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U.S. Census Bureau May Delay Data Release If Forced to Disclose Records – NBC10 Philadelphia
The U.S. Census Bureau could be forced to delay even further the release of redistricting data used for drawing congressional and legislative districts if it's ordered to disclose more records in response to a lawsuit, the agency's chief scientist said in court papers this week.
The redistricting data is set to be made public by the middle of next month. That could be postponed by as much as six additional months, however, if the statistical agency is ordered to release more records dealing with how it counted people living in what it refers to as "group quarters," Census Bureau Chief Scientist John Abowd said in a declaration.
The bureau designates group quarters as dormitories, prisons, nursing homes and group homes.
The release of the redistricting data already was postponed by five months from its original March 31 deadline because of delays caused by the coronavirus pandemic, sending states scrambling to revise redistricting deadlines. Two states, Ohio and Alabama, sued the Census Bureau in an unsuccessful effort to get it to release the data before August.
"The effect on the schedule for delivering redistricting data would likely be substantial," Abowd said of any potential order to disclose further group quarter records.
The Republican advocacy group, Fair Lines America Foundation, sued the Census Bureau in a public records lawsuit for information about how the census count was conducted in group quarters. The group says it's concerned about the accuracy of that count and wants to make sure anomalies didn't affect the state population figures used for divvying up congressional seats among the states.
The group facilities were among the most difficult places to count people during the 2020 census because the pandemic forced colleges to shutter dorms and send students home, and nursing homes and other facilities restricted access in an effort to protect vulnerable residents from the virus.
Abowd said that if the Census Bureau is required to release additional records as part of the Fair Lines lawsuit it will need as much as six months to recalibrate a new statistical tool meant to protect people's privacy so that they can't be identified through the data.
Delaying the release of the redistricting data past Aug. 16 could get the Census Bureau in trouble with a federal court in Ohio. As part of a settlement of the state of Ohio's lawsuit, the Census Bureau promised to release the redistricting data no later than Aug. 16.
The privacy method adds calibrated error to the data, most noticeably at small geographic levels such as neighborhood blocks, in order to prevent people being identified by high-powered computers through matches with third-party data such as voting records or credit card data.
Because of the privacy method, data at the neighborhood block-level may look "fuzzy," with weird situations such as blocks showing children living with no adults or the number of people not matching the number of housing units in a block, acting Census Bureau director Ron Jarmin said Wednesday in a blog post.
Jarmin said that blocks should be added together to produce accurate results.
"Though unusual, situations like these in the data help confirm that confidentiality is being protected," Jarmin said.
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School Council
The aim of the School Council is to promote citizenship and to give the children a voice within the school.
The School Council encourages the children to develop a sense of responsibility towards their community and an understanding of the democratic process.
Each class elects two children to represent them on the School Council. The School Council meets with Mrs Hatswell to discuss school issues, raised by both children and staff. After meetings, School Council members report back to their classes.

subset: commoncrawl


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The Nikon D7100 doesn't come with a memory card as standard. Some retailers put together bundles that include a few accessories–sometimes including a memory card–but if you haven't gotten one of those bundles, chances are you'll need to pick up an SD card separately.
But you'll find that the instruction manual isn't especially helpful in guiding you to a good choice in SD cards. So I'm hoping to make things easier by giving a rundown of what to look for in SD cards for the Nikon D7100, along with providing some practical recommendations.
Best SD Cards for the Nikon D7100: Quick Recommendations
If you're just after some quick recommendations so you can get on with shooting asap, here you go. These are usually pretty easy to find at major retailers, come from reliable manufacturers, and are cost-effective.
- Video Speed Class: U1
- UHS Speed Class: UHS-I
- Storage Capacities: 32GB, 64GB, 128GB, 256GB
- Video Speed Class: V30
- UHS Speed Class: UHS-I
- Storage Capacities: 32GB, 64GB, 128GB, 256GB
- Video Speed Class: V30
- UHS Speed Class: UHS-I
- Storage Capacities: 32GB, 64GB, 128GB, 256GB, 512GB
Recommended Memory Cards for the Nikon D7100: The More Detailed Version
First, the basics. The Nikon D7100 takes SD cards. That's the larger of the SD sizes; there's a smaller microSD size that often used in action cameras, smartphones, and gaming devices.
The D7100 has two memory card slots (or dual slots), and you have some options in how those slots are used. You don't have to fill both slots if you don't want to–it'll work just fine with only one memory card–but using two opens up some useful features.
For example, the "overflow" option uses them in sequence, automatically rolling over to the card in slot 2 when the card in slot 1 is full. The "backup" option lets you create duplicate copies at the time you take the photo, one on each card. And, finally, Or you can designate a JPEG version of the image to save to one card while a RAW version is saved to the other (the "RAW slot 1 – JPEG slot 2" option). You can also designate which slot is used for recording video.
The D7100 is compatible with both SDHC and SDXC memory cards. When it comes to buying memory cards, the practical difference is that SDHC cards are 32GB or smaller, while SDXC cards are 64GB or larger. In fact, the difference is more technical–those two specifications refer to the filesystem they're formatted with–the SDHC specification uses FAT32 formatting, while the SDXC specification uses exFAT–but when it comes to buying memory cards, the practical difference is that cards 32GB and smaller will be labeled SDHC and cards 64GB and larger will be labeled SDXC.1
The D7100 is an older camera now, and compared to newer cameras it's not especially demanding on the speed requirements of the memory cards you put in it. The most intensive process is when it's recording video. When shooting photos, the camera will take advantage of its own internal buffer memory. This is a temporary memory space where photos can be stored while they're waiting in the queue to be written to the memory card. Depending on the file format you're saving the photos in, you can get up to 100 photos in the memory buffer (or as few as 6 if you're shooting in NEF lossless compressed 14-bit mode). Once the buffer is full, you'll notice a slowdown as the camera has to wait for images to be written to the memory card (writing to the memory card is much slower than writing to the internal buffer).
With video, it works a little differently. That's because there's no opportunity for the camera to stop and wait with video. If the internal buffer were to fill up, there's no way to slow down the shutter speed to wait for the card to catch up. So you'll need a card that can handle a constant stream of data being written to it quite quickly (known as sequential write speed).
Put another way, when shooting still photos, having an SD card that's fast enough is mostly about convenience. But when it comes to shooting videos, it's essential.
That said, the D7100 was released back in February 2013. Since then, memory card manufacturers have been releasing ever faster cards. The upshot is that it's easy these days to find a card that's fast enough, and you don't need to stress the wallet to do it.
It's also worth pointing out that there's no need to get the latest and greatest (and that usually means expensive) SD cards for the D7100. By all means, use them if you want or if you already have them on hand–you won't do any harm, but you also won't see much meaningful benefit from it in the camera.2
Nikon's Officially Approved Memory Cards for the Nikon D7100
Nikon's instruction manuals (or those from many camera manufacturers, for that matter) are not especially helpful in suggesting which memory cards work best in the camera. It's not really their fault–they can't keep the manual updated constantly as new memory cards come out.
For the D7100, this is their guidance for Approved Memory Cards (from p.347 of the manual:
Finding a card that's class 6 or faster is easy these days because memory card specs have moved well beyond class 6. In fact, you'll be hard-pressed to find a card that's not at least class 10 now.
Recommended Memory Cards for the Nikon D7100
With Nikon's guidance in mind, combined with the findings from my own real-world speed tests of SD cards, here are some specific, practical recommendations for memory cards to use in the Nikon D7100. I've updated this to account for current models of memory cards that you should be able to find pretty easily.
My emphasis here is on cards that meet the requirements to use all of the camera's features, are readily available at major retailers, and are cost-effective. But these are by no means the only SD cards that will work in the D7100. My objective here, after all, is to help choose a good card that works so you can get on with the fun stuff, not to catalog every possible card that works in this camera. I have, however, tried to include a few different brands in case you have your own preferences for brands or some are easier to find in some locations than others.
These aren't necessarily the fastest SD cards on the market, but they're fast enough for this camera. This isn't necessarily a comprehensive list of every SD card that will work in this camera—there are also others that might work well, too.
My emphasis here is on cards that meet these criteria:
- fast enough for all the features of this camera
- from a reputable and reliable brand
- readily available at retailers
- good value for money
If you want to use a faster, fancier card you can, but you won't see any extra benefit in doing so while you're operating the camera (but you might see some faster speeds when downloading the photos to a computer, depending on your computer and memory card reader combination).
SanDisk Ultra U1 UHS-I
- Great choice for compact to mid-range point-and-shoot cameras
- Quick transfer speeds up to 150MB/s (Up to 150MB/s read speed engineered with proprietary technology to...
The SanDisk Ultra line is their cost-effective mid-range option. The latest versions of the Ultra cards are much faster than older versions, and it's a good basic option for cameras that don't demand too much of their SD card. The next level up—the Extreme cards—are also a good option, but the Ultra cards are often priced slightly lower. They're usually very easy to find in stores, too.
SanDisk recycles its model names, and you can still find older, slower versions with the Ultra name. This latest version of the Ultra card is rated for U1 for video recording and uses a UHS-I interface.
It comes in sizes ranging from 64GB up to 512GB.
Buy at: Amazon
Lexar 633x V30 UHS-I
- High-speed, Class 10 performance leverages UHS-I (U1 or U3 depends on capacity) technology for a read...
