by Jennifer F. Kawwass, MD and Heather S. Hipp, MD

Polycystic Ovary Syndrome, or PCOS, the enigmatic syndrome ascribed to infertile, overweight females with irregular menstrual cycles, may be simpler to understand than it seems. The syndrome can be confusing: no clear linear causal pathway has been elucidated, and many endocrine axes interact to accentuate the classical physical manifestations. In addition, it is a broad diagnosis, and many women with PCOS do not fit the stereotypical PCOS mold.

Despite the heterogeneity of women that can meet criteria for PCOS, understanding the diagnostic basics can make the syndrome much easier to recognize.

Importantly, the diagnosis is independent of body mass index (BMI) or weight. In fact, 10-15 percent of women with PCOS are lean with a normal BMI. According to the 2003 NIH Rotterdam criteria, a diagnosis of PCOS requires two of the following three characteristics:

1. Oligoovulation and/or anovulation (i.e. irregular menstrual cycles)
Can be determined by patient history: menstrual cycles occurring in an unpredictable pattern or greater than 42 days apart are suggestive of anovulation.

2. Elevated androgens (clinical and/or biochemical)
Can be determined by laboratory value of testosterone above the female reference range or by clinical signs of hirsutism/ acne that exceed ethnic norms.

3. Polycystic appearing ovaries on transvaginal ultrasound
Can be determined by ultrasound assessment of the ovaries having a “PCOS” appearance. A formal antral follicle count (12 or more follicles measuring 2-9mm in diameter) on each ovary can also be done.

Although AMH is not part of the diagnostic criteria, an elevated AMH (e.g. over 4 ng/mL) in combination with the other diagnostic criteria is suggestive of PCOS.

Given that the criteria only requires two of the three above characteristics, women may have PCOS without hyperandrogenism or irregular cycles. There is a sub-category of women with PCOS who are lean (aka “lean PCOS”). These women often do not have hyperandrogenism and present with infertility due to anovulation. Due to their BMI, they are sometimes diagnosed with functional hypothalamic amenorrhea (see below), which is treated in a different fashion.

The primary tenet in diagnosing PCOS is appreciation that it is a diagnosis of exclusion. One can only clearly diagnose a woman as having PCOS after ruling out all potential masqueraders. As women with PCOS often present with irregular or absent menstrual cycles, excluding other causes of amenorrhea or oligomenorrhea is usually a good place to start. Common masqueraders include pregnancy, thyroid disease and hyperprolactinemia, which can be assessed with a laboratory evaluation including bHCG, a TSH a prolactin. A more rare cause is delayed onset congenital adrenal hyperplasia (CAH), which is screened for with 17-hydroxyprogesterone.

On a patient-specific basis, one can also screen for other rare causes of oligomenorrhea: Cushing’s syndrome in someone with rapid weight gain and new-onset hypertension, an ovarian or adrenal testosterone-secreting tumor in an individual with rapid-onset severe virilization, or acromegaly in someone with increasing glove, shoe or hat size. Most often, however, ruling out pregnancy, pituitary and thyroid disease, and CAH is a reasonable place to start.

Particularly in a lean woman with absent cycles, functional hypothalamic amenorrhea (FHA) may cause absent periods and may even be present in addition to underlying PCOS. Women with FHA typically present with a low BMI and a history consistent with excessive exercise or calorie restriction. If the FSH, LH, and estradiol are all low or in the low range of normal, referral to a reproductive endocrinologist for help with treatment of FHA would be reasonable.

Lastly, severe diminished ovarian reserve can cause irregular cycles. It can be very helpful to ascertain ovarian reserve and hypothalamic-pituitary-ovarian function. An overweight patient with irregular cycles may actually have diminished ovarian reserve and not PCOS. Obesity and irregular cycles are not synonymous with PCOS. An FSH and estradiol in the early follicular phase or after a progesterone-induced bleed may help clarify ovarian reserve in a patient that is not on oral contraceptives. An FSH over 10 would suggest diminished ovarian reserve and not PCOS. An anti-mullerian hormone (AMH) or transvaginal ultrasound with antral follicle count (AFC) may also help in the differentiation.

Adolescents are a unique population. Because of young age and resultant robust ovarian reserve, polycystic ovarian morphology may not necessarily represent PCOS. Moreover, oligomenorrhea is normal around the time of menarche. Some researchers argue that to give a diagnosis of PCOS to an adolescent, she must have all three of the Rotterdam criteria.

Lifestyle counseling is warranted in women with a diagnosis of PCOS. For women who are overweight, a 5-10 percent weight loss has been associated with improvement in menstrual regularity and resumption of menses. Counseling regarding heightened risk of insulin resistance compared to women without PCOS may also help guide dietary and exercise choices for patients with the syndrome. Finally, when not trying to conceive, the importance of uterine lining protection with some form of hormonal contraception, including intrauterine devices, is worth discussing.

The next step is to determine fertility intentions. The treatment course diverges based on desire for either fertility or contraception. For those who are not currently interested in conceiving, oral contraceptive pills (OCPs) are often the first line of treatment. OCPs offer endometrial lining protection and can also improve symptoms of hyperandrogenism.

For those who desire pregnancy, the first line agent for ovulation induction is letrozole. Referral to an REI is reasonable before attempt at ovulation induction or after one to three cycles of failed attempts at pregnancy with the use of ovulation induction.

Women who have PCOS are at a higher lifetime risk of diabetes and, when pregnant, gestational diabetes, even if they are lean. Screening for diabetes should be strongly considered in any women with PCOS; this can be done with a hemoglobin A1c or a 2-hour oral glucose tolerance test. If pre-diabetes is diagnosed, Metformin can be offered to aid in insulin resistance and, in some women, weight loss.

It is also possible that someone on the PCOS-spectrum may develop more overt symptoms with weight gain. As such, a female with mild PCOS may benefit from counseling regarding the avoidance of weight gain.

PCOS affects 10-15 percent of reproductive-age women. As a result, it warrants the attention of not only obstetrician gynecologists, but also physicians in other specialties. The associated cardiovascular, endocrine and fertility sequelae can impact all aspects of a PCOS female’s medical care.

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References
Carmina, E, Oberfield, SE, Lobo, RA. “The diagnosis of polycystic ovary syndrome in adolescents.” Am J Obstet Gynecol; 2010; 03 (3): 201. E1-5.

Good C, Tulchinsky M, et al. “Bone Mineral density and body composition in lean women with polcystic ovary syndrome.” Fertility and Sterility 1999; 72: 21-25.

Goodman NF, Cobin RH, et al. “American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society Disease State Clinical Review: Guide to the Best practices in the Evaluation and Treatment of Polycystic Ovary Syndrome- Part 2.” Endocr Pract 2015; 21: 1415-1426

Goyal, M, Dawood, AS. “Debates regarding lean patients with polycystic ovary syndrome: A narrative review.” J Hum Reprod Sci. 2017; 10 (3): 154-161.

By Alexis P. Calloway, M.D.

Much focus is given to the long- and short-term impact of commonly tested sexually transmitted infections such as HIV, chlamydia, gonorrhea and HPV on reproductive health. As the medical landscape of diagnosis and therapeutic options for infertility evolve, it is just as important to focus on viral hepatitis as well, with particular emphasis on Hepatitis B and C.

Viral Hepatitis in the United States
According to the Centers for Disease Control and Prevention (CDC), there were an estimated 33,900 new Hepatitis C virus ( HCV) infections in 2015, representing a 2.9-fold increase since 2010 with 75 percent to 85 percent of infections becoming chronic. The estimated number of new Hepatitis B virus (HBV) infections in 2015 was 21,900, however these rates are decreasing.

HCV is generally acquired through IV drug use and blood transfusions until changes in screening regulation for donations in the early 1990s. HCV can rarely also be acquired through sexual transmission. Alternatively, HBV is commonly acquired through sexual transmission, particularly in heterosexuals with multiple partners and unvaccinated men who have sex with men. Other common sources of transmission for HBV include mother-to- child transmission (MTCT), intravenous drug abuse and rarely through paternal transmission. (Iqbal et al., 2015) Chronic viral hepatitis, with HCV accounting for the majority of cases, is one of the most common causes of cirrhosis in the U.S. and carries a significant burden on the healthcare system. Given the multifaceted impact to the body, it is unknown what the specific burden to reproductive health may be.

