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Killexams : CMT-Association Level exam Questions - BingNews Search results Killexams : CMT-Association Level exam Questions - BingNews Killexams : Canadian Securities Course (CSC™)

What is the Canadian Securities Course (CSC™)?

The Canadian Securities Course (CSC™) is an entry-level education program offered by the Canadian Securities Institute (CSI). Successful completion of the program and exam permit an individual to work in the Canadian securities industry as a registered securities representative for a securities broker. The CSC can also be used to satisfy the educational requirements needed to sell and trade mutual funds, exchange-traded funds (ETFs), stocks, and fixed income assets.

Key Takeaways

  • The Canadian Securities Course is an exam conducted by the Canadian Securities Institute (CSI) for individuals interested in trading securities or providing investment advice.
  • It consists of two multiple-choice exams that must be completed within one year of registration. exam takers must score 60% or above in order to pass the exam.
  • Subjects covered in the exam include fundamental and technical analysis, as well as an overview of investing services for retail and institutional clients.

Understanding the Canadian Securities Course (CSC™)

The Canadian Securities Course is often the first step for many individuals in Canada looking to pursue a career that involves trading securities and providing investment advice. The CSC involves two exams, typically referred to as exam 1 and exam 2. Each exam includes 100 multiple-choice questions to be completed within two hours. By estimates, the exam requires 150-200 hours of prep time. Registrants must complete the exam within one year of registration.

Subject matter on the exams is broad and reflects what a finance professional in Canada is expected to be conversant in. The first exam covers the Canadian investment marketplace, the economy, features and types of fixed-income securities, pricing and trading of fixed-income securities, common and preferred shares, equity transactions, derivatives, financing and listing securities, and corporations and their financial statements.

Exam 2 includes questions pertaining to fundamental and technical analysis, company analysis, introduction to the portfolio approach, portfolio management, mutual funds, segregated and hedge funds, managed and structured products, Canadian taxation, and working with institutional and retail clients.

The Canadian Securities Course under the Canadian Securities Institute

The Canadian Securities Institute, which was established in 1970, offers a series of licensing courses, advanced certifications, continuing education, and training programs. The non-profit CSI transitioned to a for-profit enterprise, known as CSI Global Solutions, in 2003. In 2010, the Moody’s Corporation acquired the CSI for C$155 million. It now operates as a separate company within Moody’s Analytics. The Investment Industry Regulatory Organization of Canada (IIROC) and the Canadian Securities Administrators (CSA) endorse the CSI. Headquarters for the CSI are in Toronto and Montreal. 

The CSI continues to evolve by offering an increasing number of comprehensive services that help financial professionals advance in their chosen field; to date, it offers nearly 300 different courses. The reach of the organization extends beyond Canada; it is known for developing educational content for securities industries in emerging financial markets, such as those in China, Europe, the Middle East, the Caribbean, and Central America. 

The CSC™ Exam

The CSC™ exam is an two-part course offered by the Canadian Securities Institute (CSI) that allows an individual to become a qualified mutual fund representative. Completion of the Canadian Securities Course™ (CSC™) is also one of the first required steps in pursuing a career that involves trading securities and providing investment advice to clients.

Exam Details:

  • Time Limit: Two hours per exam
  • Cost: Varies
  • Number of Questions: 100 questions per exam
  • Passing Score: 60% per exam
  • Format: Multiple choice
  • Prerequisites: Not applicable. However, it is usually common practice to complete the Canadian Securities Course (CSC™) prior to the CPH course
  • Exam Date: Varies according to the Canadian city in which the exam will be taken
  • Exam Locations: Canada; computer-based exams also available in Toronto and Montreal
  • Official exam Website: Canadian Securities Institute

Exam course Weights:
The current Canadian Securities Course™ consists of two volumes of textbooks.

Exam 1:

  • The Canadian Investment Marketplace: 16%
  • The Economy: 13%
  • Features and Types of Fixed-Income Securities: 12%
  • Pricing and Trading of Fixed-Income Securities: 11%
  • Common and Preferred Shares: 13%
  • Equity Transactions: 10%
  • Derivatives: 10%
  • Financing and Listing Securities: 7%
  • Corporations and Their Financial Statements: 8%

Exam 2:

  • Fundamental and Technical Analysis: 12%
  • Company Analysis: 10%
  • Introduction to the Portfolio Approach: 12%
  • The Portfolio Management Process: 10%
  • Mutual Funds: 14%
  • Segregated and Hedge Funds: 8%
  • Other Managed and Structured Products: 13%
  • Canadian Taxation: 6%
  • Working with the Retail Client: 10%
  • Working with the Institutional Client: 10%
Fri, 08 Jul 2022 05:43:00 -0500 en text/html
Killexams : The Basics of Options Profitability

Options traders can profit by being an option buyer or an option writer. Options allow for potential profit during both volatile times, regardless of which direction the market is moving. This is possible because options can be traded in anticipation of market appreciation or depreciation. As long as the prices of assets like stocks, currencies, and commodities are moving, there is an options strategy that can take advantage of it.

Key Takeaways

  • Options contracts and strategies using them have defined profit and loss—P&L—profiles for understanding how much money you stand to make or lose.
  • When you sell an option, the most you can profit is the price of the premium collected, but often there is unlimited downside potential.
  • When you purchase an option, your upside can be unlimited and the most you can lose is the cost of the options premium.
  • Depending on the options strategy employed, an individual stands to profit from any number of market conditions from bull and bear to sideways markets.
  • Options spreads tend to cap both potential profits as well as losses.

Basics of Option Profitability

A call option buyer stands to make a profit if the underlying asset, let's say a stock, rises above the strike price before expiry. A put option buyer makes a profit if the price falls below the strike price before the expiration. The exact amount of profit depends on the difference between the stock price and the option strike price at expiration or when the option position is closed. 

A call option writer stands to make a profit if the underlying stock stays below the strike price. After writing a put option, the trader profits if the price stays above the strike price. An option writer's profitability is limited to the premium they receive for writing the option (which is the option buyer's cost). Option writers are also called option sellers. 

Option Buying vs. Writing

There are fundamental differences between buying and writing options. An option buyer has the right to exercise the option, while the option writer must exercise the option. Time decay benefits the option writer and works against an option buyer.

An option buyer can make a substantial return on investment if the option trade works out. This is because a stock price can move significantly beyond the strike price. For this reason, option buyers often have greater (even unlimited) profit potential. Alternatively, option writers have comparatively limited profit potential that is tied to the premiums received.

An option writer makes a comparatively smaller return if the option trade is profitable. This is because the writer's return is limited to the premium, no matter how much the stock moves. So why write options? Option writers receive upfront premium earnings, may collect the full premium amount regardless of whether the option expires out of the money, and can trade out of liquid options.

Evaluating Risk Tolerance

Here’s a simple test to evaluate your risk tolerance to determine whether you are better off being an option buyer or an option writer. Let’s say you can buy or write 10 call option contracts, with the price of each call at $0.50. Each contract typically has 100 shares as the underlying asset, so 10 contracts would cost $500 ($0.50 x 100 x 10 contracts).

If you buy 10 call option contracts, you pay $500 and that is the maximum loss that you can incur. However, your potential profit is theoretically limitless. So what’s the catch? The probability of the trade being profitable is not very high. While this probability depends on the implied volatility of the call option and the period of time remaining to expiration, let’s say it is 25%.