- Capture high quality images of stunning 1080p full-HD, 3D, and 4K video
The Lexar 633x range has been one of the mainstays of Lexar's SD cards for a while now. There are now faster cards available, but this one is again fast enough for this camera while also representing good value for money.
One distinctive thing about this range is that they're available from 32GB up through `TB.
Buy at: Amazon.
Kingston Canvas Select Plus V30 UHS-I
- Faster speeds — Class 10 UHS-I speeds up to 100MB/s.
- Capture in full HD & 4K UHD video (1080P) — the advanced UHS-I interface makes the card ideal for...
Kingston is a brand that isn't as well known as some of the others, but they've been making reliable memory cards for a very long time. As a brand, they don't tend to focus on the cutting edge speeds but rather on reliable and good-value memory cards.
This particular card (model SDS2 Canvas Select Plus) isn't the fastest in Kingston's range, but it's fast enough to work well in this camera. It's available in sizes from 16GB through 128GB.
PNY Elite-X V30 UHS-I
- Class 10 U3 V30 speed rating with read speeds up to 100MB/s
- Class 10 U3 V30 rating delivers speed and performance for burst mode HD photography and 4K Ultra HD...
PNY is another brand that isn't as well known as some others, but they've been around a long time and make very good memory cards that are usually very competitively priced and good value.
This particular model is available in sizes ranging from 64GB to 512GB.
Buy at: Amazon
Delkin Devices Advantage V30 UHS-I
- Supports 4K & Full HD 1080p Video Recording at High Frame Rates
- RAW Continuous-Shooting Approved
Delkin Devices have been around for a long time, but they've had something of a resurgence in recent years after simplifying their product lineup and updating the performance of their cards up to current specs.
This card is on the lower end of their range, but it works well in this camera without the higher price point of the faster cards. The Advantage card is rated to V30 and has a UHS-I interface. It currently comes in sizes up to 512GB.
Other Brands
There are also a lot of smaller, mostly unknown brands. In general, I'd recommend sticking to a brand you know and trust or one of the brands I've mentioned on this page because they have well-established reputations for putting out high-quality cards. Some of the other lesser-known brands might work, but they also might not be all they claim to be. The ones above should give a good selection of ones you can find fairly easily at retailers near you.
Faster SD Cards
If you're looking to use a faster card, take a look at the ones that I've subjected to my independent SD card speed tests.
What Size Memory Card Works Best in the Nikon D7100?
You can use cards from 4GB up in the D7100, including some of the larger SDXC cards available these days in the 256GB+ range. Which size you choose to use comes down to convenience, your budget, and your own preferences. The larger the card, obviously, the more you can shoot before filling it up. That is one area where the dual slots of the D7100 come in handy, especially if you're using the overflow setting. You can quite often find that two smaller cards are less expensive than one larger one.
The size of the photo and video files created by the D7100 depends on what settings you're using. For instance, if you're shooting photos in the JPEG Normal setting, the files will be much, much smaller than if you're shooting in the 14-bit NEF mode.
The same goes for video. The top-end 1080p video modes are recorded at higher bitrates than lower-resolution modes, so those files will be much larger for a corresponding duration of footage.
Here are some estimates. These are based on Nikon's own figures, but bear in mind that they're only estimates. Any compressed formats will vary slightly from file to file–that's the nature of how these types of image compression work. So it's possible you might get a few more or a few less, and it's always a good idea to leave yourself some wiggle room. These figures refer to using the DX crop mode, the larger of the two crop modes available on the D7100; the files when using the 1.3x crop mode are significantly smaller.
|Quality Setting
|Size Setting
|File Size MB (approx)
|Buffer Capacity
|NEF (RAW), Lossless compressed, 12-bit
|NEF (RAW), Lossless compressed, 14-bit
|NEF (RAW), Compressed, 12-bit
|NEF (RAW), Compressed, 14-bit
|JPEG Fine
|JPEG Normal
|JPEG Basic
Do You Need to Fill Both Memory Card Slots in the D7100?
No, it will work just fine with only one SD card inserted–you don't need to fill both slots. Obviously, though, you won't be able to take advantage of some of the added features that depend on two cards, such as the overflow or backup recording features.
Do the Memory Cards Have to be the Same?
No, you can mix and match sizes and brands of the SD cards in each slot.
How to Format the SD Card in a Nikon D7100
While it's possible to format SD cards in a computer, it's much better practice to format them in the camera. That way the camera can set the card up exactly how it wants it, and it greatly reduces the risk of something going wrong.
There are two ways to format the memory cards in the d7100. The basic way is to use the menu system (Setup / Camera Setup > Format Memory Card).
There's also a two-button shortcut. I've outlined that method in detail for the D7500 here. The process is the same for the d7100, with the exception that you can choose which slot to format on the d7100 because it has two slots to the D7500's one.
How to Recover Photos if You've Accidentally Deleted Them
If you format the card before you've backed up the photos from it, it might still be possible to recover them. To do that you'll need to fire up the computer–it's not something that you can do in the camera. I've put together an overview on how to recover deleted photos from a memory card here.
Is it Normal for the Memory Cards to Get Hot?
Yes, it's quite normal for the SD cards to get hot after some intensive writing, such as when happens when shooting photos rapidly or recording video.
Popular Accessories for the Nikon D7100
- Compatible with Nikon D7500, D7200, D7100, D7000, D850, D750, D500, D810a, D810, D800e, D800, D610, D600,...
- Support data transfer and charger; 5 feet / 1.5 meter
- 【Two EN-EL15B Rechargeable Batteries】Each battery has 2200mAh REAL HIGH CAPACITY, performs the same...
- 【Multi-Function EN-EL15 Battery Charger】Upgraded Four-in-one charger case design. 1,) charge Nikon...
- Warning: This is a MANUAL Lens, NO Electronic Contacts, the camera will not detect the lens when mounted,...
- - FULL MANUAL FOCUS OPERATION: require complete manual focus operation on dslr camera to align with lens...
- Ideal viewfinder eyecup eyepiece for Nikon DSLR cameras
- Replaces Nikon DK-28 DK-25 DK-24 DK-23 DK-21 DK-20 eyecup
- LENS ATTACHMENT: Easily screws on to the front of your lens, and instantly expands the field of view for...
- LENS COMPATIBILITIES: Popular 52MM Lens models including Nikon AF-S DX NIKKOR 55-200mm f/4-5.6G ED VR II,...
- It is technically possible, using a computer, to format a card that's 32GB or smaller with exFAT or a card 64GB or larger with FAT32, but that goes against the specifications set by the SD Association. It can cause problems with some cameras, though, and you can end up with inconsistent results. And when you format the card in the camera, the camera reverts to the "correct" filesystem for the card. ↩
- The one place you might see some benefit is in saving photos from the in-camera buffer to the memory card more quickly. Depending on your setup, it is also possible that you might see faster download speeds from faster cards when you're downloading from the memory card to your computer using a fast memory card reader. ↩
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Our hospital is located across the street from the Saint Robert Municipal Center and the Saint Robert Police Station. After leaving Ft. Leonard Wood on Missouri Blvd. continue north one mile. Turn right at the third stop light (onto the road opposite Auto Zone) and continue straight approximately 1/2 mile. We are located in the red brick building with the red metal roof on the left. We are also located 4 miles from Waynesville.


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April 25th, 2016 by Yale Schalk / 0
Once a high-end alternate signature shoe for Michael Jordan during his 2002-03 season, Air Jordan 17+ "Copper" returned for its first retro release on April 9th. Smooth leather construction, croc skin detailing, and copper colored accents teamed up to create one of the classiest Jordans ever. If you missed the retail release, hook up pairs now at Stadium Goods.
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Shoe brand Bionda Castana reinvents itself with bespoke and zero-waste strategy
Luxury British brand Bionda Castana is relaunching this month after a two-year break with a an interesting new approach that it says will tackle the issue of unsold stock and help it cut waste.
Co-founders Jennifer Portman and Natalia Barbieri announced on Friday that the brand is starting a new chapter with a made-to-order approach. As well as cutting waste, this also underlines the importance of bespoke products as luxury sector growth continues to outstrip that of lower price points.
Each month, four limited-edition styles from the brand's archive will be available to buy via the Bionda Castana website. The brand will take orders from the first Wednesday of the month until the first Sunday, with the shoes being delivered to the consumer direct from a Milan-based factory within three weeks.
Each pair will be produced using surplus material from the Bionda Castana library, a move that will give the collections a "more accessible price point" than before.
"We felt it was imperative to balance the need to create alongside the absolute necessity to preserve our planet too," said co-founder Natalia Barbieri.
Before it ceased trading in 2016, the brand had many celebrity fans including Keira Knightley, Alexa Chung, Eva Mendes, Kate Bosworth and Jessica Alba. Global stockists included Harrods, Selfridges and Harvey Nichols, and it had a standalone boutique in London's Belgravia.
This November, Bionda Castana is bringing back its Lana, Nicole and Bay pumps, as well as the Denni flat.
Copyright © 2023 FashionNetwork.com All rights reserved.


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Top Chef Jeremy Ford, in partnership with Miami's premier boutique restaurant firm, Grove Bay Hospitality Group (GBHG), announced the highly anticipated opening of Stubborn Seed. The first of two concepts between the group and chef, the restaurant is open in the vibrant South of Fifth neighborhood at 101 Washington Avenue.