Viral Hepatitis and Male Fertility
It is already known that many chronic viruses have the ability to infect sperm and adversely impact male fertility. Specifically in the last decade, it has been found that HCV causes a statistically significant decrease in semen volume, sperm count and progressive sperm motility and an increase in abnormal sperm morphology compared with healthy controls. Furthermore, the duration of HCV infection has been negatively correlated with semen volume and sperm motility where the HCV RNA viral load was negatively correlated with sperm count and sperm motility. (Hofny et al., 2011) In a study published in 2011, it was found that couples whose male partner was infected with HBV had a higher risk of low fertility rates after IVF, a risk which was independent from the initial sperm motility. (Oger et al., 2011)

As viral hepatitis may be asymptomatic until the onset of advanced disease, these barriers may not be identified as a potential etiology for infertility in younger populations. Targeted screening in this at-risk group may be of benefit in reproductive counseling, though no clear guidelines have been established. Some literature does attempt to address the issue of disparity of screening asymptomatic men in comparison to their heterosexual partners.

In a study of 1,243 male partners of 2,400 women who attended ultrasound examinations between 2010 and 2011, 430 accepted HIV and STI testing. It was ultimately found this is an acceptable time to feasibly engage the heterosexual male partner for screening. (Dhairyawan, Creighton, Sivyour, & Anderson, 2012) Other opportunities may arise to address screening and should be pursued on an individual basis by the patient’s healthcare provider.

Viral Hepatitis and Female Fertility
Menstrual disorders serve as the predominant cause of reproductive barriers in a patient affected with HBV and HCV due to intra- and extrahepatic pathology (as displayed in Table 1). (Kurmanova, Kurmanova, & Lokshin, 2016) Premenopausal women who are HCV positive or have chronic liver disease are at risk for premature ovarian failure impacting their lifelong fertility.

A study published in 2017 found that most new cases of HCV infection are among people who inject drugs, including reproductive-age females. Reproductive-age women who are HCV positive display markers of ovarian failure. This is associated with infertility and adverse pregnancy outcomes such as stillbirth, miscarriage, fewer live births and gestational diabetes. (Karampatou et al., 2017)

There is not much research surrounding the impact of HBV on reproduction in women specifically. One small study measuring pregnancy rates and implantation rates of HBV-sero- positive women and their partners found a higher rate of tubal blockage, often leading to signficantly higher rates of IVF and embryo transfer cycles if at least one partner was positive when compared to seronegative control couples. (Lam et al., 2010)

No matter the etiology, there are overarching impacts of cirrhosis on the reproductive health of women. Cirrhosis leading to generalized infertility and pregnancy is rare, but when it does occur specialized care is required.

Viral Hepatitis and the Pregnant Patient
Mother-to-child transmission is responsible for more than one third to one half of chronic HBV infections worldwide and can occur during pregnancy, delivery or after birth if not treated. Acute HBV infection during pregnancy is usually mild and not associated with increased mortality or teratogenicity. However, transmission rates significantly increase if acute infection occurs in the perinatal period, with rates as high as 60 percent reported. (Sookoian, 2006)

Chronic hepatitis B serves as a larger medical management consideration with emphasis on decision to treat during pregnancy with anti-retroviral therapy. This decision is generally influenced by ALT elevation greater than two times the upper limit of normal, HBV DNA levels, detection of Hepatitis B Surface Antigen (HBSAg) and anti-Hepatitis B e antibody (anti-HBe), and the presence or absence of cirrhosis.

Women with high viral loads (HBV DNA) in the third trimester should be treated even in the setting of normal ALT to decrease the vertical transmission risk to the infant. Furthermore, neonates of HBSAg-positive mothers should receive monovalent hepatitis B vaccine and HBIG 0.5ml as soon after delivery as possible (preferably within 12-24 hours) regardless of birth weight. (Committee On Infectious, Committee On, & Newborn, 2017) As perinatal transmission of HCV is unlikely, decision to treat can be deferred until after delivery. Subspecialist assistance may serve valuable in determining patient candidacy and timing for treatment.

Though HCV can be detected in maternal colostrum, this is not considered a factor associated with vertical transmission. In a study of 76 samples of breast milk from 73 chronically HCV-infected mothers, none of the samples contained HCV RNA and only one of the breastfed infants had evidence of HCV one month after birth without clear correlation to breastfeeding itself. (Polywka, Schroter, Feucht, Zollner, & Laufs, 1999) It is accepted by multiple organizations that breastfeeding is considered generally safe in asymptomatic HCV-positive mothers.

Reproductive Planning
Though initially targeted for the baby boomer population, emerging and highly effective therapies for HCV may prove beneficial to improving infertility in reproductive-age individuals burdened with this disease as well. Rates of sustained virologic response (SVR) have been found to be in the high 90th percentile for patients with common genotypes of the virus undergoing eight or 12 weeks of treatment. (Terrault et al., 2016)

Additionally, treatment is beneficial as early menopause in patients with chronic HCV was associated with low likelihood of SVR likely due to inflammatory factors and physiologic variations in estrogen that change at menopause. (Villa et al., 2011) Vaccination should also be pursued in household and sexual contacts for those with HBV.

As providers, viral hepatitis should be a part of the reproductive health discussion, with appropriate screening and treatment as indicated in this special and occasionally missed population.

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References
Committee On Infectious, D., Committee On, F., & Newborn. (2017). Elimination of Perinatal Hepatitis B: Providing the First Vaccine Dose Within 24 Hours of Birth. Pediatrics, 140(3). doi:10.1542/peds.2017-1870
Dhairyawan, R., Creighton, S., Sivyour, L., & Anderson, J. (2012). Testing the fathers: carrying out HIV and STI tests on partners of pregnant women. Sex Transm Infect, 88(3), 184-186. doi:10.1136/sextrans-2011-050232

Hofny, E. R., Ali, M. E., Taha, E. A., Nafeh, H. M., Sayed, D. S., Abdel-Azeem, H. G., . . . Mostafa, T. (2011). Semen and hormonal parameters in men with chronic hepatitis C infection. Fertil Steril, 95(8), 2557-2559. doi:10.1016/j.fertnstert.2011.05.014

Iqbal, K., Klevens, R. M., Kainer, M. A., Baumgartner, J., Gerard, K., Poissant, T., . . . Teshale, E. (2015). Epidemiology of Acute Hepatitis B in the United States From Population-Based Surveillance, 2006-2011. Clin Infect Dis, 61(4), 584-592. doi:10.1093/ cid/civ332

Karampatou, A., Han, X., Kondili, L. A., Taliani, G., Ciancio, A., Morisco, F., . . . Investigators, P. (2017). Premature ovarian senescence and a high miscarriage rate impair fertility in women with HCV. J Hepatol. doi:10.1016/j.jhep.2017.08.019

Kurmanova, A. M., Kurmanova, G. M., & Lokshin, V. N. (2016). Reproductive dysfunctions in viral hepatitis. Gynecol Endocrinol, 32(sup2), 37-40. doi:10.1080/0951 3590.2016.1232780

Lam, P. M., Suen, S. H., Lao, T. T., Cheung, L. P., Leung, T. Y., & Haines, C. (2010). Hepatitis B infection and outcomes of in vitro fertilization and embryo transfer treatment. Fertil Steril, 93(2), 480-485. doi:10.1016/j.fertnstert.2009.01.137

Oger, P., Yazbeck, C., Gervais, A., Dorphin, B., Gout, C., Jacquesson, L., . . . Rougier, N. (2011). Adverse effects of hepatitis B virus on sperm motility and fertilization ability during IVF. Reprod Biomed Online, 23(2), 207-212. doi:10.1016/j.rbmo.2011.04.008

Polywka, S., Schroter, M., Feucht, H. H., Zollner, B., & Laufs, R. (1999). Low risk of vertical transmission of hepatitis C virus by breast milk. Clin Infect Dis, 29(5), 1327-1329. doi:10.1086/313473

Sookoian, S. (2006). Liver disease during pregnancy: acute viral hepatitis. Ann Hepatol, 5(3), 231-236.

Terrault, N. A., Zeuzem, S., Di Bisceglie, A. M., Lim, J. K., Pockros, P. J., Frazier, L. M., . . . Group, H.-T. S. (2016). Effectiveness of Ledipasvir-Sofosbuvir Combination in Patients With Hepatitis C Virus Infection and Factors Associated With Sustained Virologic Response. Gastroenterology, 151(6), 1131-1140 e1135. doi:10.1053/j.gastro.2016.08.004

Villa, E., Karampatou, A., Camma, C., Di Leo, A., Luongo, M., Ferrari, A., . . . Francavilla, A. (2011). Early menopause is associated with lack of response to antiviral therapy in women with chronic hepatitis C. Gastroenterology, 140(3), 818-829. doi:10.1053/j.gastro.2010.12.027

By Helen K. Kelley

Melanoma, typically a malignant tumor associated with skin cancer and the cause of the vast majority of skin cancer deaths, can also occur in the eye or any mucous membrane of the body. While the risk of melanoma increases with age, it is one of the most common cancers found in young adults, particularly young women.

Georgia is one of the states with the highest incidence of melanoma in the U.S. To learn more about why this number is rising and how doctors are treating the disease, Atlanta Medicine recently spoke with two physicians who are specialists in melanoma.