On the other hand, if you write 10 call option contracts, your maximum profit is the amount of the premium income, or $500, while your loss is theoretically unlimited. However, the odds of the options trade being profitable are very much in your favor, at 75%.

So would you risk $500, knowing that you have a 75% chance of losing your investment and a 25% chance of making a profit? Or would you prefer to make a maximum of $500, knowing that you have a 75% chance of keeping the entire amount or part of it, but have a 25% chance of the trade being a losing one?

The answer to those questions will deliver you an idea of your risk tolerance and whether you are better off being an option buyer or option writer.

It is important to keep in mind that these are the general statistics that apply to all options, but at certain times it may be more beneficial to be an option writer or a buyer of a specific asset. Applying the right strategy at the right time could alter these odds significantly. 

The Securities and Exchange Commission recognizes risks involved in trading options and encourages traders to educate themselves about the various types of options and how basic options strategies work.

Option Strategies Risk/Reward

While calls and puts can be combined in various permutations to form sophisticated options strategies, let’s evaluate the risk/reward of the four most basic strategies.

Buying a Call

This is the most basic option strategy. It is a relatively low-risk strategy since the maximum loss is restricted to the premium paid to buy the call, while the maximum reward is potentially limitless. Although, as stated earlier, the odds of the trade being very profitable are typically fairly low. "Low risk" assumes that the total cost of the option represents a very small percentage of the trader's capital. Risking all capital on a single call option would make it a very risky trade because all the money could be lost if the option expires worthless.

Buying a Put

This is another strategy with relatively low risk but the potentially high reward if the trade works out. Buying puts is a viable alternative to the riskier strategy of short selling the underlying asset. Puts can also be bought to hedge downside risk in a portfolio. But because equity indices typically trend higher over time, which means that stocks on average tend to advance more often than they decline, the risk/reward profile of the put buyer is slightly less favorable than that of a call buyer.

Writing a Put

Put writing is a favored strategy of advanced options traders since, in the worst-case scenario, the stock is assigned to the put writer (they have to buy the stock), while the best-case scenario is that the writer retains the full amount of the option premium. The biggest risk of put writing is that the writer may end up paying too much for a stock if it subsequently tanks. The risk/reward profile of put writing is more unfavorable than that of put or call buying since the maximum reward equals the premium received, but the maximum loss is much higher. That said, as discussed before, the probability of being able to make a profit is higher.

Writing a Call

Call writing comes in two forms, covered and naked. Covered call writing is another favorite strategy of intermediate to advanced option traders, and is generally used to generate extra income from a portfolio. It involves writing calls on stocks held within the portfolio. Uncovered or naked call writing is the exclusive province of risk-tolerant, sophisticated options traders, as it has a risk profile similar to that of a short sale in stock. The maximum reward in call writing is equal to the premium received. The biggest risk with a covered call strategy is that the underlying stock will be “called away.” With naked call writing, the maximum loss is theoretically unlimited, just as it is with a short sale.

Options Spreads

Often times, traders or investors will combine options using a spread strategy, buying one or more options to sell one or more different options. Spreading will offset the premium paid because the sold option premium will net against the options premium purchased. Moreover, the risk and return profiles of a spread will cap out the potential profit or loss. Spreads can be created to take advantage of nearly any anticipated price action, and can range from the simple to the complex. As with individual options, any spread strategy can be either bought or sold.

Reasons to Trade Options

Investors and traders undertake option trading either to hedge open positions (for example, buying puts to hedge a long position, or buying calls to hedge a short position) or to speculate on likely price movements of an underlying asset.

The biggest benefit of using options is that of leverage. For example, say an investor has $900 to use on a particular trade and desires the most bang-for-the-buck. The investor is bullish in the short term on XYZ Inc. So, assume XYZ is trading at $90. Our investor can buy a maximum of 10 shares of XYZ. However, XYZ also has three-month calls available with a strike price of $95 for a cost of $3. Now, instead of buying the shares, the investor buys three call option contracts. Buying three call options will cost $900 (3 contracts x 100 shares x $3).

Shortly before the call options expire, suppose XYZ is trading at $103 and the calls are trading at $8, at which point the investor sells the calls. Here’s how the return on investment stacks up in each case.

  • Outright purchase of XYZ shares at $90: Profit = $13 per share x 10 shares = $130 = 14.4% return ($130 / $900).
  • Purchase of three $95 call option contracts: Profit = $8 x 100 x 3 contracts = $2,400 minus premium paid of  $900 = $1500 = 166.7% return ($1,500 / $900).

Of course, the risk with buying the calls rather than the shares is that if XYZ had not traded above $95 by option expiration, the calls would have expired worthless and all $900 would be lost. XYZ had to trade at $98 ($95 strike price + $3 premium paid), or about 9% higher from its price when the calls were purchased, for the trade just to break even. When the broker's cost to place the trade is also added to the equation, to be profitable, the stock would need to trade even higher.

These scenarios assume that the trader held till expiration. That is not required with American options. At any time before expiry, the trader could have sold the option to lock in a profit. Or, if it looked like the stock was not going to move above the strike price, they could sell the option for its remaining time value to reduce the loss. For example, the trader paid $3 for the options, but as time passes, if the stock price remains below the strike price, those options may drop to $1. The trader could sell the three contracts for $1, receiving $300 of the original $900 back and avoiding a total loss.

The investor could also choose to exercise the call options rather than selling them to book profits/losses, but exercising the calls would require the investor to come up with a substantial sum of money to buy the number of shares their contracts represent. In the case above, that would require buying 300 shares at $95.

Many private investment firms enter into options contracts. As of March 31, 2022, Berkshire Hathaway held six open contracts with an aggregate fair value liability of $121 million and an aggregate notional value of $2.6 billion.

Selecting the Right Option

Here are some broad guidelines that should help you decide which types of options to trade.

Bullish or Bearish

Are you bullish or bearish on the stock, sector, or the broad market that you wish to trade? If so, are you rampantly, moderately, or just a tad bullish/bearish? Making this determination will help you decide which option strategy to use, what strike price to use and what expiration to go for. Let’s say you are rampantly bullish on hypothetical stock ZYX, a technology stock that is trading at $46.


Is the market calm or quite volatile? How about Stock ZYX? If the implied volatility for ZYX is not very high (say 20%), then it may be a good idea to buy calls on the stock, since such calls could be relatively cheap.

Strike Price and Expiration

As you are rampantly bullish on ZYX, you should be comfortable with buying out of the money calls. Assume you do not want to spend more than $0.50 per call option, and have a choice of going for two-month calls with a strike price of $49 available for $0.50, or three-month calls with a strike price of $50 available for $0.47. You decide to go with the latter since you believe the slightly higher strike price is more than offset by the extra month to expiration.

What if you were only slightly bullish on ZYX, and its implied volatility of 45% was three times that of the overall market? In this case, you could consider writing near-term puts to capture premium income, rather than buying calls as in the earlier instance.

Option Trading Tips

As an option buyer, your objective should be to purchase options with the longest possible expiration, to deliver your trade time to work out. Conversely, when you are writing options, go for the shortest possible expiration to limit your liability.