Ford, the season 13 winner of the nationally televised Bravo cooking competition, Top Chef, has turned his dream of opening his own restaurant into reality. "This concept has been years in the making and I'm stoked to finally be able to unveil what I've been cooking up," says Ford.
The 32-year-old chef, originally from Jacksonville, Florida, first developed a love for cooking after meeting his maternal grandmother when he was 14 years old. Throughout his career he has worked alongside some of the most celebrated chefs in the industry including South Florida chef Dean Max and Michelin-star celebrity chef, Jean-Georges Vongerichten.
"The passion that Jeremy has put into this project will be visible from every plate that comes out of the kitchen," says GBHG Co-CEO, Ignacio Garcia-Menocal. "At Stubborn Seed, guests can expect an up close and personal culinary experience with an exceptionally talented and creative chef guiding their journey," adds GBHG COO Eddie Acevedo. "The restaurant will offer an intimate, elevated yet approachable dining experience that will leave guests in awe," adds Co-CEO Francesco Balli.
Ford and his teami—which includes longtime friend, Chef Joe Mizzoni—play with different textures and flavors in the kitchen creating a rich menu with natural ingredients seasonally sourced. Servers guide guests through the rotating menu of seasonal specialties encouraging them to share and explore various dishes from the categories Raw, Snacks, Meats, Fish / Shellfish, and Others. Featured items can be ordered a la carte or diners can opt for the Chef's Tasting—a menu of seven courses —for a special experience. Highlights from Raw include a Jojo Tea Cured Snapper with sorrel, celery, clementine and hearts of palm and a stand-out crudo—Wahoo— with a spicy buttermilk dressing, jalapeño ferment, sea grapes and Asian pear. Olive oil and citrus braised Warm Celery Root will be a delightfully intense starter with crunchy maitake mushroom, alongside a mustard espuma topped with fresh herbs and flower blossoms. Main courses include an Herb Roasted Wagyu accompanied by trumpet mushroom, carrot textures, and mustard butter. Slowly Cooked Snapper with poblano, cucumber and lime littleneck clams and bitter lettuce "butter". Decadent desserts follow including a Corn Pavlova—corn custard topped with white meringue; Croustillant, a chocolate layer cake; Snickerdoodles—cookies with a gooey chocolate center; and Stout Cake accompanied by ginger ice cream.
The bar program is as exceptional as the cuisine with visually inventive cocktails such as the Desert Daisy presented in a unique sphere; Follow the Light with a web of candied sugar as a garnish; and the Half Baked with smoke emitting from a beaker-like glass.
Located on Miami Beach, the Washington Avenue locale was designed by New York-based, Celano Design Studio. The design is a mixture of influences with components reflecting the area's whimsical Art Deco aesthetic, along with 1970's inspired earth tones of rich browns and yellows with rust-colored accents throughout. Contemporary, industrial greys and exposed concrete complete the interior with an atmosphere that is relaxed, yet sophisticated – no white tablecloths. The intimate space seats only 74, guaranteeing it will be one of the most coveted reservations of the season.
News and information presented in this release has not been corroborated by WTWH Media LLC.


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In April 2008 I delivered a paper to the ACT Division of the Planning Institute of Australia about the threat of global warming. Some months later we were to have the Copenhagen Climate Conference that was to solve all humanity's problems. Many leaders said we had only a few weeks/months/years to save the planet. Al Gore, walking on stage to get his Nobel Peace Prize, barked to an interviewer that 'the science is settled!' Carbon dioxide in the atmosphere had been rocketing up, and so had seemed to be global temperature. So 2008 was a year where global warming was much on the national and international agendas. Our Prime Minister had already proclaimed that it was the most serious moral, economic and social challenge to humanity, or words to that effect.
My paper, which had grown out of a few years of close study of the issue, was profoundly sceptical of this apocalyptic talk. Yes, there might be something in it, but if you looked hard at the way the issue was set out you did begin to stroke your chin and shake your head. Above all, the data of all kinds were rubbery, spotty and inconclusive. For example, while the oceans make up a little more than 70 per cent of the earth's surface our knowledge of sea-surface temperatures for much of the 20th century depended on where ships sailed, and the measuring of sea-water temperature in leather buckets. The location of land-temperature measurement sites is (unsurprisingly) heavily dependent on where people, and indeed where people in wealthy countries live.
My address made it to the local paper, and I gave a couple of talks on the subject on Robyn Williams's 'Ockham's Razor' program, plus a few addresses to Rotary, farming and other organisations. At one of them the German science attaché took me aside after the talk and discussion, and almost wagged his forefinger at me. 'You are a senior figure,' he said. 'It is not right for you to say these things. The world is in great danger.' I replied, as politely as I could, that I was used to reading scientific papers and judging how valuable they were. What I had said was what I thought was the case, after a lot of reading. How much reading in the area had he done? The conversation ended somewhat abruptly. I had come across my first 'believer'. I was to meet many more, and argued with them too, twice in public.
Five years later I checked to see whether my judgments in 2008 were justified. They seemed to be. This year, the tenth anniversary, is a moment to look more comprehensively at the issue, and that requires two essays, of which this is the first. Two prefatory remarks are needed. The first is that a great deal more scientific work has been done in the past decade on the nature of 'global warming' and its running mate 'climate change'. But quite a lot of it now does not support the central tenets of the climate orthodoxy. The second is that the international and national urgency to address the issue has passed. Governments occasionally talk the talk, but where they can they have stopped walking the walk. The Paris Accord of two years ago is without teeth and is not much referred to any more, except by believers. And these two terms, 'global warming' and 'climate change', have nowhere near the salience they had ten years ago in the media (for Australian newspapers, for example, see here).
Nonetheless, those who believe that the planet is in great danger are still about, and if anything more worried than they once were, because they can perceive that by and large they do not have the political clout they used to have. Governments are in a bind, because they committed themselves to certain actions a decade or more ago and find it difficult now to get out of them. What we have is a kind of policy impasse. In 2008 I set out what I thought was the central proposition of the global warming issue. It is still the core of the scare.
Human activity in burning coal and oil, and clearing forests has, over the past century, put an enormous amount of carbon dioxide into the atmosphere where it has combined with water vapour and other gases like methane to increase global temperatures in an unprecedented way. The evidence that this has occurred is clear-cut, and the increase in temperature will have, according to our computer models, dire effects on the planet, causing the melting of polar ice, the raising of sea levels, droughts, floods, storms and desertification. We must put an end to this prospect by changing our way of life lest catastrophe strike us. It may already be too late.
I then listed what seemed to me the seven important assumptions built into this scenario. The first was
1. The extent to which the planet is warming
In 2008 it was commonly accepted that the 20th century had seen a rise in average global temperature of 0.6 ± 0.2 degrees Celsius. I pointed out then how imprecise the data were to support such numbers, but was prepared to accept a rough equivalent. One great problem with all this is the considerable warming that occurred in the first half of the 20th century, when the burning of fossil fuels was not as pronounced as it became later in the century. Attention has since been paid to the same metric for the 21st century. One reason is that the steady upward movement in temperature mimicking the rise in CO2 accumulations in the 1980s and 1990s flattened out quickly in the new century, though CO2 accumulations continued to rise steadily. Another was that much more notice is taken of satellite measurements, which only began in 1979, and are almost completely global in their coverage. You can see the trends at page 6 in Ole Humlum's Climate in 2017 paper, which is based on observations and the data from the five major climate datasets. Yes, temperatures began to rise again in the last three years, but they were accompanied by, if not caused by, the el Nino spike of 2016/7. They have begun to decline since, as the diagram below shows.
What we can say is that the approximately 1.5 degree C rise in temperatures in the last 150 or so years has been irregular. How much of this has been due to greenhouse gas emissions is moot. To this date no one has been able to distinguish the supposed CO2 'signal' from the noise in the climate system, though there have been some efforts (for example, here). The tendency is to try to measure what is thought to be known (volcanic eruptions, ENSO etc), and then suggest that what is left must be caused by greenhouse gas emissions, and therefore by human activity. Such a method implies that all components of natural variability are known and easily measured, which is quite unlikely to be the case.
In any case, the level of warming is not great, and plainly has cyclic aspects. We don't understand those very well, either.
2. Whether or not this warming is unprecedented
The allegedly 'unprecedented' nature of this warming is an important part of the global warming scare. If such warming never happened before, then it must be greenhouse gas emissions that have produced the warming. But what does 'unprecedented' mean? We have less than forty years of really good global data, and that's not nearly enough to say anything much. The rubbery data put together from all sorts of sources for the 20th century, and back to the 1880s (where the evidence is increasingly scant) shows a similar warming in the first half of the century to that in the second half.
The similarity must raise doubts. It is sometimes argued that the first warming period was due to natural variability and the second to greenhouse gas emissions. But, to make the point again, there is as yet no way of isolating greenhouse gas emissions from natural variability. We do know, or at least we can estimate pretty accurately, that there have been a lot more greenhouse gas emissions in the last forty years than there were in the 1900 to 1940 period. But then, if it wasn't greenhouse gas emissions, what caused the earlier warming period? And can some of the recent warming, or even most of it (a few sceptics would argue, all of it) be attributed to natural variability? If not, why not?