Multidisciplinary approach to treatment; physicians should know signs
“I think a multidisciplinary team approach is crucial in the successful treatment of melanoma,” says B. Scott Davidson, M.D., a surgical oncologist with Northside Hospital Cancer Institute’s Melanoma and Sarcoma Program.

“It’s important to have close collaboration between surgical, medical and radiation oncologists who share their ideas about treating individual patients.”

He adds that since there are many variations in patient care, having input from a team of practitioners with different knowledge and skills can create a more effective treatment for each individual.

“There are a lot of components to treating melanoma, all of them important. It’s best to review those options during a multidisciplinary conference,” he says. “During these meetings, we form a game plan. We determine the best treatment options – immunotherapy, radiation and/or surgery – and the sequence of their delivery for the individual patient.”

Davidson adds that all physicians can play a role in the early detection of melanoma in their patients.
“It can be tricky to identify a melanoma just on gross examination. Certainly, any changing mole should be suspicious and the patient referred to a dermatologist for biopsy,” he says. “It’s good for every doctor to know the signs of skin cancer.”

He recommends following the guidelines set forth by The American Academy of Dermatology (AAD), known as the ABCDEs of melanoma:
• Asymmetry: Is one half of a mole unlike the other half?
• Border: Does a mole have an irregular, scalloped or poorly defined border?
• Color: It there more than one color in a mole, such as shades of tan and brown, black, white, red or blue?
• Diameter: Is a mole bigger than 6 mm (the size of a pencil eraser)? Melanomas are usually bigger than 6 mm when diagnosed, but they can be smaller.
• Evolving: Does a mole or another spot on the skin that look different from the rest? Is a mole or another spot changing in size, shape or color?

“The majority of melanoma occurs on sun-exposed areas, although there are certainly exceptions. And it is still a disease of all age groups,” Davidson adds. “The changing of a mole from benign to malignant probably calls into question the genetics that a person may harbor.”

Stimulating the immune system; rising numbers of skin cancer in younger people
According to Andrew Page, M.D., director of pancreas, liver and cancer surgery at Piedmont Hospital, the landscape in melanoma treatment has made phenomenal progress, particularly for patients with metastatic melanoma.

“Up until about seven years ago, the medications available to treat metastatic melanoma were not very good. Patient responses were not durable, and side-effects were not tolerable,” he says. “But starting in 2011, many groups began publishing remarkable outcomes for patients using novel treatments that were previously not available. Specifically, researchers had identified medications that target both the molecular pathogenesis of melanoma and the patient’s own immune system – and the results have revolutionized the treatment landscape for melanoma. Effectively, we now have medications to treat patients better with durable responses, without as severe toxic side effects.”

Newer drugs like Opdivo (nivolumab), used in the past couple of years for patients who have advanced (stage IV) melanoma, are now approved for people with stage III disease.

“In the past, if a person had comorbidities, the treatment itself – Interleukin-2 – could have killed them,” Page says. “But today, we have immunotherapeutic agents like Opdivo that are used, with some success, to treat advanced-stage melanoma. That’s amazing progress.”

Page warns that even though treatment of the disease is improving, the incidence of melanoma continues to rise.

“We have medications that work so much better today, yet melanoma is on the rise, about 90,000 incidences in the U.S. annually. While certainly many factors contribute to melanoma, young people, even children, are still getting too much sun exposure,” he says. “I’m seeing younger patients coming in with melanoma. Almost every single one of my young female patients admits to using tanning beds throughout high school.”

Study finds timing of diagnosis, treatment critical to survival
A new Cleveland Clinic study underscores the importance of early detection and treatment of melanoma, the deadliest form of skin cancer. The research, recently published in the Journal of the American Academy of Dermatology, indicates that the sooner patients were treated, the better their survival, particularly for stage I melanoma.

Using the National Cancer Database, researchers from Cleveland Clinic’s Dermatology & Plastic Surgery Institute studied 153,218 adult patients diagnosed with stage I-III melanoma from 2004 to 2012 and found that overall survival decreased in patients who waited longer than 90 days for surgical treatment, regardless of stage. In addition, the delay of surgery beyond the first 29 days negatively impacted overall survival for stage I melanoma, though not for stage II or III.

Compared to patients who were treated within 30 days, patients with stage I melanoma were 5 percent more likely to die when treated between 30 and 59 days; 16 percent more likely to die when treated between 60 and 89 days; 29 percent more likely to die when treated between 91 and 120 days; and 41 percent more likely to die when treated after 120 days. Patients with a longer time to treatment initiation tended to be older and male, and have more co-morbidities.

According to the authors, it is likely that more advanced cases represent delays in diagnosis, and these delays overwhelm the impact of a speedier treatment. However, in early-stage cases, early diagnosis allows for the opportunity to improve the chances of survival with a prompt surgery. Although many physicians follow a rule-of-thumb to treat melanoma surgically three to four weeks after diagnosis, there is no official recommendation on time to treatment.

The study is a stark reminder of the importance of detecting skin cancer early, when it’s most treatable. Anyone who notices any new, changing or suspicious spots on their skin, or any spots that are changing, itching or bleeding, should see a board-certified dermatologist for diagnosis.

The public can take steps to reduce their melanoma risk by protecting themselves from exposure to harmful ultraviolet radiation from the sun and indoor tanning beds, a risk factor for all types of skin cancer. The AAD recommends that everyone protect their skin from the sun by seeking shade, wearing protective clothing and using a broad-spectrum, water-resistant sunscreen with an SPF of 30 or higher.

By Kalinda D. Woods, M.D.

Those of us who study science may remember sitting in an introductory general biology lecture hall at some point in our academic past. An esteemed lecturer after formal introduction and orientation to the course may have opened the semester of study by insisting students internalize a single concept to begin to study biology: life persists. The desire to reproduce a version of ourselves is very human and innate to a sense of being for many people. It is estimated that approximately ten percent of couples will experience infertility, a diagnosis which can be emotionally and socially
devastating for families desiring pregnancy. Preventable causes of infertility include environmental exposures, and certain sexually transmitted
infections play a significant
role. As physicians, it is imperative that we educate about, screen for and address these disease processes to maximize best outcomes for our patients.

The term “sexually transmitted infection” encompasses several disease entities some of which have little or no impact on fertility directly. In fact, the most common STI worldwide is high-risk human papilloma virus, which is the causative agent of cervical dysplasia and cervical carcinoma. Although high-risk HPV infection, which will typically resolve with no consequence, is almost ubiquitous in young sexually active individuals, it appears to have no impact on fertility. The infections which more significantly affect fertility are gonorrhea, chlamydia and HIV. Physicians can impact fertility in many ways with regard to the preceding three infections.

According to the CDC¹, if untreated, about ten to fifteen percent of women with chlamydia will develop pelvic inflammatory disease, a condition determined by fever, pelvic pain and ascending infection associated with inflammation of the endometrium, fallopian tubes, and possibly peritonitis/tubo-ovarian abscess formation. Chlamydia can also cause fallopian tube infection without any symptoms. PID and “silent” infection in the upper genital tract can cause permanent tissue damage leading to infertility by way of tubal obstruction. An estimated 2.86 million cases of chlamydia and 820,000 cases of gonorrhea, which infects similarly, occur annually in the United States and most women are asymptomatic.² For these reasons, the CDC recommends screening of all sexually active women younger than 25 years, as well as older women with risk factors. Risk factors are further determined as new or multiple sex partners, or a partner who has had a recent STI.

We know that infertility is determined as no conception after 12 months of unprotected sex. We also know that with heterosexual couples, the male factor represents a significant percentage of identifiable causes of infertility. In men, chlamydial infection is known to cause urethritis, epididymitis, and prostatitis. There has been recent evidence suggesting that there is molecular damage to chlamydia-exposed sperm, which is irreparable and seems to be associated with poor sperm parameters among infertile individuals.³ Given these data, it is prudent to screen asymptomatic men with the same scrutiny and the same criteria as their female counterparts above.
 Syphilis infection rates have been rising in the US since 2014. While there is no specific relationship between syphilis and fertility or the ability to spontaneously conceive per se, congenital syphilis can be a devastating diagnosis. CDC data tells us that among 458 mothers of infants with CS in 2014, 100 (21.8%) received no prenatal care, and no information about prenatal care was available for 44 mothers (9.6%). (Among the 314 mothers with one or more prenatal visit, 135 (43.0%) received no treatment for syphilis during the course of their pregnancy and 94 (30.0%) received inadequate treatment. The 135 mothers who received no treatment include 21 mothers who were never tested for syphilis during pregnancy and 52 mothers who tested negative for syphilis in early pregnancy and subsequently acquired syphilis before delivery. The remaining 62 mothers tested positive, but were not treated. Benzathine penicillin G is the only known effective treatment for preventing CS. Maternal treatment was considered inadequate if it was initiated too late (<30 days before delivery), if a non-penicillin therapy was administered, or if the dose of penicillin administered was inadequate for the mother’s stage of syphilis.⁴

Identifying this very treatable spirochete therefore offers physicians yet another opportunity for intervention and prevention. Screening guidelines for syphilis are similar to those for chlamydia and gonorrhea above: sexually active individuals up to age 25 and older individuals with risks factors (IV drug use, men having sex with men, sex industry workers, multiple partners) annually. Pregnant women are also screened at initiation of prenatal care and again in the third trimester. Patients are typically screened via rapid plasma reagin (RPR) serum testing which is widely available, and inexpensive. Positive screening RPR will prompt further treponemal antibody testing which is confirmatory when positive.