Trying to balance the point above, when buying options, purchasing the cheapest possible ones may Strengthen your chances of a profitable trade. The implied volatility of such cheap options is likely to be quite low, and while this suggests that the odds of a successful trade are minimal, the option may be underpriced. So, if the trade does work out, the potential profit can be huge. Buying options with a lower level of implied volatility may be preferable to buying those with a very high level of implied volatility, because of the risk of a higher loss (higher premium paid) if the trade does not work out.

There is a trade-off between strike prices and options expirations, as the earlier example demonstrated. An analysis of support and resistance levels, as well as key upcoming events (such as an earnings release), is useful in determining which strike price and expiration to use.

Understand the sector to which the stock belongs. For example, biotech stocks often trade with binary outcomes when clinical trial results of a major drug are announced. Deeply out-of-the-money calls or puts can be purchased to trade on these outcomes, depending on whether one is bullish or bearish on the stock. It would be extremely risky to write calls or puts on biotech stocks around such events unless the level of implied volatility is so high that the premium income earned compensates for this risk. By the same token, it makes little sense to buy deeply out of the money calls or puts on low-volatility sectors like utilities and telecoms.

Use options to trade one-off events such as corporate restructurings and spin-offs, and recurring events like earnings releases. Stocks can exhibit very volatile behavior around such events, allowing the savvy options tradertrader an opportunity to cash in. For instance, buying cheap out-of-the-money calls before the earnings report on a stock that has been in a pronounced slump, can be a profitable strategy if it manages to beat lowered expectations and subsequently surges.

How Do Options Work in Trading?

Options traders speculate on the future direction of the overall stock market or securities of individual companies. Instead of outright purchasing shares, options contracts can deliver you the right but not obligation to execute a trade at a given price. In return for paying an upfront premium for the contract, options trading is often used to scale returns at the risk of scaling losses.

What Are the 4 Types of Options?

The four basic types of option positions are buying a call, selling a call, buying a put, and selling a put. A call is the right to buy a security at a given price. Therefore, a trader can buy a call if it wishes to own the ability to buy at a certain price. A put is the right to sell a security at a given price. Therefore, a trader can buy a put if it wishes to own the ability to sell at a certain price. On the other side of the trade is the option writer who collects an upfront premium for entering into the contract and selling the option.

When Should You Buy Options?

Options are most useful to capitalize on volatile markets. It doesn't matter which direction the market is going; all option traders need is price movement in one direction or the other. In general, it's usually best to enter into an option position when you expect market volatility to increase and best to exist an option position when you expect market volatility to decrease. This is because low price movement is not beneficial for an options contract (especially if the option is current out of the money).

How Do Call Options Make Money?

A call option writer makes money from the premium they received for writing the contract and entering into the position. This premium is the price the buyer paid to enter into the agreement.

A call option buyer makes money if the price of the security remains above the strike price of the option. This gives the call option buyer the right to buy shares at a price lower than the market price.

Can I Sell Options Immediately?

Options contracts can often be bought and sold during normal market hours through a broker on many regulated exchanges. As long as the market is open, you can usually buy an option and sell it the next day (assuming the market is also open the following day).

The Bottom Line

Investors with a lower risk appetite should stick to basic strategies like call or put buying, while more advanced strategies like put writing and call writing should only be used by sophisticated investors with adequate risk tolerance. As option strategies can be tailored to match one’s unique risk tolerance and return requirement, they provide many paths to profitability.

Sat, 02 Jul 2022 12:00:00 -0500 en text/html
Killexams : PSI Services Partner with American Association of Medical Assistants® to Implement and Expand CMA (AAMA)® Certification Testing Sites Nationwide

(GLENDALE, CALIFORNIA) — PSI Services LLC (PSI), a leading provider of high-stakes testing solutions, announced today its partnership with the American Association of Medical Assistants® (AAMA), the only organization devoted exclusively to the medical assisting profession. The partnership will enable co-development and administration for the CMA (AAMA)® Certification Exam, making the exam more convenient and accessible for candidates across the country.

PSI’s advanced credentialing solutions allow candidates to promptly register for the exam from a network of over 500 testing sites across the U.S. — increasing CMA (AAMA) Certification exam testing locations by 77%. Later this year, PSI will implement single sign-on to further streamline the test scheduling experience and minimize web user authentications.

“We’re pleased to be partnering with PSI to make the CMA (AAMA) Certification exam more widely available to candidates, while benefiting from the latest innovations to greatly streamline and Strengthen the testing experience,” says Vicki Sokolnik, CMA (AAMA), chair of the Certifying Board of the AAMA. “PSI is a thought leader in psychometric services, and their expertise will prove invaluable in building on the quality of the CMA (AAMA) Certification Exam, while helping to maintain and enhance its excellence.”

Medical assisting is one of the nation’s careers growing much faster than average for all occupations, according to the United States Bureau of Labor Statistics (BLS). With the ever-changing health care landscape, the CMA (AAMA) Certification exam will continue to evolve, using exam development services provided by PSI.

“We are thrilled to be supporting the mission of the AAMA in delivering more high-quality certified medical assistants and helping them take the next steps in their professional journey,” says Scott Hazlett, Vice President Certification, PSI.

Certification exams like the CMA (AAMA) Certification Exam offer proof that a medical assistant has achieved the highest standards of education and credentialing in the medical assisting field.

Exam candidates may begin scheduling with PSI on immediately.

For more information about the CMA (AAMA) Certification Exam, please visit or call the AAMA directly at 800/228-2262.


PSI Services LLC (PSI) is a global leader in secure, data-driven workforce solutions, providing best-in-class assessment content through technology. PSI’s Credentialing solutions deliver a science-based approach to testing across sectors, including certification, education and licensure. Leveraging next-generation technology, PSI’s proven test delivery model features world-class security, test development, multimodal and online proctoring and professional services. For more than 70 years, PSI has been a trusted provider to the world’s leading corporations, federal and state government agencies, professional associations, certifying bodies and leading academic institutions.


The American Association of Medical Assistants®, the only organization in the world devoted exclusively to the medical assisting profession, was established in 1956 and serves the interests of more than 92,000 medical assisting professionals. The American Association of Medical Assistants provides quality resources and educational opportunities for medical assistants by offering certification, advocacy for quality patient-centered health care, credential acknowledgment and scope-of-practice protection. For more information, visit

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Thu, 14 Jul 2022 04:43:00 -0500 eCampus News Staff en-US text/html
Killexams : News test scores show one-fifth of Alabama students are not proficient readers

HUNTSVILLE, Ala. (WHNT) — The state of Alabama has taken several steps in accurate years to try and Strengthen the practicing scores of elementary school students across the state, but practicing scores released from the part year show students are still performing at about the same level as 2019.

According to the 2021-22 ACAP scores, 22% of third graders in Alabama are not proficient readers.

However, the state average of a 78% practicing proficiency rate is better than some local averages.

The number of Huntsville City School students testing at or above their grade level is two points lower than the state average. 13 of the 26 elementary schools in Huntsville City Schools fall below the state average, including two schools where more than half of the students tested are not practicing at their grade level: Martin Luther King Jr. Elementary and James Dawson Elementary.

Huntsville City Schools board member Ryan Renaud said the problem starts before students reach the third grade, so early intervention is important.