On the face of it, there is nothing at all unprecedented about the warming of the recent past. And it is well to remember that proxy data from ice cores, tree rings, sediments and the like suggest that there were past periods just as warm, or even warmer. The Romans enjoyed one around the time of the birth of Jesus Christ, and the Minoans much earlier enjoyed another, before they were wiped out, probably by a tsunami. Go to the beginning and consider Figure 3 in Ole Humlum's climate4you.com. The ice-core data come from Greenland. Of these four warm periods (the other is the mediaeval), our present day is much the coolest. OK, Greenland isn't the world…
[to be continued]


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California Health Sciences, University College of Pharmacy, Clovis, California
Received Date: June11, 2017; Accepted Date: June 28, 2017; Published Date: July 05, 2017
Visit for more related articles at Research & Reviews in Pharmacy and Pharmaceutical Sciences
Tricyclic antidepressants and SSRIs, prescribed for major depressive disorders, anxiety and/or neuropathic pain, are associated with therapeutic failures in approximately 40% of patients after initial dosing. Pharmacogenetic variances play a significant role in these failures and therefore, using genetic data in decision-making to personalize dosing may both enhance efficacy and reduce adverse effects. Polymorphisms affect several pharmacodynamic and pharmacokinetic variables that modulate efficacy and adverse effects; however, clinical data at this time most strongly associate variant diplotypes of cytochrome P450 (CYP) enzymes with potentially altered metabolism. Four potential patient phenotypes can result from these variants: normal-, poor-, and intermediate- and ultrarapid-drug metabolizers. Plasma concentrations of amitriptyline, nortriptyline and fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline are strongly influenced by the actions of two CYP450s: CYP2D6 and CYP2C19. These CYPs are two of the most polymorphic cytochromes. Pharmacogenetic genotyping of these CYPs has led to phenotype-guided TCA and SSRI recommendations, although current guidelines are limited to drugs with sufficient accumulated clinical evidence. Overall, these guidelines call for patients phenotyped as CYP2D6 or CYP2C19 poor or ultrarapid metabolizers to consider modifications such as dose adjustments or alternative antidepressants. Most newer antidepressants are not supported by the volume or strength of clinical data as are TCAs and SSRIs and thus fewer genomic-based guidelines exist for these newer drugs, although some recommendations are being made. Pharmacogenomic testing is likely to be most useful in early treatment and is limited by identification of known variants, sufficient clinical data sets, epigenetic factors such as pheno-conversion, other drugdrug interactions and comorbidities such as liver disease.
Pharmacogenetics, Pharmacogenomics, Single nucleotide polymorphisms, Metabolizers, CYP2D6, CYP2C19.
CPIC: Clinical Pharmacogenetics Implementation Consortium; CYP: Cytochrome P450; DPWG: Dutch Pharmacogenetics Working Group (Royal Dutch Pharmacist Association Pharmacogenetics Working Group); FDA: Food and Drug Administration (U.S.); NDRI: Norepinephrine and Dopamine Reuptake Inhibitor; PD: Pharmacodynamic; PK: Pharmacokinetic; SNP: Single Nucleotide Polymorphisms; SNRI: Serotonin Norepinephrine Reuptake Inhibitor; SSRI: Selective Serotonin Reuptake Inhibitor; TCA: Tricyclic Antidepressants.
Antidepressant medications of the tricyclic antidepressant (TCA) and selective serotonin reuptake inhibitor (SSRI) classes are prescribed for major depressive disorders, anxiety and/or neuropathic pain. Traditional empiric therapy with these classes has been associated with therapeutic failures in approximately 40% of patients after initial dosing and it is believed that pharmacogenetic variances play a significant role in these failures [1]. Therefore, personalizing antidepressant selection and dosing for individual patients could significantly enhance efficacy and/or reduce adverse effects. Personalized medicine, which has been characterized often as "the right patient with the right drug at the right dose at the right time" [1] is the use of genomic and other data to select a drug and/or a dose for a patient that will provide efficacy with minimal undesired toxicity when they first present with an illness. This strategy aims to improve upon the estimated 40 – 70% of drugs that are not initially effective or the approximately 7% which produce serious adverse effects [2]. Efficacy and adverse effects for an individual patient or population of patients are governed by both pharmacokinetic and pharmacodynamic drug properties [3]. Pharmacokinetics (PK), the effect of the body on drug, includes variables involved in absorption, distribution, metabolism and excretion (ADME). Pharmacodynamics (PD), the effect of drug on the body, encompasses targets such as receptors, enzymes, nucleotides, lipids, etc. The most reasonable approach to personalizing antidepressant therapy would involve accurate profiling of a patient's PD and PK as they pertain to specific antidepressants. This personalization could involve both understanding of genetic (such as gene sequences) as well as epigenetic factors (such as drug-drug interactions or liver disease). At this point in time, insufficient clinical data exists to completely personalize antidepressant therapies; however, pharmacogenomic data do now support potential dosing adjustments for some TCAs and SSRIs. This review begins with an overview of several pharmacologic variables that can in theory be used to guide personalized medication decisions for antidepressants followed by identification of metabolic enzymes that are being used now. Next, we provide a brief, general description of nomenclature relevant to pharmacogenomics and then current guidelines for specific antidepressants.
Variables that Affect Personalized Responses to Antidepressants
Ideally, pharmacogenomics should be applied to relevant aspects of both a patient's PD and PK. Of potential pharmacodynamic effectors relevant to antidepressants, the serotonin transporter linked polymorphic region, 5-HTTLPR, has been intensely studied; however, conflicting clinical responses do not presently allow strong enough evidence for dosing recommendations based on genetic variances and protein expression of this transporter [3]. Three other genes which encode proteins relevant to the PD of antidepressants have been investigated through large population clinical trials: the serotonin 2A receptor (HTR2A), the FK506 binding protein 5 and the glutamate receptor ionotropic, kainite 4 (GRIK4GluK4). As with the 5-HTTLPR transporter, conflicting clinical correlative results have prevented recommendations for dose adjustments [3]. Therefore, although PD effectors of antidepressant drugs should ideally be part of the basis of therapeutic decision making, available clinical evidence does not support use of variances in PD genes to predict clinical outcomes.
Of potential pharmacokinetic effectors, the cytochrome P450 (CYP) enzymes are the major family of drug-metabolizing enzymes that influence antidepressant metabolism. Genetic polymorphisms are generally common in drug metabolizing enzymes and particularly so in CYP enzymes [4]. CYP2D6 is considered the most relevant of the CYP enzymes and CYP2C19 the second most relevant CYPs for antidepressant metabolism [2]. Both are extensively polymorphic and have allelic frequencies that vary by ethnicity [5]. Clinical evidence backs the use of several variant alleles to guide dosing of some antidepressants [5-7].
Other pharmacokinetic effectors that ideally should be included in the pharmacogenomics of antidepressants are the protein transporters that allow antidepressants to cross from the brain capillaries into the neuronal tissues. These include the major P-glycoprotein, a 170-KDa glycoprotein encoded by the ABCB1 (ATP-Binding Cassette transporter, also known as MDR1 - multi drug resistance 1) gene. However clinical correlations between allele variants and clinical responses are not established sufficiently at the present time [3]. Therefore, in the field of antidepressant pharmacogenomics, therapeutic recommendations are not yet largely based on PD variables or on PK variables other than the cytochrome P450 subtypes 2D6 and 2C19 that have gained sufficient correlative clinical evidence for dosing recommendations based upon patient genotypes.
Pharmacogenomic Nomenclature
Pharmacogenomic testing laboratories determine a patient's diplotypes for each gene analyzed. The diplotypes represent haplotypes from maternal and paternal sources and typically, the panel tests for the most common genetic variants. Haplotypes are composed of a set of alleles and alleles are described by multiple nomenclatures; however, the star (*) nomenclature is often the basis for grouping CYP450 genes into categories such as allele typing listed in CPIC Guidelines [8]. In this nomenclature, a symbol of a star precedes a number corresponding to a uniquely identified variant in the genetic code for an enzyme. A diplotype is reported by a listing both star (*) haplotypes. As an example, a CYP450 2D6 diplotype may be expressed as CYP2D6 *1/*1. The *1 corresponds to the most common allele set and is considered the population norm. i.e., if sequencing detects no variation in the alleles, the star 1 (*1) is assigned. Variances from the most common sequence are assigned different numbers, for instance, CYP2D619*1/*10, has one allele set that is the common *1 sequence while the second allele set sequence is a variant identified as *10. Gene duplications can be reported by listing the number of copies if known or pharmacogenetic reports may only indicate that additional copies are present [8].
Variances most often arise from single nucleotide polymorphisms (SNPs). SNPs are the most common genetic variation in people and result when a single nucleotide in a gene sequence is different than the wild-type. SNPs occur on average of every 300 nucleotides and usually have no functional effect on the final protein product coded by a gene. However, if a SNP occurs within a gene's coding region or in a regulatory region near a gene, it may affect the gene's function [9]. For instance, for CYP2D6, the *10 variant has a thymidylate at position 100 substituted for the normal cytidylate at that position (100XC>T). As a result of this substitution, the translated amino acid sequence changes from a proline to a serine at position 34, and the modified enzyme has decreased activity [5].
Pharmacogenetic genotypes show the allelic sequences; however, these data must be translated into an understandable clinical outcome to be useful. The genotypes must indicate a clinical phenotype, which in turn must be strongly correlated with patient outcomes. For CYP genes, the clinical phenotypes are the overall enzyme activities, which can be normal, increased, decreased/absent, or in some cases, unknown.