HIV infection poses a significant roadblock with regard to fertility when partners are sero-discordant. Typically, barrier forms of contraception will be necessary to prevent viral transmission from one partner to the other, which is in itself a hindrance to fertility. While transmission rates between discordant partners continue to fall largely due to the sophistication of antiviral therapy and low to un- detectable viral loads in compliant individuals; HIV infection is obviously an impediment to achieving pregnancy. Factors which are considered by HIV positive individuals when making pregnancy planning choices are understudied. Contradicting factors, such as higher risk of horizontal transmission with condomless sex, versus sperm washing and IVF for example, which is costly are real life tradeoffs for those affected by HIV.⁵ As providers, routine screening for early diagnosis and options counseling are most appropriate for these patients.

Fertility is certainly achievable without increasing risk of transmission, but may be costly and must be carefully planned for. The USPSTF recommends that clinicians screen for HIV infection in adolescents and adults aged 15 to 65 years. Younger adolescents and older adults who are at in- creased risk should also be screened. Screening intervals will vary based on the HIV frequency in the community, presence of high risk behaviors, homelessness. The task force also recommends screening at initiation of prenatal care for women and again in the third trimester of pregnancy.

As with all things in medicine, we will never have the answers to the questions we don’t or won’t ask. Family planning and fertility are essential parts of the human experience and integral to the happiness and feeling of wholeness and wellbeing for many people. Although uncomfortable at times, it is important for physicians to ask the hard questions, obtain a thorough sexual history and inquire about reproductive goals so we are able to offer important testing, counseling and referral when needed, for our patients as part of our goals of comprehensive evidence based and compassionate care.

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References
1. Centers for Disease Control. Division of STD prevention, national center for HIV/ AIDS Prevention
2. CDC 2015 STD treatment Guidelines
3. Moazenchi et al. The impact of CT infection on sperm parameters and male fertility: a comprehensive study. International Journal of STD and AIDS 2017. 1-8.
4. CDC Morbidity and Mortality Weekly Report, November 2015
5. Loutfy, et al. Pregnancy planning preferences among people and couples affected by HIV: Piloting a discrete choice experiment. J of Obstetrics and Gynec Can 2012; 34: 575-590
6. Final Recommendation Statement: Human Immunodeficiency Virus (HIV) Infection: Screening. U.S. Preventive Services Task Force. December 2016. https://www.uspreventiveservicestaskforce.org/Page/Document/
RecommendationStatementFinal/human-immunodeficiency-virus-hiv-infection-screening

By Helen K. Kelley

 Altitude sickness, also called acute mountain sickness, is caused by climbing or walking to a higher and higher altitude too quickly, not giving the enough time to adapt to the lower air pressure and oxygen level in the higher elevation. To understand more about altitude sickness and how to prevent or treat it, we spoke with three Atlanta area physicians who shared their expertise and experience.

Symptoms, prevention and the heart of the matter
At higher altitudes, the barometric pressure decreases, resulting in fewer oxygen molecules available to breathe, ultimately resulting in decreased oxygen delivery to tissues. According to Andrew Smith, M.D., a cardiologist and Medical Director of the Advanced Heart Failure Program at Emory Healthcare, this decreased oxygen availability causes a number of physiological symptoms identified with altitude sickness.

“With the decreased oxygen availability to the tissues, the result is an increased release of adrenalin, which can cause increase in heart rate and also possibly an increase in pulmonary artery pressures,” he said. “Additionally, what occurs within this is an increase in respiratory rate, and therefore, hyperventilation occurs, at least initially. Resting heart rate increases. Often the humidity tends to be lower at high altitudes, so, along with the increased adrenaline drive, there is a tendency to become dehydrated.”

Along with dehydration, people who are experiencing altitude sickness may have symptoms like mild headaches, nausea, more rapid breathing, fatigue and difficulty sleeping at night. In fact, because the breathing rate tends to be lower when sleeping, the lower level of oxygen delivery to the tissues can put more stress on the body at night.

Smith adds that more serious symptoms can occur at extreme altitudes in both normal people and those with genetic predispositions or health issues.

“For example, high altitude pulmonary edema can happen to anyone. If you develop a bad cough, become short of breath or cough up frothy sputum, that is a sign,” he said. “High altitude cerebral edema, or HACE, can cause a change in mental status, with symptoms like worsening headaches, lethargy, ataxia and confusion. ‘Leaky capillary syndrome,’ in which fluid leaks out of the capillaries in lungs, can also occur in the brain. Symptoms like these indicate you need to get down to a much lower elevation and seek medical attention immediately.”

For those who are traveling to higher elevations, Smith says there are a number of measures they can take to prevent the symptoms.

“Hydrate well and travel slowly to different degrees of elevation, so that some degree of acclimation occurs every few days. If you’re going to be doing something strenuous at a higher elevation, take breaks,” he advised. “Hiking and climbing to higher levels may be fine, but not camping and sleeping there. You can also prepare by getting yourself in better physical condition before you go.”

Most of all, common sense should prevail, especially for people who lead a sedentary lifestyle or who haven’t gotten regular check-ups.

“Travel to a high altitude location can unmask preexisting heart disease. I’d advise anyone planning to do so and who hasn’t been exercising regularly, to see a physician in advance for a cardiac stress test. Chest pain, angina, persistent shortness of breath… those are all warning signs,” Smith said. “Of course, for patients who have known heart disease, travel to high elevations can be extremely risky. It’s important that they recognize that they will be in situations where they don’t have control of their environment; environment will be controlling things like their heart rate response.”

One physician’s personal experience
Allen Dollar, M.D., Associate Professor at Emory University School of Medicine and Section Chief of Cardiology at Grady Memorial Hospital, has been an avid backpacker since his teens. In recent years, Dollar and two friends have made an annual trip to Colorado to go hiking in the San Juan Mountains. It was there that he experienced altitude sickness for the first time in his life.

“The first year we made the trip I had no problems, but the second year, we ascended more rapidly from the ground level — we went from 6,500 ft. to 13,200 ft. in just two days,” he recalled. “I became sick as a dog. Basically, altitude sickness felt like the worst hangover you could ever have.”

While the treatment is to immediately descend to a safer level, Dollar and his friends were on the far side of a ridge that meant ascending another 500 ft. on a treacherous trail before being able to travel downward. It took an additional 24 hours before Dollar felt well enough to make the ascent and the descent.

He says that he was fortunate not to experience worse symptoms.

“I never developed shortness of breath or high-altitude cerebral edema,” he said. “My friends tested my mental clarity with math problems to be sure I was all right.”

Dollar said that one of his group had been taking Diamox (acetezolomide), a drug that been shown to help in preventing altitude sickness. After seeing his positive results, the others now begin taking Diamox two days prior to starting their climb and the regimen has proved successful.

He adds that there is no way to predict who will experience altitude sickness and who won’t.

“What I can tell you is that altitude sickness doesn’t have anything to do with a person’s fitness level,” he said. “You’re either susceptible or you’re not.”

Q & A:  Altitude and the lungs
To learn more about how altitude affects the lungs, we asked Abubakr Chaudhry M.D., a pulmonary and critical care physician and specialist in pulmonary vascular diseases with Northside Hospital, to share his insights in a two-part Q & A.

Q. How does altitude affect breathing?
AC: In order to understand how altitude effects breathing, we first have to understand what happens physiologically when we experience rapid changes in barometric pressure, such as during an ascent from sea level (760 mmHg) to the summit of Mount Everest (253 mmHg) per say. It is important to note that there is not a depletion of atmospheric oxygen content at higher altitudes, but rather a change in the driving pressure of the gas in the lungs. The higher you go, the lower the barometric pressure, and thus the lower the driving pressure.

Next, we must understand how gas exchange occurs in the membranes of the lung and how our bodies react to this change in driving pressure. The decreased driving pressure results in tissue hypoxia, decreasing the substrate available for aerobic respiration and stimulating us to hyperventilate. This phenomenon can be quantified by the alveolar-ventilation equation, which demonstrates an inverse relationship between the level of alveolar ventilation and the alveolar PCO2 (if CO2 production is constant). Thus, the more we breathe the less CO2 we retain. Furthermore, at higher altitudes it has been reported that climbers can decrease their PCO2 from a normal value of 40 to a value of 8 ( five-fold!). This change in breathing patterns leads to respiratory alkalosis. Alkalosis has the deleterious effect of increasing hemoglobin’s affinity to oxygen but it also enhances the uptake of oxygen in the pulmonary capillaries, an effect that is highly beneficial in these individuals. With changes in breathing patterns comes the question of need for oxygen.