“We really have to identify our students that are not on grade level before the third grade, which is why the ACAP specifically targets the third grade,” Renaud said. “A lot of our intervention strategies really focus on K-3, Kindergarten, first, second, and third grade because we know once they get to third grade, it’s much harder to get them back on track.”

In 2019, the Alabama Legislature passed the literacy act which offered to fund and created practicing programs for school districts, all to raise literacy rates in the state. According to the National Center for Education Statistics, Alabama consistently ranks in the bottom 25% of states for literacy.

Renaud said literacy is difficult to address on a broad scale.

“Education is not a one size fits all box, so you may have a student that’s on or below grade level. You may have one that’s two grades ahead, and all of those students are going to have a different strategic plan. That is where the burden falls on the educator in the classroom to work individually with each student.”

Renaud said the school district is working to support individual teachers and offer them resources, but state legislators may soon require schools to take more action.

The state’s literacy act includes a retention requirement which calls for students who fail to reach a proficient practicing level to be held back and repeat the third grade. The requirement was originally set to take effect during the 2021-22 school year, but through the pandemic, state officials pushed back the retention requirement to the 2023-24 school year.

Going by current scores, 419 third graders in Huntsville City Schools would be at risk of being held back, but schools have two more years to bring up practicing levels before they have to take that action.

Wed, 13 Jul 2022 12:05:00 -0500 en-US text/html
Killexams : Whole genome sequencing identifies causal variants in CMT

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Züchner, S. Whole genome sequencing identifies causal variants in CMT. Nat Rev Neurol 6, 424–425 (2010).

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Tue, 04 Jun 2019 08:14:00 -0500 en text/html
Killexams : USD/JPY Technical Analysis: A Classic Downtrend Faces a Major Test

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Talking Points:

  • USD/JPY Technical Strategy: As Resistance Holds, Bears Get Confidence
  • 200-WMA at 105.95 Feels Like The ‘Line In the Sand’ For Abenomics
  • US Dollar Direction In Question Amidst A Very Volatile Month

The Great Technical Squeeze Is Upon Us

On June 05, 2015 all was right in the world of USD/JPY Bulls. We had a daily high of 125.85, and many thought 130s were just around the corner. Then a quiet summer became a scary summer when China devalued the Yuan to bring their currency into alignment with “market realities” and a deflationary shock was sent through global markets. The JPY seemed to take this even the hardest providing a price range of 919 pips over August, and continuing to fall through June.

Over the last year, USD/JPY has fallen ~16%, and it’s easy to say the worst may not be over. While members of the Bank of Japan have warned that they’re keeping an eye on the exchange rate, we could be entering into a cyclical bull market much like we saw in 2008-2011.

One such evidence of a JPY Bull Market lies at 105.95 and the 200-Week Moving Average. The last time the price of USD/JPY broke below the 200-Week Moving Average was in 2008 at the ~113 level where the price would eventually fall to 75.55 for a ~33% drop.

While we are almost assured not to see a similar decline, it’s fair to say that a seismic shift could be underway in USD/JPY. Not only would we need to hold support, but we’d need to break above resistance, which hasn’t been possible lately. Therefore, it’s difficult to say with confidence that we’ll come out of this continual cycle of JPY strength.

Naturally, such a development would also further the evidence against the success of Abenomics, which appeared to use a weak JPY as a foundation to bring the export-dependent Japan back to its former economic glory.

USD/JPY Has Run Into LT Moving Average Support

USD/JPY Technical Analysis: A Classic Downtrend Faces a Major Test

The long-term chart that goes back to May 2013 shows three key macro technical developments. As mentioned above, the most significant is the 200-week moving average that currently sits at 105.95. Second to the 200-WMA is the ~105 zone which has been a long-term price pivot since 2013. The 105 handle has acted as a polarity point, and a break below this level could show a larger shift that continues to favor JPY bullishness. Last, but not least is the corrective price channel (red) that is drawn off the June 2015 high and August/November pivots.

The price of USD/JPY has traded within this channel successfully with only temporary, yet failed pushes toward resistance. Should homeostasis remain with JPY strength and gradual US Dollar weakness, we would expect to stay in this channel only further down. Current channel resistance aligns with the late April and late May highs of 111.87/43.

While Oscillating Since Late April, Support Is Expected To Be Tested & Possibly Break

USD/JPY Technical Analysis: A Classic Downtrend Faces a Major Test

Key USD/JPY Technical Levels:

When considering the technical evidence above, it appears clear that the burden of proof lies on the Bulls of USD/JPY. There is currently a good deal more preference for the downside even though we’re coming into major support at the 105 zone.

For the Bulls to get bragging rights, the first level we’d like to see break is the Weekly Pivot at 108.14, which lies close the 38.2% retracement of the June range. A break above there would start to turn attention to the Weekly Pivot Resistance levels and ultimately the late April & May highs of 111.87 and 111.43 respectively.

Until those levels breaks, time is likely better spent on understanding downside scenarios. June is not making this easy for us (or maybe making it very easy) given the significant event risk with FOMC & the EU Referendum over the next two weeks. Should a risk-off event, at least in terms of heightened volatility, develop, it would not be unlikely to see 100 USDJPY. In fact, across the board, the Japanese Yen could see a week akin to late August that could be a death blow to remaining JPY bears.

However, USD/JPY SentimentShows Bulls Are Getting Confident

USD/JPY Technical Analysis: A Classic Downtrend Faces a Major Test

As of mid-day Friday, the ratio of long to short positions in the USDJPY stands at 2.94 as 75% of traders are long. Short positions are 4.9% lower than yesterday and 7.0% above levels seen last week. Open interest is 11.5% above its monthly average. We use our SSI as a contrarian indicator to price action, and the fact that the majority of traders are long gives a signal that the USDJPY may continue lower. The trading crowd has grown further net-long from yesterday but moderated since last week.

Shorter-Term USD/JPY Technical Levels

For those interested in shorter-term levels of focus than the ones above, these levels signal important potential pivot levels over the next 48-hours.

USD/JPY Technical Analysis: A Classic Downtrend Faces a Major Test


DailyFX provides forex news and technical analysis on the trends that influence the global currency markets.

Sat, 16 Jul 2022 12:00:00 -0500 en text/html
Killexams : 2 Possible Market Outcomes After Incoming Inflation Data

Last Friday was the lightest full session of the year, regarding volume for the S&P 500 Index (SPX – 3,899.38). This is ahead of the much-anticipated inflation data set to be released on Wednesday, which is at the forefront of market participants’ minds as we head into options expiration week. Economists and strategists have been expecting inflation growth to slow, as expectations become more difficult to beat from the previous year. Still, we’ve yet to see this come to fruition in accurate reports, with the last consumer price index (CPI) practicing coming in at roughly 8.6% year-over-year.  

Furthermore, Federal Reserve committee members have remained steadfast in accurate comments that slowing the economy to curb inflation is the priority, no matter the pain it may cause. Members speaking last week continued to call for 50- to 75- basis point rate hikes in July, as inflation pressures remain. 