If a predictive association is determined to exist between a polymorphic genotype and enzymatic activity, then the genotype can be used as one tool to predict responses and perhaps modify the regimen to provide personalized medicine. Two major bodies have evaluated pharmacogenomic associations with clinical drug responses and set predictive guidelines based on an individual's genotype: the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) [10]. CPIC publishes peer-reviewed guidelines and posts them to the website PharmGKB.org along with supplemental data. CPIC member institutions are largely in the U.S. and DPWG members largely European. Although many recommendations between CPIC and DPWG overlap, in this review, we have summarized CPIC guidelines where they exist [11].
Polymorphisms can give rise to four potential populations. Those with "normal" metabolism shared by the majority of the human population have been referred to as "extensive metabolizers", but are now referred to as normal metabolizer by CPIC [8] Individuals with low or no metabolism compared to the general population are referred to as "poor metabolizers" and those with less metabolism compared to the general population are termed "intermediate metabolizers" [5,7]. Individuals with greater enzymatic metabolism compared to the general population are referred to as "ultrarapid metabolizers". While the first three populations result through polymorphic sequences, often SNPs, the ultrarapid metabolizers usually result from the expression of multiple functional allele copies or increased transcription of a gene due to variant sequences in the promoter [5,7]. All four genotypes may affect efficacy or safety response to a drug. As shown in Figure 1, if an individual's drug metabolizing phenotype leads to more active drug than expected by the dosing regimen, the risk of toxicity increases.
Figure 1: Drug metabolizing enzymes regulate the PK of drug molecules by inactivating active drugs or by activating prodrugs. Active drug forms (left side of Figure) are generally dosed at a level that anticipates they become inactivated at the rate of an extensive metabolizer's enzymes. This normal metabolism leaves fewer biologically active molecules and more less-active or inactive metabolites before the next dosing interval. Poor metabolizers inactivate at a slower rate leaving more active drug than anticipated, while ultrarapid metabolizers inactive at a faster rate leaving less active drug than anticipated in a general dosing scheme. Prodrugs (right side of Figure) are dosed in anticipation that some molecules will be metabolized into the active form(s) at a normal rate. Ultrarapid metabolizers produce more active drug than anticipated, while poor metabolizers produce less active drug than anticipated. In both scenarios, when more active drug than expected is present, the risk of toxicity increases (active drug and poor metabolizer or prodrug and ultrarapid metabolizer). When less active drug than expected is present, the risk of therapeutic efficacy decreases (active drug and ultrarapid metabolizer or prodrug and poor metabolizer).
This can occur as the result of administering normal doses of active drug to a poor metabolizer because the poor metabolizer cannot clear the active drug as expected. More-than-expected active drug can also occur when a prodrug is administered to an ultrarapid metabolizer since the prodrug is converted faster. Alternatively, if an individual's drug metabolizing phenotype leads to less active drug than anticipated by dosing, the risk of therapeutic failure increases. This can occur as the result of an active drug being inactivated by an ultrarapid metabolizer or a prodrug not being activated by a poor metabolizer. Clinical pharmacogenomics laboratories commonly give an interpretation of the genotype result and provide a predicted phenotype [5]. An example of the application of an identified diplotype to a clinical phenotype is CYP2D6*10/*10. This diplotype individual inherited two copies of the *10 variant. This variant encodes a protein with reduced enzymatic activity. This individual is predicted to have less than full activity and could be described phenotypically as an intermediate metabolizer. An example of a poor metabolizer would be an individual who inherited two non-functional allele sets such as CYP2D6*5/*6 since both *5 and *6 encode non-functional protein products [5].
In addition to inherited genomic effects, an individual's clinical phenotype may be influenced by other molecules that affect a metabolic enzyme. The process of phenoconversion occurs when one or more factors such as drug molecules convert an existing phenotype to another phenotype. An example of enzymatic phenoconversion is when an individual with a normal diplotype for a metabolic enzyme expresses a poor metabolizer phenotype due to a drug-drug or drugenzyme interaction [4]; for example, enzyme inducers or inhibitors can phenoconvert an individual's CYP activities.
Pharmacogenomic Guidelines for TCAs based on Metabolic Enzyme Activity Phenotyping
TCA drugs are used as options to treat depression, although they are now more commonly prescribed at lower doses for neuropathic pain management. Mechanistically, tricyclic antidepressants inhibit the reuptake of the neurotransmitters serotonin and norepinephrine. Tricyclics with a tertiary amine show greater inhibition of serotonin uptake while TCAs with a secondary amine show greater inhibition of norepinephrine. Thus, tertiary amines amitriptyline, clomipramine, doxepin, imipramine, and trimipramine are greater serotonin reuptake inhibitors. The secondary amines desmethyl-clomipramine, desmethyl-doxepin, desmethyl-trimipramine, desipramine, and nortriptyline are greater norepinephrine reuptake inhibitors [5].
Plasma TCA levels are strongly influenced by cytochrome P450 enzymes CYP2D6 and CYP2C19 [4]. As of 2014, CYP2D6 had 105 allelic variants and CYP2C19 had 34 [5]. CYP2D6 metabolizes TCAs into less active molecules, thereby reducing a drug's activity. CYP2C19 de-methylates tertiary amines producing secondary amines, thereby shifting serotonin reuptake towards norepinephrine. The genetic sequences encoding some CYP2D6 and 2C19 variants have correlated strongly enough with clinical phenotypes and patient dosing outcomes that they support guidelines for dosing of amitriptyline and nortriptyline and potentially other TCAs [5,6].
The 2D6 enzyme has at least two variants which encode functional enzymes, designated in the star nomenclature as CYP2D6*1 and CYP2D6*2. Three reduced function allele sets exist and are designated CYP2D6*9, *10, and *41. Four nonfunctional allele sets are designated CYP2D6*3 - *6. Of these non-functional alleles, the *5 is a deletion of one allele. The most common allele set, *1 of CYP2D6 has been found to be duplicated in instances in which a patient holds multiple copies of the gene [5]. Such duplications are identified by an "xN" after the name of the haplotype, i.e., a patient with three copies of the 2D6 gene would be identified as "CYP2D6*1X3".
The CYP2C19 is encoded mainly by three of the 34 identified allelic variants: CYP2C19*1 (most common or wild-type), *2 (encodes a loss of function enzyme) and *17 (enhanced transcription and therefore more copies of the enzyme). Based upon 2D6 and 2C19 genotyping, patients are assigned to a phenotype of either poor metabolizers, intermediate metabolizers, normal metabolizers or ultrarapid metabolizers [5]. The approximate percentage of the population with these phenotypes for 2D6 is: poor metabolizer, 5-10%; intermediate metabolizer, 2-11%; normal metabolizer, 77-92%; ultrarapid metabolizer, 2%. For 2C19 the population percentages are approximately, poor metabolizer, 2-15%; intermediate metabolizer, 18-45%; normal metabolizer, 35-50%; ultrarapid metabolizer, 5-30% [5].
Dosing recommendations which follow are categorized by the CYP enzyme and then list the drug guidelines according to patient phenotype (e.g., poor metabolizers, intermediate metabolizers, ultrarapid metabolizers). The strength of clinical evidence used to make recommendations is generally considered by CPIC to be strong for 2D6 phenotypes; for 2C19 phenotypes, recommendations are stronger for normal and intermediate metabolizers than for poor or ultrarapid metabolizers [6]. Although most data acquired and used to guide dosing recommendations for TCAs are based upon amitriptyline and nortriptyline [5], CPIC has recently also made recommendations for other TCAs based on PK similarities [6].
For the use of TCAs to treat neuropathic pain, 2D6 or 2C19 poor or intermediate metabolizer patients do not need dose modifications since neuropathic pain generally is dosed with TCAs at lower levels than for depression. For 2D6 ultrarapid metabolizers, an alternative therapy is recommended since these patients may fail therapy. For 2C19 ultrarapid metabolizers, no CPIC recommendation exists [5]. Normal metabolizers (i.e., those who carry the common, functional alleles) should receive initial therapy at the recommended starting doses.
For therapy of depression (Table 1) with amitriptyline or nortriptyline, for 2D6 poor metabolizers, an alternative therapy or a 50% dose reduction is recommended; for intermediate metabolizers, a dose reduction of 25% is recommended; for ultrarapid metabolizers, alternative drug therapy is recommended [5]. Normal metabolizers receive initial therapy at the recommended starting doses are therefore not listed in the Tables.
|Clinical Phenotype of CYP2D6a
|Amitriptyline/ Nortriptyline
|bother TCAs
|Alternative drug or 50% dose reduction
|cOptional: Alternative drug or 50% dose reduction
|Consider 25% reduction and therapeutic drug monitoring
|Optional: Consider 25% reduction and therapeutic drug monitoring
|Alternative drug
|Optional: Avoid TCAs or consider higher dose and therapeutic drug monitoring.
|Clinical Phenotype of CYP2C19
|dother Tertiary TCAs
|50% dose reduction
|Optional: Avoid tertiary amines such as amitriptyline, clomipramine, imipramine, trimipramine, doxepin or consider a 50% reduction of starting dose of tertiary amines and use therapeutic drug monitoring.
|No change to dosing
|No change to dosing
|Consider alternative drug
|Optional: Avoid tertiary amines or use therapeutic drug monitoring
|aExtensive-metabolizers receive routine starting dosing are therefore not listed in the Table.b Other TCAs include both secondary and tertiary classes.
c Recommendations for other TCAs are considered optional because of less direct PK or trial data.
d Other Tertiary TCAs include clomipramine, imipramine, trimipramine, doxepin.