We used the extreme example of Mount Everest but most normal individuals will not need supplemental oxygen unless they are ascending above 6500 meters.

Q: What are some ways an individual with a lung condition can prepare for travel to a high altitude?
AC: If someone has an underlying lung condition and is preparing for high altitude travel, the best thing to do is see a pulmonologist to assess his or her “hypoxic ventilatory response.” As previously stated, the major physiologic change that occurs with ascent is hyperventilation. If a patient cannot decrease their carbon dioxide levels, it will be unlikely they will have the energy required to oxygenate well, either. Supplemental oxygen can help, but the amount needed will likely change depending on the barometric pressure (the elevation to which the person climbs). If the patient’s hypoxic ventilatory response is poor, I would recommend against high altitude travel.

Preparing for high altitude travel is possible, but not in the way usually advertised. There are a lot of gimmicks out there that promise to “increase your red blood cells” with “hypoxia training.” I do not recommend these even in normal individuals, as the physiologic change is transient. I do recommend safe intensive strength and endurance training with a plan that is doctor supervised. Particularly in patients who have underlying lung disease, not only does training improve mortality, but it also improves the hypoxic ventilatory response by maximizing the body’s utilization of oxygen.

To someone who is planning a climb and has been cleared by their doctor, I recommend remembering the climber’s adage of “climb high and sleep low.” This means you should acclimatize yourself progressively. Once you get above 3000m, try not to climb more than 300m a day and rest every third or fourth day. If you experience symptoms of mountain sickness, you don’t have to run down the mountain, but try to descend at least 500m. In most cases of acute mountain sickness this descent will resolve the symptoms.

By Marisa Lawrence, MD

According to the Centers for Disease Control and Prevention, 36.5 percent of adults in the United States 2011-2014 are obese – a body mass index (BMI) greater than 30kg/m². ¹ Health effects include diabetes, coronary artery disease, hypertension, osteoarthritis, obstructive sleep apnea and deep venous thrombosis (DVT).

Severe obesity is a BMI above 35 kg/m²; morbid obesity is a BMI above 40 kg/m².

The American Society of Bariatric and Metabolic Surgery reports 196,000 bariatric procedures in the United States in 2015.² Many physicians will encounter post-bariatric surgery patients, so understanding their medical and psychological issues enable us to better care for them.

Patients undergoing weight loss surgery experience health benefits, but the skin envelope deflates throughout the body. Skin folds can cause poor hygiene, intertrigo, skin breakdown and functional impairment. Surgical recontouring can relieve these symptoms.

Such surgery improves quality of life, self-esteem and body image. ³ Therefore, post-bariatric plastic surgery has both reconstructive and aesthetic components.

Patient selection is important for satisfactory outcomes and minimal morbidity. The preoperative evaluation considers the bariatric procedure performed, BMI, comorbidities, nutritional deficiencies and psychological issues; all must be optimized prior to surgery.

Among 511 post–bariatric surgery body contouring cases, higher pre-bariatric surgery maximum BMI and higher BMI at presentation were associated with increased complications.⁴ The best candidates for extensive body contouring surgery after weight loss have a BMI below 30 kg/m² and may have multiple procedures.⁵ Patients with a BMI between 30 and 35 kg/m² are higher risk; surgical planning is individualized . Symptomatic patients with a BMI between 35 and 40 kg/m² may have one functional operation, e.g.panniculectomy or reduction mammoplasty. Patients with a BMI above 40 kg/m² need further weight loss unless symptoms are very severe.

Following bariatric surgery, weight typically decreases exponentially over three to six months and stabilizes after 15 to 18 months. Body contouring surgery is done after the weight has plateaued for three months or longer ⁶ – weight loss after body contouring surgery generally leads to continued skin deflation and patient dissatisfaction.

Nutritional deficiencies are common in this population. Roux-en-Y gastric bypass patients have malabsorption from a bypassed proximal small bowel. Caloric restriction and noncompliance with prescribed diets lead to malnutrition. Protein malnourishment can impact wound healing. Mal-absorbed vitamins include thiamine, vitamin D, calcium, iron, vitamin B12 and folate.⁷ Anemia may occur, associated with decreased iron and vitamin B12.⁸ Preoperative laboratory work up includes complete blood count, electrolytes, albumin and pre-albumin. Patients should increase their protein intake before surgery to 70-100 g/day. Supplemental iron, calcium, B12, folate and thiamine may be required.

Smokers should stop smoking one month before and one month after surgery.* Major body contouring surgery creates large tissue flaps; nicotine causes vasoconstriction, risking flap necrosis, infection and poor wound healing.⁹ Preoperative cessation of smoking is confirmed by urine cotinine tests; positive tests will delay surgery.

Patient also have many risk factors for venous thromboembolism (DVT): obesity, immobility, increasing age and venous varicosities. The overall DVT risk for body contouring surgery is 2.9-8.9 percent.¹⁰ A hematologist should see patients with histories of DVT, pulmonary embolism and hypercoagulable states for perioperative management. Intermittent pneumatic compression devices are placed before general anesthesia. Peri-operative unfractionated or low-molecular-weight heparin depends on the Caprini Risk Assessment Model.¹¹

Patient expectations are discussed at the consultation – there will be visible scars and prolonged recovery times. Emotional stability and the patient’s support network are also evaluated. Up to 68.6 percent of bariatric surgery candidates have had a psychiatric disorder during their lifetime.¹² Those with issues relating to body image and body dysmorphic disorder are less likely to be satisfied, so realistic expectations are discussed prior to scheduling surgery.

Up to 85 percent of post-bariatric patients desire body contouring, but only 12 percent to 21 percent actually have it.¹³ Many expect insurance to cover the cost. Insurance may cover panniculectomy, ventral hernia repair and breast reduction; patients can have cosmetic procedures performed at the same time to reduce the cosmetic costs.

Fig. 1

Several variables affect the staging of procedures, including the patient’s personal goals, finances and insurance as well as the surgeon’s experience and operative team. Longer operating times increase complications; shorter operations and staging procedures appropriately mean less anesthetic time, blood loss and infection.¹⁴ The patient’s complaints and desires are the most important determinants of the first area of the body to approach.

Fig. 2

The abdomen is of most concern; the hanging skin pannus overlaps the pubis, affecting hygiene. A panniculectomy removes this lower abdominal apron of skin and is often a functional operation, performed on significantly overweight patients who have skin irritation from hanging skin. This surgery reduces skin problems but not the abdominal contour. Traditional abdominoplasty excises redundant abdominal skin, plicates the rectus muscles, elevates the mons and repositions the umbilicus. (See Figure 1.) The belt lipectomy is a circumferential operation that excises hip and lower back rolls and elevates the buttocks. The lower body lift is similar, but incisions are lower and less conspicuous in clothing. (See Figure 2.)

Fig. 3

Some patients have vertical and horizontal laxity, so a fleur-de-lis abdominoplasty is performed with a vertical midline incision in addition to the lower incision. (See Figure 3.) Gluteal augmentation may be combined with these procedures; many weight loss patients experience flatter buttocks with tissue deflation. Options include a de-epithelialized back flap using redundant skin, fat grafting or implants.

Fig. 4

After massive weight loss, the female breast deflates. A breast lift, or mastopexy, rejuvenates the breasts by raising and reshaping them – lifting nipples, removing extra skin and repositioning breast tissue higher on the chest. Scars are around the nipple-areola complex, vertically from the areola to the inframammary fold and along the fold. Skin folds that extend laterally may be removed with an upper body lift, extending the inframammary fold incision to excise excess back skin. (See Figure 4.) Breast implants can be placed with the breast lift, but complication rates of 20 percent are reported.¹⁵

Fig. 5

A brachioplasty, or arm lift, contours the excess skin and fat of the upper arm. (See Figure 5.) This involves an incision from the axilla to the elbow. If the deformity extends to the lateral chest wall, the incision may extend into the axilla with a Z-plasty and along the chest wall. Liposuction may be performed concomitantly. Scars are initially conspicuous; scar management with silicone cream and lasers improves their quality.

Fig. 6

Thigh lifts remove excess thigh skin and fat to improve thigh appearance. (See Figure 6.) Patients with excess proximal tissue may need horizontal resection, leaving the scar along the groin and infra gluteal creases. Patients with excess tissue from groin to knee require a vertical scar down to the knee as well as the horizontal scar. Liposuction can help reduce the size of the thigh and can be performed three to six months before the thigh lift to allow skin retraction.