Additionally, widening credit spreads are a concern. One big difference I’ve noticed is the pace that the spreads are widening. In 2020, the rate was rapid, giving equities the capitulation moment they needed for a V-shaped recovery. This year’s momentum is much more aligned with the 2008-2009 and the 2014-2016 periods. Since bonds are just the inverse of yields, we can use proxy exchange-traded funds (ETFs) to see this spread action by utilizing the HYG/IEI ratio spread. As you can see in the chart, the slower the momentum, the longer it takes for the equity markets to find an ultimate bottom.


“...A move back above 3,850 in the SPX, at the very least, could drive a small rally to test the 40-day moving average, currently at the 3,948. This is where price action was capped multiple times in the early June bear rally. If price action can breach the 40-day moving average this time around, I'd expect a move back toward the upper rail of its current down trend that could push the SPX to the round 4,000-millennium level.”.”

Monday Morning Outlook, July 5, 2022 

Last week, bulls defended the SPX 3,750-level resiliently, as intraday breaks could never be held into the close. Moreover, Friday’s intraday high was just 6 points away from the 40-day moving average, which was the first bullish target we highlighted last week. Wednesday’s CPI data release will likely be the deciding factor in the near-term market direction.


If we see inflation cool, we can trade higher towards the upper rail of the downtrend and the July peak call level at the 400-strike. If inflation remains hot, a break back through 3,840 to resume the prolonged downtrend is the likely scenario. In that case, watch for a break of the SPDR S&P 500 ETF Trust (SPY – 388.67) 380-strike put, as that would open the vacuum to the large open interest 370-strike put, which had been the peak put level last week. Peak put now resides at the 350-strike, so an adverse reaction has the potential for a waterfall type of price action even if the probability is small.


The Nasdaq-100 (NDX – 12,125.69) is in a similar backdrop. Last week we saw the 40-month moving average continue to act as support, something it has done since November 2009. Furthermore, the NDX moved back above the three-year moving average and the 12,000-millennium level, after putting in a higher low. This is a critical technical step to re-establishing a bull market in the tech-heavy index.

While it’s too early to take a victory lap, since a lot can change between now and the end of July, it’s a constructive step in the right direction. When looking at the open interest configuration for the Invesco QQQ Trust (QQQ – 295.35), we see similarities, too. Peak call resides overhead at the 300-strike, which coincides with the June 9 gap down level. This could very well cap bullish price action for options expiration.


Unlike the SPY, the QQQ is already above the 40-day moving average that smothered the early June rally, and capped the upper bounds of the mid-April bear flag that led to an eventual -17% collapse over the next month. A definitive close above the 300 level and the tech-centric index could see a move to 315. The most likely scenario is we stay in a range between 280-300 for the week, but only time will tell.


“But that leaves questions that, unfortunately I cannot answer, but will certainly monitor. That question is: Does the sudden emergence of VIX call buyers mean significantly higher levels of volatility, despite the VIX near the top of this year's range? Or are the accurate actions of this crowd a contrarian indicator since the call buying occurred during, versus before, a VIX spike? Stay tuned.”

Monday Morning Outlook, June 18, 2022 

The CBOE Volatility Index (VIX – 24.64) dropped below the 25 level during the modest rally, after the 30 level capped volatility the prior week. However, the VIX call/put 10-day volume ratio continued to surge throughout the week, now at 4.36. This brings back the question we contemplated the other week: Is this a contrarian indicator this time, or is this another signal that we’re on the verge of experiencing another bout of volatility?

The 25-level contained VIX spikes in mid-2021, so will it act as support? In my opinion, the deciding factor will be a break below 24. This is the level we saw break during the March bear market rally, and the level that held in early June before we saw the next leg lower in equities.


With that said, the sentiment indicators we follow are still primed for a rally. Previously, we’ve discussed that just because sentiment is ripe for a rally, it often can act differently in bear market environments. The American Association of Individual Investors (AAII) data this past week clearly shows that bulls threw in the towel, as the bull practicing is in the 2nd percentile of all-time readings.

The bulls minus bears 4-week moving average has reached levels we have not seen since March 2009. However, bulls initially gave up in 2008 when, bear sterns went belly up, right before the worst of the Great Financial Crisis drawdown. Finally, our 10-day buy-to-open volume ratios for the SPX and NDX components continue decreasing leisurely. This isn’t optimal when looking at past behavior, and a more rapid descent would make me feel better about this rally.


Two very different outcomes are indeed at work here. Can the Fed engineer a softer landing, or can they spin the illusion of a soft landing long enough for a bear market rally to further develop? Or will we see that all confidence is lost in the Fed’s ability to control inflation, pushing them to become more aggressive with rate-hiking measures to stop inflation?

While I’d love to deliver you a concrete direction, I must continue to express caution during this modest rally until we see how markets react to the CPI data on Wednesday. So, keep your long equity exposure stops tight, and only add to long exposure with the VIX below 24. Conversely, if the 24 level holds, think about adding some hedges through VIX call options.    

Matthew Timpane is a Senior Market Strategist at Schaeffer's Investment Research

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Mon, 11 Jul 2022 01:14:00 -0500 en text/html
Killexams : More Than Meets the Ear No result found, try new keyword!The erythrocyte sedimentation rate was 117 mm per hour (normal value, <20), and the C-reactive protein level was 15 mg per deciliter (normal value, <3). A test for antinuclear antibodies (ANA ... Wed, 13 Jul 2022 12:00:00 -0500 en text/html Killexams : CTET exam Notification 2022: CTET notification to be released SOON at check details here No result found, try new keyword!A CTET certificate is essential for teaching candidates seeking employment in both public and private schools. Sun, 10 Jul 2022 23:51:05 -0500 en-in text/html Killexams : Painful and Non-painful Diabetic Neuropathy, Diagnostic Challenges and Implications for Future Management

Diagnostic Challenges

The diagnostic criteria of DN and painful DN vary considerably in questionnaires,[16] electrophysiological techniques,[17] hierarchical classification schemes,[18–20] and pathological and imaging diagnostic tools.[21,22] Each of these criteria have their pros and cons. There is a need for identifying criteria and classifications that consider both general practice and research requirements. To date, no single gold standard diagnostic test exists for DN or painful DN. It is still unknown which clinical questionnaires and neurological assessment parameters best distinguish individuals with DN and painful DN from those without these conditions. DN diagnosis is complex and no specific biomarker is available for the condition. To paraphrase England and Asbury[23] in a review over 15 years ago, diagnosing neuropathy depends on the examiner's skill for tying together symptoms, signs, and diagnostic test results. Unfortunately, this is still the case today.

Definitions and Hierarchical Classifications of DN and Painful DN

Numerous DN definitions have been suggested.[8,15,17,24–26] The Toronto Consensus Panel on Diabetic Neuropathy[15,17] distinguishes between typical and atypical DN, and defines typical DN as 'a symmetrical length-dependent sensorimotor polyneuropathy attributable to chronic hyperglycaemia, associated metabolic derangements, cardiovascular risk covariates, and microvessel alteration'. The Toronto definition also requires excluding other neuropathy causes, but does not specify which conditions require evaluation. The American Diabetes Association (ADA)[8] suggests that a simple definition for clinical practice is 'the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes'. Although electrodiagnostic tests are conventional for assessing large nerve fibre dysfunction, the ADA definition does not require an abnormal electrodiagnostic test for clinical neuropathy diagnosis. This position is supported by studies indicating that electrodiagnostic tests rarely change the aetiology and/or management of patients meeting a clinical DN definition.[27,28] For research purposes, however, it may be necessary to include additional tests to provide quantitative information on nerve injury and greater certainty that participants have DN.