Table 1: Pharmacogenomic guidelines for amitriptyline, nortriptyline and other TCAs based on metabolic enzyme activity phenotyping.
For therapy of depression with other TCAs, recommendations are considered optional since they are supported by less clinical data. Poor metabolizers should avoid other tertiary amine TCAs or receive a reduced initial dose and therapeutic drug monitoring. Ultra-rapid metabolizers should avoid other tertiary amines [6].
Legend: Dosing recommendations are based on published CPIC guidelines [5,6] and are for CYP2D6 and CYP2C19 phenotypes. These guidelines pertain to the use of amitriptyline, nortriptyline and for other TCAs for treatment of conditions such as depression, not neuropathic pain. Because CYP2C19 affects metabolism of tertiary amine TCAs, recommendations for 2C19 variants apply only to tertiary amine TCAs. For therapy of depression with amitriptyline in 2C19 phenotypes, poor metabolizers should receive a 50% dose reduction; intermediate metabolizers receive no dose change; Ultrarapid metabolizers should consider either an alternative drug or no changes (Table 1)[5]. For therapy of depression with other tertiary amines in 2C19 phenotypes, recommendations are considered optional. Poor metabolizer status patients should either avoid tertiary amines or else consider a 50% dose reduction and therapeutic drug monitoring. Ultrarapid metabolizers should either avoid tertiary amines or use therapeutic drug monitoring [6].
For patients with genetic variants in both 2D6 and 2C19, recent CPIC guidelines make recommendations for amitriptyline (not shown). These guidelines suggest avoiding amitriptyline use in patients with opposite CYP phenotypes (i.e., phenotyped as a poor metabolizer for one CYP and an ultrarapid metabolizer for the other) [6]. For patients phenotyped as normal metabolizers for one CYP, recommendations are to follow guidelines for the other CYP phenotype if it is variant. Patients who are intermediate metabolizers for both CYPs should consider a 25% reduction of the recommended starting dose [6].
Pharmacogenomic Guidelines for SSRIs based on Metabolic Enzyme Activity Phenotyping
SSRIs are the most common options for depression and anxiety [12]. Other uses are for social anxiety disorder, posttraumatic stress disorder and obsessive-compulsive disorder, and bulimia nervosa [13]. These agents act by inhibiting the reuptake of the neurotransmitter serotonin. Up to 50% of patients treated with SSRIs fail therapy and accumulating data suggest polymorphisms of either CYP2D6 or CYP2C19 contribute to clinical drug failures or adverse effects [7]. Adverse effects associated with SSRIs include gastrointestinal upsets, sexual dysfunction, headache, insomnia, and with citalopram and escitalopram, prolongation of the QT interval which can precipitate arrhythmias [12]. Dosing recommendations based on CYPs 2D6 and 2C19 genotypes exist for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline [7].
CYP2D6 metabolizes SSRIs paroxetine and fluvoxamine to more inactive molecules and therefore decreased or increased activity of 2D6 can alter response to these SSRIs. Fluoxetine, the most frequently prescribed SSRI, is metabolized by both CYPs 2D6 and 2C19 resulting in a mixture of active and inactive metabolites with varying half-lives. The net effect of parent and metabolites on a patient's clinical phenotype and response to fluoxetine is unclear, and at this time, there are no pharmacogenetic-based guidelines for fluoxetine [7].
Notably however, the FDA label warns that fluoxetine should be used with caution in patients with conditions that predispose to QT prolongation and that such conditions include use of CYP2D6 inhibitors and CYP2D6 poor metabolizer status [14]. CYP2C19 also plays a role in SSRI metabolism; however, as with TCAs, its role is not inactivation but rather a shift in substrate affinity; in this case leading to weakened serotonin inhibition for citalopram, escitalpram and sertraline.
Therapeutic recommendations for SSRIs based on CYP2D6 genotyping are as follows (Table 2): for patients identified as poor metabolizers, paroxetine and fluvoxamine should be replaced with alternatives not metabolized by 2D6; for intermediate metabolizers, no changes are recommended; for ultrarapid metabolizers, an alternative therapy is recommended for paroxetine [7].
|bClinical Phenotype of CYP2D6a
|cAlternative drug or 50% dose reduction
|Alternative drug or 25-50% dose reduction
|No change to dosing
|No change to dosing
|Alternative drug
|No recommendation
|Clinical Phenotype of CYP2C19
|Citalopram / Escitalopram
|Alternative drug or 50% dose reduction
|Alternative drug or 50% dose reduction
|No change to dosing
|No change to dosing
|Alternative drug
|No change to initial dosing; consider alternative for lack of efficacy.
|a Extensive metabolizers receive routine starting dosing are therefore not listed in the Table.
b Clinical phenotype based on genotype interpretation;
c Alternative drugs should not be extensively metabolized by the CYP enzyme
Table 2: Pharmacogenomic Guidelines for Paroxetine, Fluvoxamine, Citalopram, Escitalopram and sertraline based on metabolic enzyme activity.
Therapeutic recommendations for SSRIs based on CYP2C19 genotyping are as follows (Table 2) for poor metabolizers, citalopram, escitalopram and sertraline should be replaced with alternatives or else the initial dose should be reduced by 50%; for intermediate metabolizers, no changes are recommended; for ultrarapid metabolizers, citalopram, escitalopram should be replaced with alternatives, while for sertraline, no dosing change is recommended [7].
As with TCAs, phenoconversion of normal to poor metabolizer status is possible if patients are co-administered CYP2D6 inhibitors such as paroxetine or fluoxetine. Dosing recommendations are based on published CPIC guidelines [7] and are for CYP2D6 and CYP2C19 phenotypes.
For fluoxetine, recommendations have not been written because of inconsistent and conflicting clinical studies; however, polymorphisms of SLC6A4, HTR1A and MAO-A genotypes are involved in patient's response to fluoxetine and several other gene products as well as gender and ethnicity may modulate therapeutic activities [15].
Genomic-Based Recommendations for Newer Antidepressants
Although SSRIs are generally first–line drugs, newer generation antidepressants present alternatives with less adverse effects than TCAs. These new generation agents include newer Serotonin Norepinephrine Reuptake Inhibitors (SNRIs), the serotonin and α2-adrenergic receptor antagonist mirtazapine, the norepinephrine and dopamine reuptake inhibitor (NDRI) bupropion and mixed serotonergic medications.
Of the newer SNRIs (Table 3), Venlafaxine is extensively metabolized by CYP2D6 into O-desmethy-venlafaxine, which is an active metabolite. 2D6 poor metabolizers have much higher serum venlafaxine to O-desmethyl-venlafaxine ratios and although these patients have similar efficacy to other phenotype groups, 2D6 poor metabolizers experience greater adverse effects such as nausea, vomiting and diarrhea [16]. CPIC guidelines are not established for venlafaxine; however, the Dutch Pharmacogenetics Working Group (DPWG) evaluated overall available data for venlafaxine based on CYP2D6 genotypes and recommend the selection of either an alternative drug or adjustment of venlafaxine dosage for poor and also for intermediate metabolizers. For ultra-rapid 2D6 metabolizers, DPWG recommends dosing to a maximum of 150% of the normal dose or selecting an alternative drug [17]. The new SNRI duloxetine is also metabolized by CYP2D6; however, after evaluating dose recommendations for duloxetine based on CYP2D6 genotype, the DPWG concluded no therapeutic dose changes should be recommended [18]. CPIC also makes no recommendations for duloxetine [19]. Milnacipran, a third new SNRI, appears to undergo minimal CYP metabolism; patients who are poor metabolizers for either CYP 2D6 or 2C19 show no altered levels of either milnacipran or its metabolites [20]. Neither CPIC nor DWPG recommend altering Milnacipran based on genotyping.
|CYP in metabolism
|Pharmacogenomic Guidelines or Recommendations (Yes and source or No)
|Clinical Phenotype of Metabolism & Applicable Recommendations
|Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)
|Yes (DPWG)
|Poor/Intermediate --alternative drug or dose adjustment.
Ultrarapid -- alternative drug or dose to a maximum of 150% of the normal dose
|a N/A
|Serotonin and α2-Adrenergic antagonist
|Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)
|Mixed Serotonergic Medication
|Yes (FDA)
|Poor – dose reduction
Table 3: Pharmacogenomic status for newer generation antidepressants.
Newer agents are shown with their major CYP involved in metabolism, genomic-based recommendations if available with the source of recommendations and brief explanation of recommendations for metabolizer phenotype.
The serotonin and α2-adrenergic receptor antagonist mirtazapine is metabolized by CYP2D6 and has been evaluated by DPWG based on CYP2D6 genotype; however, neither they nor CPIC recommend dosing adjustments [21]. The NDRI bupropion is metabolized by CYP2B6, a liver CYP with at least 28 allelic variants [22] into a less active metabolite, hydroxy bupropion. However, clinical evidence associated with variants has not been strong enough to lead to altered dosing guidelines by either CPIC or DPWG [19].
