viral in no time.
In this throwback photo, SRK and Gulshan are attempting to kiss a girl who is none other than Aamir dressed as a woman. The hilarious picture is a behind-the-scenes photo from the making of Ashutosh Gowariker's directorial 'Baazi', which hit the screens in 1995.
In Baazi, Aamir Khan had played the role of a police officer who goes undercover as a woman to get into the roots of a conspiracy and blow it. Aamir's infamous song 'Dole Dole' where he is dressed as a woman is actually from this movie.
Meanwhile, on the work front, Aamir Khan will next be seen playing a Thug in Vijay Krishna Acharya's directorial Thugs Of Hindostan. This action-adventure film also features Amitabh Bachchan, Fatima Sana Shaikh, and Katrina Kaif and is slated to release on November 7.
Shah Rukh Khan, on the other hand, has been busy shooting for Aanand L Rai's Zero in the USA. In this film, SRK will be seen playing a vertically challenged character (a dwarf) for the first time. The film also features Katrina Kaif and Anushka Sharma in the lead roles.


text:
Friday May 25, 2018
Flip van der Merwe slams ban after pushing referee out the way
Clermont second row Flip van der Merwe was suspended for four weeks for pushing the referee out of the way in a recent French Top 14 match. This week he took to Twitter to express his disappointment in the decision, and in what rugby has become.
"I love rugby, but I do hate what it has become! 4 weeks for this? #getoutofmyway" tweeted the 36-times capped Springbok, along with the video.
In doing so, Van der Merwe shed light on the incident and received a large amount of support, with most echoing his sentiments on what was unfortunate but also appeared fairly innocuous.
Laying your hands on a referee is, of course, frowned upon and should never be done, it would appear that in this case he was merely moving the official out of the way as he was clearly blocking the lock's entrance to the breakdown.
While perhaps he could have been gentler, the referee himself was not particularly bothered, and he and Van der Merwe had a very brief chat about it at the time, with no on field sanction given.
Some former players joined Van der Merwe in condemning the ban, most agreeing that it is harsh.
Hang in @flipvandermerwe if it whas me it whas 8 weeks. I'm happy I retired become a joke now. Take care. ????????
— Bakkies Botha (@BakkiesBotha4) May 25, 2018
That can't be right & it's a joke if you got 4 weeks for that?
@brettgosper
— Warren Brosnihan (@WarrenBroz) May 25, 2018
"Crazy" tweeted Victor Matfield, while Bakkies Botha joked that if it were him, it would have been an eight week ban. Botha went on to say that he is happy he's retired now, because [this type of thing] has become a joke.
This follows recent similar comments by James Haskell, who said that rugby is becoming a 'pretty pathetic sport', after he was penalised for a questionable high tackle.
It's not the first time we've seen players in trouble for pushing referees.
In 2009 Brian Mujati infamously received a 6-week ban for pushing Nigel Owens, while in that same year flanker Neil Best was yellow carded for pushing George Clancy.
In 2014 big Ben Tamiefuna was suspended for 5 weeks for pushing Glen Jackson, then in 2017 Worcester Warriors prop Val Rapava Ruskin was suspended for 6 weeks for his shove of referee Greg Garner.
So while those are heavier bans than what Van der Merwe got, the incidents themselves are all slightly different. Is the ban fair or are things getting a bit ridiculous? Let us know what you think
I love rugby, but I do hate what it has become!! 4 weeks for this? #getoutofmyway pic.twitter.com/lyT0H3ZOly
— flip van der merwe (@flipvandermerwe) May 24, 2018
Posted By: Grant Constable


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