Because of the lack of a gold standard test for diagnosing DN, hierarchical systems have been proposed over the years. In 2005, a report from three different American associations concluded that 'the combination of symptoms, signs and electrodiagnostic findings provides the most accurate diagnosis of distal symmetric polyneuropathy'.[29] The report further added that multiple symptoms and signs combined with electrodiagnostic examinations provide the highest degree of certainty for polyneuropathy. A limitation of this approach is that it does not specify which symptoms and signs should be used, nor does it specify clear DN categories.

Similarly, the Toronto Consensus Panel proposed a hierarchical DN classification, but provided distinct DN categories graded as possible, probable, or definite neuropathy (Figure 1). Fulfilling the Toronto Consensus Panel definition for a definite DN diagnosis requires symptoms or clinical signs of nerve dysfunction together with a positive confirmative test of either small or large nerve fibre dysfunction.[15,17] Although DN usually causes injury to both small and large nerve fibres, a pure or isolated SFN also exists. SFN represents a separate entity characterized by specific damage to unmyelinated C and thinly myelinated Aδ type fibres.[9,31–35] Like DN, no gold standard exists for diagnosing pure or isolated SFN. Therefore, a grading system has been suggested for SFN in diabetes, similar to the one proposed by the Toronto Consensus panel for DN.[9]

Figure 1.

Research definition of DN by the Toronto classification15 and painful DN, modified from the NeuPSIG grading system of neuropathic pain.30

Neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory nervous system.[36] Accordingly, painful DN can be defined as pain caused by damage to the peripheral somatosensory system attributable to diabetes and manifests as sensory abnormalities in the innervation territory of the damaged nerves. Like DN, no gold standard definition of painful DN exists; however, a hierarchical grading scheme has been proposed for neuropathic pain, which can be applied to painful DN.[30,37] Specifically, painful DN can be rated as either possible (diabetes and pain distribution in stocking glove distribution), probable (sensory signs in a stocking glove distribution), or definite (confirmatory DN test) (Figure 1). The grading system represents the level of certainty that the pain is neuropathic in nature, which is naturally based on a clinical judgement in which the skills and experience of the examiners are important elements.

Currently, hierarchical systems that combine symptoms, signs, and confirmatory tests are recommended for clinical research. However, issues remain, including clarification of the specific symptoms, signs, and confirmatory tests to use, as well as the incorporation bias that typically exists when comparing other neuropathy outcomes to these hierarchical systems. In clinical practice, confirmatory tests are often not needed, but challenges remain, for weighing specific symptoms and signs to draw a clinical diagnosis.

Sensory Manifestations of DN

DN is characterized by multiple manifestations of which sensory symptoms and examination findings are the most common and earliest features. Diagnosing the sensory manifestations of DN relies on the history and presence of clinical signs (Figure 2). DN manifests as bilateral, symmetric, and length-dependent nerve fibre damage, which affects the longest and most susceptible nerve fibres first and progresses distally-to-proximally in a stocking glove pattern.[23] Thus, the history is generally straightforward, with symptoms of negative or positive sensations, starting in the toes and soles of the feet, and gradually ascending to involve the lower leg. When symptoms have reached the upper shins or knees, they often begin to appear in the fingertips and may subsequently spread further up the arms.[10,11,38,39] Negative sensations include numbness or a lack of sensation to feeling; for SFN, it is specifically loss of pain and thermal sensation. Positive sensations are multiple in character, reflecting activity in nerve fibres of varying calibres and serving various sensory modalities.

Figure 2.

Summary of symptoms, examination for signs, and additional tests to diagnose DN or painful DN. Clinical testing should fulfil typical DN pattern, i.e. symmetrical presentation with a distal-to-proximal gradient. Touch examination is performed with a 10 g monofilament, vibration with a 128 Hz tuning fork, pinprick with a sharp pin, and cold and warm with standardized cold and warm thermorollers.

Many patients with sensory DN are asymptomatic and abnormalities may only be revealed during the clinical examination. The sensory examination in DN usually reveals impaired nerve function with reduced or abolished sensation to touch, pinprick, temperature, vibration, and, more rarely, proprioception. Clinically evaluating small fibre function can involve determining the distal sensation to pinprick and a cold or warm thermal stimulus. The proximal limit of sensory abnormality is determined by moving the individual test paradigms proximally. Generally, sensory losses have the same characteristic stocking glove-like distribution as the sensory symptoms. Positive signs in DN, such as allodynia and hypersensitivity to different sensory stimuli, can be quantitated by measuring the intensity or area of these phenomena.[40] However, in DN, these positive signs are rare compared to other types of peripheral nerve disorders with pain. Clinically assessing large fibre function can include examining vibration sensation to a 128 Hz tuning fork, light touch perception with a 10 g monofilament on the dorsal aspect of the great toe,[41] and position sense of the same toe. Reduction or loss of ankle reflexes and other deep tendon reflexes is also a common DN feature. However, reduced ankle reflexes are common in older individuals without other neuropathy symptoms or signs.

DN sensory examinations are challenging, in part due to the large degree of variation in study populations and how, when, and where clinicians should test for different clinical signs.[42] For example, the modified version of the Toronto Clinical Neuropathy Score[20] excluded the tendon reflex score from the earlier version[43] because of its low sensitivity for detecting early DN. In a study by Dyck and colleagues[44] of 12 experienced physicians who assessed in a blinded manner 24 diabetes individuals with and without neuropathy for the presence of clinical neuropathy signs, there was 'considerable and excessive variability among physician judgement of signs, symptoms, and diagnosis'. This study indicates that clinical findings have limitations, which may be surmounted in a setting where specific tests or scales are performed (see 'Clinical scaling of DN' section).

It is generally held that DN begins with small unmyelinated nerve fibre injury, followed by damage to small myelinated nerve fibres, and, as the disease progresses, injury to large myelinated nerve fibres.[12,45] However, no prospective longitudinal studies are available to confirm or refute this idea. The accurate Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen Detected Diabetes in Primary Care (ADDITION-Denmark) study showed that progression did not necessarily occur from small to large fibre symptoms based on the Michigan Neuropathy Screening Instrument questionnaire (MNSIq).[46] Future studies are needed to longitudinally examine the symptoms and pathological changes in DN. Because of the uncertain course in the relative temporal dysfunction in and large fibre neuropathy, a single diagnostic DN criterion may not be expected to be valid throughout DN course. Currently, the ADA recommends that the annual clinical assessment should include a careful history, examination of vibration sensation using a 128-Hz tuning fork (large fibre function), and temperature or pinprick sensation (small fibre function) assessed at the base of the first toe to follow the progression of neuropathy. On the other hand, a 10-g monofilament sensory test in specified areas on the plantar surface of the feet has been proposed as a test to determine the risk for development of foot ulcers. However, since most diabetes patients are reviewed by general practitioners or at busy diabetic clinics, where neuropathy is only one among several possible complications, there is limited time for examining the patient. As a result, rapid sensitive and specific tests that do not require specialty training will ultimately be needed.