Of drugs in the newer mixed serotonergic medications class, vortioxetine is metabolically inactivated by CYP2D6 and though no CPIC or DPWG recommendations have been published, the FDA label calls for a dose reduction in 2D6 poor metabolizers [23]. Vilazodone is metabolized primarily by CYP 3A4 and a kinetics study has recommended a dose reduction when co-administered with strong 3A4 inhibitors [24]; however, genotype-based dosing guidelines have not been developed by either CPIC or DPWG [19].
Limitations of Pharmacogenomics in Dosing Guidelines
Testing for pharmacogenomic interactions is most relevant when a drug therapy is initiated. Once patients have begun antidepressant pharmacologic therapies and achieve efficacy with the therapy, pharmacogenomic testing is of less benefit [5]. Alleles, both normal and variants, are searched for using known sequences and therefore a new or rare or undiscovered variant will not be identified and in these instances the patient would be assumed to encode a normal allele [5]. Therefore, a small possibility exists for a patient to be falsely assigned a *1 if they have an undiscovered variant sequence. In addition, the genetics of other nonmetabolic enzyme factors regulate the PD and PK of drug responses, yet reliable genetic assays for these nonmetabolic factors have not been developed and clinically validated, and thus their pharmacogenomics are not currently used to make dosing recommendations [4]. As mentioned above, phenoconversion factors can override predicted phenotypes and CYP2D6 is a commonly phenoconverted enzyme.
The benefit of genotype testing is its potential to enhance efficacy and/or reduce adverse effects. Antidepressant pharmacogenetics play a relevant role in achieving efficacy and reducing risks of adverse effects, yet at this time, guidelines for drug or dosing changes exist for only some agents and are largely based on CYP450 enzyme genotypes. CYP2D6 and 2C19 test results are only one of multiple variables that must be considered in determining therapies for depression and existing guidelines do not yet encompass the many potential variables outside of drug metabolizing enzymes such as neurotransmitter receptors and transport proteins. When these other variables gather sufficient evidence to also warrant pharmacogenomic guidelines, one clear challenge will be to integrate multiple phenotypes encompassing both PD and PK variables in a manner that will still lead to sensitive and specific personalized recommendations. The foundation however, for a process of genotype testing and application of some genotypes to drug management decisions has been established and can be used to accommodate future data.


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With so many people trying to lose weight, little thought is given to those who remain uncomfortably skinny and would do anything to add some kilos. Is there anything wrong with being skinny? Well, while it is not necessarily unhealthy, being very thin comes with its own challenges. If you fall in this category, you know how it feels to be confused for a much younger person, most likely a child. Even worse is when you clothes shopping and you're directed to the children's section to check your size.
Weight gain also takes some effort, especially if you remain thin even on a normal diet. More importantly, you need to ensure that you're gaining healthy weight that will not bring you health conditions or go overboard into excess weight. Junk food may crank up the kilos, but the side-effects will outdo the benefits in the long run.
Here are some tips to help you gain weight safely:
- Drink your Food: Liquid food is a good way to add nutrition without feeling too full and bloated. If anything, drinks like fresh juice help in digestion allowing you to eat more. Drink plenty of juice, milk, smoothies, milk shakes and even blended food where applicable. Even for those with poor appetite, drinking is easier than taking solid foods.
- Eat Nutrient-Dense Foods: Take in that extra nutrition without having to eat large quantities of food by ensuring that every bite you take is packed with nutrients and calories. Such foods include red meat, dried fruit, peanuts, peanut butter and whole grains. Dried fruit shrinks by about 75% once the water is removed, leaving every small portion richly packed with nutrients. Focusing on quality before quantity will leave your body well-nourished and add some much desired pounds.
- Combine Foods: Throw in several groups together in every meal. Aim for at least 3, which makes a balanced diet. For instance, if you're having a normal meal of rice and beef stew, add some banana slices, nuts, avocado and a drink of your choice such as milk or fruit juice. When taking slices of bread, add peanut butter or margarine. You can also add ham or bacon to make a sandwich. Always look for an opportunity to add one more food group to your meal.
- Eat regularly: Your body is continuously consuming energy. When you stay for more than 5 hours without a meal, an alternative source of energy is sought, which is muscle mass in this case. Loss of muscle will in turn make you skinnier. Ensure this does not happen by eating regularly, more than the conventional 3 meals per day. Snack often, without resulting to junk food.
- Eat right before Sleeping: Most of the food we eat during the day provides energy for the day's activities. Since we're not as active during the night, a good portion of the food will be stored as fat. If you regularly eat just before sleeping, you'll gradually add weight.
Extreme underweight is just as disturbing as being overweight. Clothes don't fit. You generally look funny and are likely to attract plenty of teasing. Hoping the above tips will help you gain just the right weight for your body.


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In March 2020, Techna reported on a workshop where 199 student suggestions were collected for the university's "Environmental Objectives and Action Plan". Many of them focused on sustainable food and gardening on campus. Now, a year later, the project Campus Garden is in full motion and has been granted funding from Uppsala University's climate pot. Techna visited them on a rainy workday in their garden at Villavägen 14.
How did the project come about?
OTILIA: "Me and Sagnik met in a community garden where we were both volunteering last summer. We were doing a lot of gardening together. We had so much to talk about, and we did it over gardening which is a fun activity and a great activity to do last summer, especially. That made us talk about spreading this thing."
SAGNIK: "I was also working on my thesis about "green roofs" – producing food in gardens on rooftops. I was thinking: 'We could do something like this in a practical way.'"
How did you hear about seeking funding from the university's climate pot?
SAGNIK: "I also volunteer for Zero Waste Uppsala and they were applying for this climate pot funding. But we never expected that we would be getting it!"
In what ways has the pandemic affected you? Do you think people are more eager to join the project because of it?
OTILIA: "I think that has been a thing we've heard a lot of people say – that it's nice to do something else than sitting by the computer. My body hurts for a good reason, that's the first time in a while."
SAGNIK: "We started our work days in the beginning of April and before that we were behind the computers, for like four months. So we were trying to prepare the whole thing in the pandemic. We used to have 'Monday meetings' from 7 o'clock and everyone would be complaining: 'When do we start the gardening?!'"
What will you be planting? How will the garden be organized?
OTILIA: "We have a designated area for a kitchen garden, that's where we will have the main, annual vegetables. We will be planting kale, onions, pumpkins, zucchinis and corn. We want to experiment and see what works. We're not really aiming for a huge harvest – we will try to plant to get as much of a variety as possible."
This will be a permaculture garden – what does permaculture mean, for you?
OTILIA: "One example of what permaculture means for us is that we are using cardboard instead of ground cloth or anything plastic on the ground. We want to preserve as much of the microlife as possible. Now we've dug the paths so we can use the soil, so we have had to disturb it a little bit, but we want to try to rebuild it and feed it as much as possible.
Permaculture is like working with the ecosystem that is here and trying to learn about the place, not just implement too much without knowing what's going on. It's a lot about observing and getting to know the place and thinking about how nature solves things – using wood chips to try to simulate paths in the forest, for example."
SAGNIK: "Another principle we follow is to keep a low carbon footprint. We try to get as much stuff as possible from recycling – these cardboards we got from dumpsters. And with the tools, we have asked people to donate, rather than getting it first hand."
OTILIA: "That's a part of the permaculture thinking as well, producing zero waste, and trying to use resources creatively, and think of ways to not hurt the planet as much."
So you have gotten a lot of stuff donated?
SAGNIK: "When we started we didn't have any tools, so we borrowed from Flogsta food. "
OTILIA: "Facebook has been great in that sense. In the beginning we didn't really know how we could receive things, but once we got a hold of that it's been really easy for people to just reach out to us and be like: 'Yeah, I have this – do you need it?' And then they drop it off and might come in on a work day. Now we refer to a lot of things as 'the table Emanuel brought' or 'the axe that Zack brought'."
So far, what has been the most difficult part of the project?
OTILIA: "There is a lot of bureaucracy and things are moving slowly. There is a hierarchy to get through to get things to happen. And when you have a lot of eager volunteers, who want to get stuff done… combining that with how slow the university can be, that has been difficult. But there are people within the university too who have been really excited about it and have helped us a lot."
SAGNIK: "Also people have a lot of questions about what will happen in one year, since this project only continues until December. What will happen after that? Answering right now, upfront, is a bit difficult. For us it's more of an ongoing thing. We didn't have all the answers from the beginning. We weren't even sure we would get volunteers but now we have 50."
What has been the easiest?
SAGNIK: "Getting all these people out. We never would have thought that. You can see how dedicated they are!"
OTILIA: "When we just had the Zoom meetings, before the meeting started we would worry: 'What if no one shows up?!' And then when the clock struck seven boom boom boom, everyone joined. I don't know how many times I've cried in those meetings because I'm just moved by how amazing it is to see people show up."
SAGNIK: "I mean, we just had an idea and then this idea was co-created by so many people coming together – it's amazing. More and more people are coming in and we have more and more of a bond together. Today we have a potluck lunch."
What's been the most valuable part of this project, for you personally?
OTILIA: "The community that's being built up. Seeing people week after week and realising that we're building it together. If someone planted a bush over there – that person is going to remember that they planted that bush there. Every single thing that we do, someone did it with their hands. When we pass this place we know that it might look a mess, but it's our mess."