After dramatic weight loss, the face loses volume, soft tissues descend and the neck loosens and sags. A face and neck lift repositions the cheeks, corrects the jowls and removes the loose, sagging skin. Fat grafting restores facial volume. The incisions are inconspicuous around the ears, extending into the hair above and behind the ear. (See Figure 7.)
With the increase in bariatric surgery procedures, physicians will encounter patients with massive weight loss requesting body contouring procedures. With comprehensive evaluation of the patient’s weight loss, timing, medical comorbidities, and nutritional and psychological statuses, these operations can be performed safely, yielding satisfactory, life-altering results.

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References

1. Centers for Disease Control and Prevention. Prevalence of obesity among adults and youth: United States 2011-2014. https://www.cdc.gov/obesity/data/adult.html

2. Maciejewski ML, Arterburn DE, Scoyoc BA et al. Bariatric Surgery and Long-term Durability of Weight Loss JAMA Surg. 2016;151 (11):1046-1055.

3. Van der Beek ES Greene R de Heer FA et al. Quality of life long term after body contouring surgery following bariatric surgery:sustained improvement after 7 years. Plast Reconstr Surg 2012:130:1133-1139

4. Coon D, Gusenoff JA, Kannan N, El Khoudary SR, Naghshineh N, Rubin JP. Body mass and surgical complications in the postbariatric reconstructive patient: Analysis of 511 cases. Ann Surg. 2009;249:397–401.

5. Rubin JP, Nguyen V, Schwntker A. Perioperative management of the post-gastric-bypass patient presenting for body contour surgery. Clin Plast Surg. 2004;31:601–610.

6. Hurwitz DJ. Single-staged total body lift after massive weight loss. Ann Plast Surg 2004;52:435–441.

7. Xanthakos SA, Inge TH. Nutritional consequences of bariatric surgery. Curr Opin Clin Nutr Metab Care 2006;9:489–496.

8. Shermak MA, Chang DC, Heller J. Factors impacting thromboembolism after bariatric body contouring surgery. Plast Reconstr Surg 2007;119:1590–1596.

9. Payne CE, Southern SJ. Urinary point-of-care test for smoking in the pre-operative assessment of patients undergoing elective plastic surgery. J Plast Reconstr Aesthet Surg 2006;59:1156–1161.

10. Shermak MA, Chang DC, Heller J. Factors impacting thromboembolism after bariatric body contouring surgery. Plast Reconstr Surg. 2007;119:1590–1596; discussion 1597–1598.

11. Pannucci CJ, Dreszer G, Wachtman CF, et al.. Postoperative enoxaparin prevents symptomatic venous thromboembolism in high-risk plastic surgery patients. Plast Reconstr Surg. 2011;128:1093–1103

12. Mitchell JE, Selzer F, Kalarchian MA, et al. Psychopathology before surgery in the longitudinal assessment of bariatric surgery-3 (LABS-3) psychosocial study.
Surg Obes Relat Dis. 2012;8(5):533-541.

13. Gusenoff J, Rubin JP, Plastic surgery after weight loss: current concepts in massive weight loss surgery. Aesthetic Surg J 2008;28:452-455

14. Gussenoff JA, Messing S, O’Malley W et cl Temporal and demographic factors influencing the desire for plastic surgery after gastric bypass surgery, Plast Reconst Surg 2008:121;2120-2126

15. Spear SL, Low M, Ducic I. Revision augmentation mastopexy: indications, operations, and outcomes. Ann Plast Surg. 2003:51:540-546.

By Sandra Adamson Fryhofer M.D., MACP, FRCP Member, MAA Board of Directors and MAA Opioid Task Force

Each day, more than 90 Americans overdose and die from opioids.¹ more than quadrupled from 1999 to 2015.² And the amount of opioids prescribed tripled since 1999.³ These are deadly, disturbing statistics.

Recent stats from the National Survey on Drug Use and Health (2015)² further emphasize the magnitude of the problem:

• More than one third (38 percent) of all US adults (nearly 92 million) used prescription opioids.²

• 5 percent (more than 11 million adults) misused them (taking them without a prescription, or longer, more often or in greater amounts than recommended by their physician).²

• 1 percent (nearly 2 million adults) had opioid use disorder.²

Fact versus Myth

This is mainly a rural problem. False. Opioid use and misuse is just as common in urban and suburban areas as in rural areas.² As highlighted recently in The Washington Post, rural areas do have additional challenges: fewer healthcare professionals to treat addicted patients and longer travel distances for first responders.⁴

Socioeconomic factors play a role. True. Adults with low incomes, as well as those without a job, were not only more likely to misuse opioids but also more likely to have an opioid use disorder. The same goes for those with behavioral health problems. Adults without health insurance were twice as likely to misuse opioids.² An accompanying editorial in Annals suggests that having health insurance should provide ways – other than opioids – to deal with pain.⁵ But even those with health insurance, higher income and higher education are still at risk.⁵ No strata of society has been spared.⁵

Most people misuse opioids to get high. False. Most people (64 percent) who misuse opioids do so to relieve physical pain.² About 22 percent use them to relax (11 percent) or to get high (11 percent).²

The longer you take opioids, the greater the risk of use disorder, overdose and death. True. Taking even low doses of opioids for more than 90 days increases odds of opioid use disorder by a factor of 153.

Reducing opioid prescribing leads to increases in heroin use. False. In a recent JAMA viewpoint, Drs. Schuchat, Houry and Guy dispel this myth by citing evidence that state policies aimed at reducing amounts of opioids prescribed reduce both opioid-involved deaths and heroin overdose deaths by reducing initial opioid exposure, thus reducing addiction risk.³

Physician prescriptions are the source of the majority of opioids that are misused. Half true. Although family and friends were the source of free drugs for more than 40 percent of opioid misusers, 86 percent of those misused opioids were diverted to the misuser from prescriptions prescribed (to the misuser’s friends and family) by physicians.² This means that many of our patients are giving away pain meds, not realizing the dangers and long-term consequences.

“The cycle of prescribing opioids begins with clinicians.”³ Our Georgia state legislature and composite state medical board seem to think so. On May 4, 2017, Gov. Nathan Deal signed into law HB 249 to address the opioid problem in the State of Georgia.⁶

This new law moved the Prescription Drug Monitoring Program (PDMP) from the Georgia Drugs and Narcotics Agency to the Department of Public Health. It also contains several requirements that directly affect Georgia physicians. To address this issue, the Medical Association of Atlanta’s (MAA) Board of Directors assigned a Task Force to create an Opioid Resources webpage: End the Opioid Epidemic on the MAA website at maa-assn.org.⁷ It includes the new requirements, deadline dates and links to resources to help physicians comply. The three new requirements are:

1. PDMP Requirement

New state requirements include PDMP sign up (mandatory as of
January 1, 2018), PDMP check and every 90 day re-check (mandatory as of July 1, 2018):

• The PDMP check requirement applies to prescriptions for all benzodiazepines but only to those opioids listed in in paragraphs 1 and 2 of § 16-13-26 Schedule II list.8 The list includes commonly prescribed opioids such as hydrocodone (Vicodin, Lortab, Zohydro), oxycodone (OxyContin and Percocet) and morphine.^{12 10}

• The PDMP check requirement does NOT apply to non- benzodiazepines including non-benzodiazepine sleeping pills: Zolpidem (Ambien, Intermezzo, Zolpimist), Eszopiclone (Lunesta), Zaleplon (Sonata) – since they are NOT benzodiazepines.⁹ The PDMP check requirement does apply to all benzodiazepines ⁹ Since Estazolam (Prosom), Flurazepam (Dalmane), Temazepam (Restoril), Alprazolam (Xanax), Chlordiazepoxide (Librium), Clonazepam (Klonopin), Diazepam (Valium), Lorazepam (Ativan) and Oxazepam (Serax) are benzodiazepines,⁹ they are included on the PDMP required checklist.

• Although checking the PDMP may be delegated to two members of your staff (registration by Georgia Board of Pharmacy required for unlicensed staff), any unauthorized use of PDMP data by a delegate can result in civil or criminal penalty for you, “the prescriber.”⁶

• PDMP checks must be documented in the patient’s chart.⁶

2. Patient Education Requirement

In addition, HB 249’s provision for mandatory (oral or written) patient education on opioid addictive risks and safe disposal when prescribing opioids became effective as of July 1, 20176 Links to free patient educational materials (in English and Spanish) are also on the new MAA Opioid Resource webpage.⁷

3. CME Requirement

The Composite State Medical Board now requires at least 3 hours of safe opioid prescribing CME prior to obtaining or renewing your medical license (effective January 1, 2018). Our MAA webpage has a link to a free CME course that will fulfill the Board’s CME requirement.¹¹

Although these new requirements present an additional administrative burden for physicians, they are now law, and we must comply. Although the requirement cannot “cure” the problem, they do shine a spotlight on the issue of opioid prescribing, use and misuse and increase awareness of the problem.