Motor Manifestations of DN

Motor dysfunction in DN can be due to different causes, including neuropathy or myopathy. Motor neuropathy only appears clinically in a small proportion of patients, primarily in more advanced DN stages. Motor neuropathy in DN may lead to motor dysfunction, resulting in postural instability, impaired gait, frequent falls, severe injuries, and, ultimately, higher morbidity and mortality.[47] Motor dysfunction negatively affects independence and capability to perform daily living activities, lowering quality of life. Motor neuropathy can be diagnosed by a clinical examination, including muscle strength and muscle atrophy evaluation combined with nerve conduction studies (NCS) to assess motor nerve function. Axonal degeneration in motor neuropathy also leads to in muscle fibre denervation. Collateral reinnervation compensates for this denervation;[48] however, as this compensatory mechanism fails, muscle atrophy and concomitant neurogenic muscle weakness develops.[49–51] In a previous DN scale proposed by Dyck and colleagues,[52] the inability to stand on heels was used to define more severe DN (stage 2B), as it was thought to reflect motor neuropathy. However, this test has not been validated in larger cohorts.

In diabetes, motor neuropathy is commonly based on NCS abnormalities, which even occur in the earlier disease stages.[53] Milder forms of motor neuropathy are often undiagnosed. This may partly be explained by a lack of screening tests for motor neuropathy in standardized DN examinations. If a diabetes patient presents with substantial motor dysfunction early in the DN course, aetiologies other than classical DN should be considered, including focal diabetic neuropathies (radiculo-plexopathies) and immune-mediated neuropathies, such as chronic inflammatory demyelinating polyneuropathy,[54] as well as a differential diagnosis for Charcot-Marie-Tooth disease (CMT) or other hereditary neuropathies.

In addition to a motor neuropathy, more accurate studies indicate that diabetes may also deliver rise to a mild myopathy resulting in lower muscle strength due to lower muscle quality.[55] Thus, in diabetes, muscle weakness may develop secondary to DN, but myopathic changes may also contribute to impaired muscle function. Alterations in muscle morphology lead to impaired muscle function, insulin sensitivity, glucose utilization, and decreased energy reserves. However, due to fat infiltration and fibrosis, the muscle may have a normal cross-sectional size. The contribution of diabetic motor neuropathy and diabetic myopathy on muscle dysfunction cannot be differentiated clinically. NCS combined with muscle biopsies and imaging (MRI and ultrasonography) may lead to a more detailed understanding of the relative importance of motor neuropathy versus myopathy in DN patients. Prospective studies of longitudinal MRI changes are needed to determine if such MRI findings are early markers of motor impairment.

In summary, DN motor dysfunction occurs much later than sensory dysfunction and is multifactorial through motor neuropathy and myopathy. The complexity of motor dysfunction in diabetes hinders identifying the underlying causes of motor weakness, poor ambulation, and falls, and hence management. Given its high morbidity, future work should focus on understanding motor disturbances as an important diabetes complication.

Additional Diagnostic Tests in DN

In addition to simple bedside tests, quantitative diagnostic tests have been developed to Strengthen the likelihood of a clinical DN diagnosis and as potential outcomes in research studies. Examples include electrophysiological examinations, quantitative sensory testing (QST), skin biopsies, cornea confocal microscopy (CCM), and point-of-care devices (POCD).[56] We briefly review the most frequently used confirmatory tests below.


Although NCS are not typically required for clinical DN evaluation, they are an important tool for quantitatively assessing large fibre involvement in DN for research studies and clinical care of patients with atypical neuropathy and/or unclear symptom localization. The sural nerve is most often examined in DN electrodiagnostic studies, usually through antidromic surface recordings, although its sensitivity is lower than needle electrode recordings.[57] However, needle recordings are only used at a few centres, mainly because it is time consuming and unpleasant. In a accurate study, examination of the distal segment of the sural and medial plantar nerves with surface electrodes was as sensitive as needle recordings in polyneuropathy of different aetiologies.[53,58]

Several studies have documented a higher sensitivity from NCS at sensory nerves more distal than sural nerve examination for DN diagnosis, but at the expense of specificity.[59,60]

Taking into account the length-dependent feature of DN, electrodiagnostic studies should include lower extremity nerves, i.e. sural, peroneal, and tibial nerves. Since DN is usually symmetric, bilateral NCS are usually not necessary for evaluating DN.[53,61] The best NCS criteria for diagnosing DN are difficult to establish given the lack of a gold standard test with which to compare different NCS definitions. Experts have proposed using an abnormality in the sural nerve with at least one other NCS abnormality.[17,53,62] Abnormality in either velocity or amplitude is often enough based on DN recommendations[17] and in polyneuropathy of different aetiologies.[53] Another approach recommended by Dyck and co-workers[17] is to use composite scores from multiple nerves calculated by taking the sum of their Z-scores compared to the same set of nerve NCS from a control population. Further studies are necessary to determine the best NCS definition for DN. While NCS is unlikely to change the management of patients with DN, these tests are essential for patients with atypical neuropathy and/or difficulty localizing symptoms within the nervous system. NCS are also key research tests to quantitatively assess large nerve fibre function.

Quantitative Sensory Testing

QST is a psychophysical method for assessing somatosensory functions, which was originally presented as a simple perceptive response measure to thermal and vibratory stimuli.[63–65] It has now developed into a detailed standardized tool where the response to multiple, well-defined painful and non-painful stimuli are measured. The QST protocol developed by the German Research Network on Neuropathic Pain[66,67] assesses 13 parameters, including thermal and mechanical detection, pain thresholds, vibration thresholds, dynamic mechanical allodynia, wind-up ratio, and pressure pain threshold. These different tests measure the function of all afferent fibre classes, Aβ, Aδ, and C fibres. Raw QST data can be transformed into Z-scores normalized to age, sex, and body location, to generate a sensory profile, which includes sensory loss and hypersensitivity to thermal and mechanical stimuli.[66,67] As such, QST can assess the functional status of sensory receptor systems, their afferent projections via large and small afferents, and how this somatosensory input is processed in the CNS.[68–70]

In patients with various types of neuropathic pain, regardless of underlying aetiology, it is possible to delineate distinct patient clusters based on their sensory profile. For example, Baron and colleagues[71] found that three different patient clusters could be delineated by 13 different types of sensory stimulation paradigms. One cluster was dominated by sensory loss, one by thermal hyperalgesia, and one by mechanical hyperalgesia. These different clusters may represent distinct pathophysiological mechanisms that drive pain. For example, patients with diabetic and other neuropathies have more signs of sensory loss than hypersensitivity, suggesting that deafferentation rather than peripheral sensitization is the most likely mechanism in this profile. However, future studies are needed to confirm this hypothesis.

Most of the functions examined in the current QST protocols reflect sensory activity from skin, but not sensory functions from deep tissue innervation. It is possible that the pain generator in certain patients with painful DN may be related to abnormalities in deep tissue somatosensory innervation, but this requires further investigation.

In conclusion, QST represents a tool to identify separate specific sensory DN profiles if used in a standardized way, possibly reflecting separate underlying pathophysiological mechanisms. As such, QST may be used in clinical trials as an instrument to link mechanisms of pain with specific drug actions, as reviewed below. However, much work is needed to clarify the role of QST in research and clinical care.