SAGNIK: "It makes us proud – that you can see your work on the ground. I have studied sustainable development and we learn a lot of things over there on theory and like making the world a better place and all. But doing something like this and evolving an idea... Seeing this substantial change that we make… yeah, you can say that that's our mess."
Taking up hobbies has been at an all time high this year, given the pandemic we live in. Many out there have started painting, become obsessed with plants, started new sports and so on. There has also been time to try other relaxing activities such as diving into the deep pool of Netflix' series and movies. Two of Techna's liaisons have reviewed the hottest out there on Netflix with the mission to find something for everyone, from murder mysteries to all time comedies. In this number you get four reviews of our top picks, for everyone out there looking to start a new show to relax to or binge on! This is a continuation of the previous Techna number.
Genre: Drama Creators : Hans Rosenfeldt Release Date: 2011
A twisted serial killer dumping bodies on the Swedish-Danish border is investigated.
Mariam's Review:
The way it is realistically filmed was really great! Big attention to detail in set up! Through different murder cases being displayed in every season, it is interesting to follow the main characters and their character development through out. The show has an originality factor in the fact that it is about local murders where Swedish and Danish authorities have to cooperate!
Score: 4/5
Elnaz's Review:
Bron follows Saga Norén, a Swedish Sherlock Holmes, as she and the Danish detective Martin Rohde solve brutal murders that take place on Öresundsbron, the bridge which connects Sweden and Denmark. It has all the attributes that make a good detective series, while maintaining originality by describing the differences and similarities between the Danish and Swedish language and culture. I appreciate that it is not just about solving murders: the show focuses a lot on characters and their relationships. This is probably the reason why the show is characterized as a drama rather than your typical murder mystery. All in all, it is a great show: but be prepared for emotionally heavy and graphic scenes!
Score: 4,75/5
Genre: Drama Creators : Jens Lapidus, Oskar Söderlund, Jesper Ganslandt Release Date: 2021
The lives of an ambitious businesswoman, a charming gang enforcer and a troubled teen collide amidst a desperate and sinister pursuit of wealth.
Fast money, fast helicopters and drugs. An over-Americanised version of drug criminality in the Swedish suburbs and an underdog with a dream to get out of the suburbs and become a successfully rich IT entrepreneur. It is an almost overplayed plot which we have seen on TV before, but the show does try to explore it through a over dramatised version of Swedish societal dynamics, which can come across as unrealistic and inauthentic. Nevertheless it was refreshing to see a show with strong female leads of color, and generally a diverse casting and a really bangin' soundtrack!
Score: 2,5/5
In this show, a mother and entrepreneur raised in the suburbs, struggles to fulfill her dream of becoming successful in life. And being successful here means earning the most money through her IT-company. "Snabba Cash", translated as Fast Money, tackles the dark topic of drug criminality in the suburbs and the consequences for the ones affected by it. For someone that is not familiar with this issue, this series manages to paint a vivid and realistic picture of what it can look like. If you exclude the Americanized success story the show was convincing, especially the very graphic scenes and the actors who fit their roles perfectly.
Score: 4,5/5
Genre: Drama Creators : Moa Herngren, Clara Herngren, Felix Herngren Release Date: 2017
A drama series exploring the complexities of relationships in modern family life in a blended family.
The show portrays in a very realistic and unfiltered way the consequence of falling involved and divorcing with children and the struggle to build a new "bonus" family. It rawly portrays the struggles and evolving dynamics of the different exposes and children, in a comic way. It was an interesting take on post divorce dynamics between exposes, children and new relationships, with many awkwardly hilarious moments. All relationships have their ups and downs, that come with baggage, but if both partners are willing to do the work, it just might be okay!
Score: 3,5/5
What is it like creating a new family amidst your old one and your partner's one? This show follows two families that break up because the father in one family and the mother in the other fall in love. When the two decide to live together, with their respective kids, they build a step family, or as you can say in Swedish a "bonus" family. Of course, this term is not always as simple as it sounds – in this show, it is more like a family disaster. The actors were good, but sometimes the manuscript didn't give them the best material to work with: look out for the cringe-worthy conversations with the family therapists. This emotional drama is at times frustrating, but it has its funny moments.
Genre: Drama Creators : Wilhelm Behrman Release Date: 2020
The exploration of terrorism and ISIS in Sweden today. Agent Fatima gets a tip that a terrorist act is planned in Sweden. At the same time, the teenager Sulle has opened her eyes to her student assistant who opens the doors to a new fascinating world.
Capturing and captivating show, exploring the ISIS recruitment issues in Swedish society. Portrays the duality and exclusion which certain individuals face, and the psychology of terrorist recruitment. A raw dual reality of two worlds which exists in parallel. Through the show the viewer was able to follow different characters, which are amazingly played (great casting) allowing us to sympathise even with the most "evil" character. Exciting, original and heart-breaking: A definite must see!
Score: 4,95/5
This series raises another dark topic that was a big problem in Sweden a few years ago – when Swedish citizens left Sweden to join ISIS. Although it is difficult to relate to these people, Kalifat succeeds in revealing the common and shocking backstories of the people making this decision and the devastating outcomes that follow. An exciting plot is accompanied by convincing actors and settings. It is educative, captivating and heart-breaking: this show is definitely worth your time!
Which of these speaks to you?
a) 0
b) x
c) 92
d) 60 (= 2x30 = 3x20 = 4x15 = 5x12 = 6x10)
Which of the following is most likely to happen to you after an exam?
a) All my answers are correct but I forgot to explain how I arrived at them
b) I am wrongfully(!) accused of plagiarism
c) I fail the exam but only because I was too controversial in my answers
d) I forgot to write my name/code…
Choose a sound
a) Thunderstorm and violent rainfall
b) The pages of a book softly turned, muffled conversations
c) The ringing of a copper bell
d) The north wind blowing in from over the sea
What are your interests? (Outside mathematics of course)
a) Astronomy
b) Astronomy and geography
c) Music… (and astronomy)
d) Philosophy, astronomy, teaching, geography, constructing cool instruments…
How do your friends describe you?
a) "The gem of the circle of mathematicians."
b ) "In the foremost rank of mathematicians of all time"
c) "Impious" :(
d) "universal genius", "... a person so renowned, their reputation seems literally incredible."
Choose a place
a) The Observatory of Ujjain
b) The House of Wisdom
c) The Ionian sea
d) The Serapeum of Alexandria
Answered mostly a)
Indian astronomer and mathematician often credited as the first to use zero as a number. Instead of zero simply signifying "nothing", Brahmagupta presented rules for computing with zero as well as with negative numbers. The only exception from modern day rules being division, since he defined 0/0 as 0.
His book Brāhmasphutasiddhānta contains findings in geometry, trigonometry, arithmetics and algebra. For example, he obtained certain solutions for Pell's equation (Nx2 + 1 = y2) by using "the pulverizer", which modern mathematicians call the Euclidean algorithm.
Brahmagupta wrote in Sanskrit verse and never included any proofs – we will never know how he arrived at his discoveries!
Answered mostly b)
Al-Khwārizmī was head of the library at the House of Wisdom in Baghdad, in the early days of the Islamic Golden Age. He is remembered today as the father of algebra. The word algebra itself is derived from the arabic word al-jabr, which appears in the title of one of his books. Al-Khwārizmī was the first to show how to systematically solve linear and quadratic equations, for example by completing the square. The latinized version of his name gave us the word algorithm.
Since at the time no concise notation existed for algebra, Al-Khwārizmī wrote everything in words rather than symbols. For instance, the equation
(10-x)2=81x was written as: "You divide ten into two parts: multiply the one by itself; it will be equal to the other taken eighty-one times."
Answered mostly c)
A mysterious Pythagorean philosopher, not much is known for certain about Hippasus. He seems to have been one of the first to mathematically analyze music. In experiments he used bronze disks to produce different tones. However, his name mainly appears in the legends of how the Greeks discovered irrational numbers. Allegedly, Hippasus died at sea, thrown overboard by his fellow Pythagoreans, after revealing the square root of 2 to be irrational. This dangerous number completely disrupted the Pythagorean worldview. Another version of the story tells that he was punished for revealing how to construct a dodecahedron inside a sphere.
Answered mostly d)
One of the oldest, most well documented female mathematicians, Hypatia lived and worked in Alexandria as a highly respected teacher and public lecturer. During her time, she was the brightest star of an academic tradition in decline. Sources tell of her constructing devices such as astrolabes and hydrometers, and annotating classical works for the benefit of her students.
In the end, Hypatia was tragically caught in the midst of rising political tensions in Alexandria and was murdered by a Christian mob. The news of an esteemed philosopher savagely beaten to death shocked and horrified the entire Roman empire.
Want to try being active in the union, express yourself creatively, or do you have a strong opinion? Then Techna is the perfect place for you!
The magazine has an editorial which is led by an editor in chief and a deputy editor in chief. We always welcome new members to Techna, regardless of past experience.
Interested? Send a mail to [email protected].
WritersCan't have a magazine without any articles – time to sharpen your pencil!
PhotographersA picture is worth more than a thousand words.
Layout designersThe design of the magazine has to look nice and work well as a whole.
IllustratorsColor brightens up even the faintest pages.
Techna has been published since 2002.
The editorial has members from various science and engineering programs, ranging from year 1 to year 5 and beyond.
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