MAA’s Opioid Resource webpage⁷ also contains links to the Medical Association of Georgia’s Think About It and Project DAN-Deaths Avoided by Naloxone initiatives, AMA’s End the Epidemic website, the Surgeon General’s Turn the Tide website, additional opioid resources from the CDC, as well as a bibliography of recent references and scholarly articles addressing opioid use and misuse.⁷

Already, we are beginning to see some encouraging prescribing trends as revealed in a new AMA report: “Between 2012 and 2016, the number of opioid prescriptions decreased by more than 43 million – a 16.9 percent decrease nationally. Every state saw a decrease in opioid prescriptions during this period.”¹²

Helping those already afflicted with opioid use disorder is also important. Gov. Deal also signed into law SB 88,13 the Narcotic Treatment Programs Enforcement Act, requiring the Department of Community Health to specify minimum standards and quality of services for narcotic treatment programs seeking licensure in Georgia.

Going forward, more research and resources are needed as we respond to this national emergency. Physician involvement is and must remain a critical part of the solution. On that, the Medical Association of Atlanta can be a vital resource for you and for the health of your patients.

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References

1. Volkow ND, Collins FS. The Role of Science in Addressing the Opioid Crisis. New England Journal of Medicine July 27, 2017: 391- 94.

2. Han B, Compton WM, Blanco C, Crane E, Lee J, Jones CM. Prescription Opioid Use, Misuse, and Use Disorders in U.S. Adults: 2015 National Survey on Drug Use and Health. Ann Intern Med. [Epub ahead of print 1 August 2017] doi: 10.7326/M17-0865

3. Schuchat A, Houry D, Guy GP. New Data on Opioid Use and Prescribing in the United States. JAMA.2017;318(5):425–426. doi:10.1001/jama.2017.8913

4. Humphreys K. Opioid abuse started as a rural epidemic. It’s now a national. Washington Post, accessed on September 3, 2017. Available at: https://www.washington- post.com/news/wonk/wp/2017/07/31/opioid-abuse-started-as-a-rural-epidemic-its- now-a-national-one/?utm_term=.c9eb36351499

5. Lasser KE. Prescription Opioid Use Among U.S. Adults: Our Brave New World. Ann Intern Med. [Epub ahead of print 1 August 2017]doi: 10.7326/M17-1559

6. 2017-2018 Regular Session – HB 249: Controlled substances; collect more information regarding dispensing and use; provisions, Available at http://www.legis. ga.gov/Legislation/en-US/display/20172018/HB/249 Accessed on Sept 3, 2017.

7. Medical Association of Atlanta website, Opioid Resources Webpage: End the Opioid Epidemic, Available at http://www.maa-assn.org/?page=OpioidEpidemic Accessed on September 3, 3017

8. Link to § 16-13-26 Schedule II list of controlled substances: Please note that HB 249 applies to drugs listed in Paragraphs 1 and 2 of this schedule : http://law.justia. com/codes/georgia/2010/title-16/chapter-13/article-2/16-13-26

9. List of Sedative-Hypnotic Drugs (Sleeping Pills) eMed Expert website. Available at http://www.emedexpert.com/lists/sedative-hypnotics.shtml Accessed on September 3, 2017.

10. Prescription Opioid Use, Misuse, and Use Disorders in U.S. Adults. Ann Intern Med. [Epub ahead of print 1 August 2017] doi: 10.7326/P17-9042

11. Notice of Intent to Amend and Adopt Rules. Georgia Composite Medical Board website (Rule 360-15-.01. Requirements for Physicians). Available at https://medi- calboard.georgia.gov/sites/medicalboard.georgia.gov/ les/intent%20360-15-01.pdf Accessed on September 3, 2017.

12. Physicians’ progress to reverse the nation’s opioid epidemic. Available on the Medical Association of Georgia website at http://www.mag.org/sites/default/ les/ downloads/AMAOpioidTaskForce2017progressreportMay2017.pdf Assessed on September 7, 2017.

13. Deal signs opioid legislation. State of Georgia website. Available at https://gov. georgia.gov/press-releases/2017-05-04/deal-signs-opioid-legislation Accessed on September 3, 2017.

By Venk Lakshminarayanan, MD, Ph.D.

Traditional bronchoscopy is a procedure allowing direct visualization of the tracheobronchial trees of the airway. Historically, the main types of bronchoscopy are rigid and flexible. Flexible bronchoscopy allows for visualization of the lumen, mucosa of the trachea, proximal airways and segmental airways to the third generation of segmental bronchi.

This device allowed for focused obtainment of specimens as part of the evaluation for infectious, malignant or alternative etiologies. Additionally, it is used to diagnose or treat abnormalities within or adjacent to these airways.

Extrinsic compression of the airway from a mass can be assessed as well as direct sampling of peribronchial masses with transbronchial needle aspiration (TBNA). With the advent and initiation of fluoroscopic guidance, there was increased sensitivity in the ability to biopsy peripheral lung lesions which were not directly visualized in an airway.

Bronchoscopy has evolved greatly over the past decade with advances in endoscopic and pathological technologies. Traditional use of fiberoptic bronchoscopy limited tissue sampling to larger (> 2 cm) and more central lesions. With the development of electromagnetic navigation bronchoscopy (ENB) and radial probe ultrasound guidance, we can now access and obtain diagnostic tissue from the peripheral lung nodules with greater sensitivity and at smaller sizes.

These procedures enable the experienced interventionalist to access most mediastinal lymph nodes to provide a complete staging procedure. ENB, which combines bronchoscopy with electromagnetic navigation, allows the interventional bronchoscopist to sample significantly smaller and more peripheral lesions. The use of a linear probe EBUS (L-EBUS) allows for sampling of enlarged mediastinal, hilar lymph nodes or masses, potentially eliminating the need for mediastinoscopy. Endobronchial ultrasound-guided TBNA is a less-invasive alternative in staging of lung cancer in addition to diagnosis.

The presence of lymph node metastasis remains one of the most adverse factors for prognosis in non-small cell lung cancer (NSCLC). The presence of mediastinal lymph node involvement may indicate the presence of stage IIIA or IIIB, thereby suggesting either inoperability or the need for adjuvant chemotherapy and/or radiotherapy.¹

Sampling Lymph Nodes and Peripheral Modules

There are three techniques involved in interventional pulmonology in the diagnosis, staging and treatment of potential lung cancers: endobronchial ultrasound (EBUS), electromagnetic navigational bronchoscopy (EMB) and photodynamic therapy (PDT).

Endobronchial ultrasound (EBUS) is a bronchoscopic technique that uses ultrasound to visualize structures adjacent to the wall of the bronchus. It allows for rapid pathologic staging of mediastinal and hilar lymph nodes,¹ as well as for pathologic evaluation of nodal disease, which may be seen during radiographic staging.

EBUS is different than endoscopic ultrasound (EUS). While both visualize and guide sampling of lymph nodes, EBUS is performed during bronchoscopy for mediastinal lymphadenopathy. There are two types of EBUS: radial probe EBUS (RP-EBUS) and linear probe EBUS (L-EBUS). The RP-EBUS provides 360-degree circumferential images of the airway wall and surrounding structures.

A major advantage of RP-EBUS is its ability to visualize the layers of the airway wall in detail. In contrast, the L-EBUS provides a view that is parallel to the shaft of the bronchoscope with view 30 degrees forward of oblique. Color flow and Doppler features permit identification of vascular, ductal, and cystic structures. The major advantage of L-EBUS is its ability to guide real-time sampling. Coupled with rapid onsite evaluation (ROSE) by a cytopathologist allows for expedited pathologic staging of lymph node. Figure 1 demonstrates a right lower paratracheal lymph node (4R station) seen with an L-EBUS probe, in a patient with a peripheral lung mass with associated adenopathy.

Another area of interventional pulmonology that has rapidly developed recently is electromagnetic navigation bronchoscopy (ENB). ENB allows for more accurate targeting of peripheral lung lesions for biopsy over traditional bronchoscopy with fluoroscopy.The combined modalities of ENB and RP-EBUS can increase the sensitivity of diagnostic yields, especially with peripheral lung nodules, which is of great advantage for nodules as small as 10 mm.

Figure 2 demonstrates a left lower lobe lung nodule biopsied under ENB. Coupled with L-EBUS, this two-staged procedure allowed for diagnostic sampling of the peripheral lung mass and mediastinal lymph nodes. This allowed pathologic staging of this lung mass, and the mediastinal adenopathy results in an expedited diagnostic pathway with increased sensitivity in lung cancer staging. The goal of these combined modalities is to provide a greater patient experience and reduce time to initiate treatment.