Skin Biopsy

Skin biopsy with intraepidermal nerve fibre density (IENFD) quantification is considered the pathological gold standard for diagnosing small fibre pathology in diabetes[9] (Figure 3). IENFD is reproducible with good diagnostic specificity and sensitivity, as well as favourable positive and negative predictive values.[72] This test is not usually needed for clinically diagnosed DN, because it has not been shown to affect clinical management. However, skin biopsies are the best quantitative small fibre measure for research studies, and are more likely to Strengthen upon reinnervation than NCS. A joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society published guidelines regarding the use of skin biopsy for demonstrating small fibre pathology.[21] The recommendation is to take a 3-mm punch biopsy from the distal leg, 7–10 cm above the lateral malleolus, and compare to normative reference values based on distal leg in age- and sex-matched populations, both for bright field microscopy and for indirect immunofluorescence.[73,74] An additional biopsy can be taken from the lateral distal thigh (7–10 cm above the knee) or at the lateral proximal thigh (7–10 cm below the greater trochanter) for evaluating small fibre pathology severity and distribution (length-dependent versus non-length-dependent).[75,76] Since DN is typically length-dependent, the distal biopsy will have fewer fibres per millimetre than at the proximal biopsy.

Figure 3.

Different skin nerve fibre changes in diabetic neuropathy. (A) PGP9.5+ intraepidermal nerve fibres (arrows) in a healthy individual. (B) DN patient with severe fibre loss. (C) High magnification of intraepidermal nerve fibres in a healthy individual (note absence of axonal swellings). (D) High magnification of intraepidermal nerve fibres in a DN patient (note presence of axonal swellings, arrows). (E) CGRP+ nerve fibres in a patient with painful DN. (F) High magnification of a CGRP+ nerve. CGRP = calcitonin gene related peptide; PGP9.5 = neuronal marker.

An important pathophysiological issue in diabetic neuropathies concerns the relationship between structural findings and function. It is still unclear whether reduced IENFD correlates with DN symptomatology, such as development or maintenance of neuropathic pain. A accurate systematic review found that only 44% of studies reported associations between IENFD and symptoms, such as patient-reported pain.[77] The same review also concluded that IENFD correlated better with objective tests, such as contact heat- or laser-evoked potentials, than with neuropathy instruments that quantify symptoms and signs (e.g. MNSI, Toronto Neuropathy Score). Importantly, the review also revealed that there may be better association between IENFD and QST measurements in DN than in non-diabetic neuropathies. Indeed, straightforward nerve fibre quantification only informs their density, not their physiological condition (e.g. whether they are hypersensitive, hyposensitive, or normal).

While most DN studies solely quantify IENFD from skin biopsies, it is also possible to measure other morphological changes in the skin, such as dermal nerve fibre length, nerve branching, and axonal swellings (Figure 4).[77,79–82] Axonal swellings, which possibly represent degenerating small nerve fibres,[75] are elevated in DN,[83,84] and may precede nerve fibre loss, as suggested by a accurate study.[85] Molecular changes can also be determined from diabetic skin biopsies. For instance, accurate data indicate that patients with painful DN have higher densities of nerve fibres that are positive for substance P, calcitonin gene-related peptide,[86] and growth associated protein 43,[80] compared to patients without painful neuropathy (Figure 4). Macrophages and 'nociceptive' Schwann cells are other biomarker examples that can be examined in skin biopsies. Specifically, accurate studies suggests that DN patients have increased macrophage infiltration into the skin, which may be leveraged as novel treatment targets for neuropathic pain in diabetes.[87,88]

Figure 4.

Correlation of median scores of the MNSI examination part, TCNS and UENS across DN groups, including controls without diabetes, and receiver operating characteristic (ROC) areas. MNSI: rs 0.61, P &lt; 0.001, ROC area: 0.71; Toronto Clinical Neuropathy Score (TCNS): rs 0.79, P &lt; 0.001, ROC area: 0.69; Utah Early Neuropathy Scale (UENS): rs 0.73, P &lt; 0.001, ROC area: 0.66. Modified from Gylfadottir et al.78

In summary, skin biopsies represent an important tool for detecting small fibre abnormalities in diabetes through straightforward structural changes in reduced epidermal nerve fibre density and in quantifiable molecular changes. IENFD continues to be an important method for understanding the structure-function relationship and a useful instrument to prospectively track small fibre structural changes induced by different interventions. The main disadvantages of skin biopsy are invasiveness, relatively high cost, and requirement for highly specialized and trained staff. Moreover, the results are highly dependent on tissue handling and staining quality.

Cornea Confocal Microscopy

CCM is a non-invasive measure of corneal small fibre damage, which has emerged as an alternative to skin biopsies. CCM quantifies corneal nerve fibre density (CNFD), corneal nerve fibre length (CNFL), and corneal nerve branch density (CNBD), which some studies have shown are reduced in DN, especially CNFD and CNFL.[22,89,90] However, a accurate study reported that CCM could not distinguish type 2 diabetes patients with and without neuropathy.[91] The largest study of diabetes patients to date (n = 998), using optimal CNFL thresholds and automated analysis, found CNFL had 73% sensitivity and 69% specificity for detecting type 1 diabetes DN, and 69% sensitivity and 63% specificity for detecting type 2 diabetes DN.[92] Other studies also found good, but not great, CCM sensitivity and specificity for diagnosing DN.[90,93]

There are methodological challenges for objectively sampling and recording CCM images because the examiner is typically not blinded during image acquisition and the selection method for 'good' images for analysis varies between studies. Additionally, due to corneal curvature, its borders are out of focus when its centre is in focus, and the size of the focused area varies. A accurate methodological study addressed these issues using stereology randomized sampling and adjusted area calculation, which was compared head-to-head to the usual method.[94,95] The updated method, which avoids subjective CCM image selection bias, increased the absolute CCM values by 8–40% versus the usual method, and showed comparable differences between healthy individuals and DN patients. Furthermore, although CCM can be assessed manually and automatically, normative reference values are only available for the manual method, whose values are higher than by the automatic method.[96] Thus, the best measurement method remains to be determined.

Another important challenge is the unclear relationship between CCM measures and IENFD from skin biopsy. The diagnostic characteristics of these two techniques seem comparable, but variation exists amongst studies and head-to-head comparisons are not available.[90,93,95] CCM is promising as a non-invasive measure of small nerve fibre loss in diabetes, but more work remains to establish its role in research studies, including patient preference between CCM and skin biopsy. Importantly, the clinical roles of CCM and skin biopsies are also unclear, as neither are established tests for routinely assessing DN.[97]

Point-of-care Devices

Most of the above additional tests are time consuming, some are invasive, and they all require specific expertise; therefore, they are not suitable for routine screening in general practice. More recently, a series of non-invasive, easy and rapid POCDs have been introduced to facilitate nerve function examination in patients suspected of having a neuropathy. These POCDs include examination of sural nerve conduction velocity,[98–100] sweat production on the foot plantar,[101] and other devices to measure sudomotor function in both hands and feet.[102] A accurate review demonstrated these POCDs have acceptable sensitivity[10] and may be useful as future screening tools in patients to evaluate risk of deleterious outcomes, such as foot ulceration and amputation.[10] However, there is a need for large, prospective studies to rigorously evaluate these POCDs versus conventional test procedures and/or clinical examination tools, to determine their value for detecting DN early.

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