Surgical resection of some early-stage tumors may be contraindicated because of concerns regarding reduced postoperative pulmonary function, ventilation or poor preoperative functional status. Up to 10 percent of patients successfully resected with lung cancer subsequently develop a second primary lung neoplasm.²

Using varying doses of low-intensity laser irradiation, cell growth functions can be stimulated or inhibited.⁴ One such treatment strategy used on cancer cells PDT, in which cancer cells are treated with a photosensitizer (PS) in combination with laser irradiation. Individually, they are non-toxic. However, with light-activation, reactive oxygen species are generated inducing cancer cell death.⁴ Cell-specific photosensitizers are in development for future cancer treatment.

After a photosensitizer is administered and the tumor is visualized, the light fiber is introduced through the working channel of the bronchoscope, and the rigid cylindrical tip of the light fiber is embedded into the lesion. This not only protects healthy mucosa from light exposure, but also delivers more energy to the tumor itself.

When the laser light is applied to the target area at the appropriate wavelength, the photosensitizer is activated, causing ROS generation that results in cancer cell death.⁵ A repeat bronchoscopy is planned 48 hours after the laser light exposure, when the inflammatory response is decreasing and tumor necrosis is achieved. At that time, all debris should be removed bronchoscopically.⁶

If a second operation may not be feasible for a patient, PDT can provide a therapeutic alternative that spares functional lung tissue required in lung cancer patients.³ Indications for PDT include treatment of micro-invasive endobronchial NSCLC in patients for whom surgery and radiotherapy are not indicated.³ Additionally, PDT can also be used to palliate symptoms in patients with completely or partially obstructing endobronchial masses due to non-small cell lung cancers.³

Figures 3A, 3B and 3C demonstrate a patient with a large right main-stem lesion recurrent NSCLC. In Figure 3A, the obstructing mass is noted in the right main-stem bronchus. Following the initial laser light therapy, the obstructing tumor was noted to have a more mucoid appearance allowing for initiating of debridement (Figure 3B). Serial light exposure and mechanical debridement allowed for local debridement of the complete obstructing mass (Figure 3C).

Interventional pulmonology is a rapidly burgeoning field providing novel and innovating, less-invasive ways of diagnosing and treating a variety of lung diseases. These are just a few of the novel diagnostic and therapeutic procedures available within the field of interventional pulmonology.

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References

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By Robert J. Albin, MD, FCCP, FAASM

Due to the ubiquitous availability of CT scanners, coupled with the ever-increasing propensity by physicians across all specialties to order advanced imaging studies, the number of incidentally detected pulmonary nodules has been soaring.

Over a recent 7-year stretch, one large integrated health sys-tem reported a 53 percent increase in the number of CT scans ordered. This trend has resulted in more than 1.5 million newly detected lung nodules in the U.S. annually. Exactly how best to manage these nodules has become an important but prickly dilemma, at times pitting the varied and potentially conflicting perspectives of patients, practitioners, medical societies and practice guideline directives against each other.

What has emerged and become clear is that the management of pulmonary nodules should be driven by the importance of distinguishing those that are malignant from those that are not by balancing the desire to intervene quickly for malignant nodules while avoiding and limiting procedures for those that are benign. What is not clear is how best to achieve this goal.

One of the first issues to resolve is to be certain that we are all speaking the same language when it comes to describing nodules. The descriptive nomenclature associated with pulmonary nodules, while endeavoring to be more precise and useful, has created an ever-expanding vocabulary of important distinctions.

Nodules may be solid, subsolid, ground-glass or contain a mixture of these components. They may be ovoid, round, smooth-bordered, spiculated or irregular. It is important to state whether they contain calcium or are non-calcified. While some nodules are detected as solitary abnormalities, in other instances, multiple nodules may be identified. Precise size measurement using proper criteria [the average of long and short diameters, both obtained on the same transverse, coronal or sagittal reconstructed images] adds to prognostic significance. Lobar localization is important, as is the presence or absence of emphysema or fibrosis. These distinctions serve the purpose of trying to identify those nodules with a less than 1 percent probability of being malignant (pCA < 1%), in order to avoid unnecessary testing and procedures.

The Fleischner Society, an international multidisciplinary medical society for thoracic radiology founded in 1969, published their latest recommendations for managing pulmonary nodules this year. Its intent was to cut down on unnecessary follow-up exams and procedures. While extremely useful and worthy of summarizing here, they are not without limitations and controversy. These guidelines apply to incidentally detected nodules in individuals at least 35 years of age.

For a single, solid, non-calcified nodule less than 6 mm in a low-risk patient, no further follow-up is recommended. Even in high-risk patients, the likelihood of this nodule being malig-nant is reported as less than 1 percent. However, suspicious morphology or upper lobe location can raise pCA to the 1 percent to 5 percent range, so a 12-month follow-up study can be considered in this subgroup of patients.

For a nodule 6-8 mm in size in a low-risk patient, a 6-12 month follow-up should suffice if stable. If high risk, additional imaging at 18-24 months should be considered. If the nodule is greater than 8 mm, PET-CT at 3 months is recommended as pCA now approaches 3 percent.

If there are multiple solid, non-calcified nodules less than 6 mm, no routine follow-up is recommended, as this typically represents healed granulomas or intrapulmonary lymph nodes. In a high-risk patient, consider a 12-month follow-up. If any nodule is greater than 6 mm, perform 3-6 month follow-up with optional follow-up at 18-24 months.

For a solitary, pure ground-glass opacity [GGO] less than 6 mm, no routine follow-up is recommended, although 2- and 4-year follow-up should be considered in selected high risk populations. If greater than 6 mm in size, 6-12 month follow-up CT is recommended and repeat imaging every 2 years through 5 years total.

For solitary part-solid nodules, no follow-up is necessary if less than 6 mm. If greater than 6 mm with the solid component less than 6 mm, obtain a follow-up scan in 3-6 months and then annually for 5 years. If greater than 6 mm with a solid component greater than 6 mm, obtain a follow-up scan at 3-6 months. For suspicious morphology or a solid component greater than 8 mm, consider PET-CT, biopsy or resection.

For multiple subsolid nodules less than 6 mm, these are likely infectious or inflammatory. If repeat imaging is stable at 3-6 months, consider scanning at 2 and 4 years. If at least one nodule is 6 mm or larger, rescan at 3-6 months. If persistent, consider multiple primary adenocarcinomas as a potential etiology.

If these recommendations seem confusing or even un-sound, take solace in knowing that you are not alone in this opinion. Unfortunately, the guidelines are based upon very low-quality evidence, as clearly stated in the Society paper. However, despite this, they are generally considered to rep-resent best practice parameters.

Additional shortcomings include the inability to accurately define “low-risk” versus “high-risk” populations. Given that the greatest recent percentage jump in the incidence of lung cancer is among never smokers, who then can be considered to be at “low risk”? Also, how can size be an absolute cutoff criterion for benign versus malignant disease? Every lung cancer was less than 6 mm at some point in its biology. In my opinion, size depends upon when, in the history of this nodule, the scan was performed. A single point in time has never been able to predict a trend.

I take these guidelines for exactly what they are – guidelines. Good clinical judgment and intuition must always weigh into the decision process. From my perspective, there is no nodule (other than a densely calcified, smooth bordered one) that does not merit additional follow-up imaging. While an extra CT(s) does add to the patient’s total radiation exposure burden, I believe the benefit outweighs the risk and so do the majority of patients.

Not surprising to me, a recent report comparing physicians’ assessment of pretest probability of whether a nodule was benign or malignant demonstrated that physicians were better at predicting malignancy than the frequently cited Mayo Clinic or VA prediction calculators. This is a very sobering finding and reaffirms the importance of clinical experience and “gut” instincts.

In the absence of strong evidence upon which to propose guidelines, the perspective and preferences of the patient and the clinician can and should play a critical role in the decision-making process. Successful management of what has now become a commonplace clinical problem depends upon shared values, concerns and frank dialogue between providers and patients.

Looking ahead, enhancing existing prediction calculators by including novel radiographic measurements, as well as analysis of exhaled, serum and bronchoscopic biomarkers, may aid in distinguishing benign from malignant disease. Until then, it might be a good idea to follow this old medical adage – what would you do if this was your mother?

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References

1. Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Im-ages: From the Fleischner Society 2017. Radiology 2017.

2. Iaccarino JM, Wiener RS. Pulmonary Nodule Guidelines: What Physicians do When Evidence-Based Guidelines Lack High-Quality Evidence. Chest. 2017; 152(2):232-234.

3. Physician Assessment of Pretest Probability of Malignancy and Adherence with Guidelines for Pulmonary Nodule Evaluation. Chest. 2017; 152(2):263-270.

4. Swensen SJ, Silverstein MD, Edell ES et al. Solitary Pulmonary Nodules: Clinical Prediction Model Versus Physicians. Mayo Clin Proc. 1999; 74(4):319-329