PRP Popular for Alopecia Despite Lack of Robust Evidence

PRP Popular for Alopecia Despite Lack of Robust Evidence

NEW YORK CITY — Results from three major national studies currently underway should soon supplement the paltry data that now support the use of platelet-rich plasma (PRP) for the treatment of alopecia, according to Neil Sadick, MD, from Weill Cornell Medical College in New York City.

Platelet-rich plasma is the “newest hot therapeutic on the block,” but there is no standardized protocol for preparation or administration, he said here at the American Academy of Dermatology 2017 Summer Meeting.

The treatment has been approved only for orthopedic uses by the US Food and Drug Administration (FDA), so it is prescribed off-label for alopecia.

Androgenetic alopecia, commonly known as male-pattern baldness, can affect women too, but the triggers are not as well understood in women as they are in men. Researchers are in the process of generating a “new view” of hair loss — in both men and women — by examining the role of factors such as oxidative stress, inflammation, lymphocytic reactions, and compromised circulation and nutrition, Dr Sadick reported.

Biopsy can help guide treatment recommendations. Patients with inflammation can be treated with high-dose minoxidil, retinoic acid, betamethasone, platelet-rich plasma, nutraceuticals, photobiomodulation with red light therapy, or a combination of treatments, he said. For patients without inflammation, all but betamethasone can be recommended. Combination approaches appear to have synergistic effects.

Despite the lack of established evidence from large, well-designed studies, dermatologists who treat men and women with alopecia should be prepared for patients seeking out platelet-rich plasma, said Maria Hordinsky, MD, from the University of Minnesota in Minneapolis.

You have to get on the bandwagon of PRP if you work with patients with hair loss.

“You have to get on the bandwagon of platelet-rich plasma if you work with patients with hair loss,” said Dr Hordinsky, Dr Sadick’s copresenter here at the meeting. “There’s just no choice. It’s very popular.”

However, “no one has a set way of doing it,” she explained. “We’re just getting off the ground, basically.”

Dr Sadick explained that he injects a concentrate into the scalp, but others coat the scalp with platelet-rich plasma after microneedling or perform a combination of techniques.

In addition to transforming growth factor beta-1, platelet-rich plasma contains several growth factors — such as epidermal, fibroblast, platelet-derived, vascular endothelial, and keratinocyte growth factors — that are believed to slow hair loss and stimulate new hair growth. Research has suggested that results are better in men than women.

In our practice, “we’ve seen up to a 10% increase in hair counts,” said Dr Sadick. And “probably about one-third of patients had increased hair growth we could document photographically.”

He also reported increased hair density and thickness in men and women who underwent microfractional radiofrequency. With this technique, a comb-like device with 36 sharp pins causes “microwounds” in the scalp, which stimulate an anti-inflammatory response and hair growth.

For most dermatologists, minoxidil, finasteride, and photobiomodulation are easy to prescribe for the treatment of alopecia. However, in a small percentage of men, finasteride induces erectile dysfunction that lasts well beyond treatment, and the exact mechanism of photobiomodulation is not known, Dr Hordinsky explained.

Several versions of at-home low-level light devices — which contain either diode lasers or LEDs that emit light continually or in pulses — have come on the market since the first device was approved by the FDA in 2007. Costs range from a few hundred to a few thousand dollars.

“Patients like them. They’re sold in stores and are affordable and convenient,” said Dr Hordinsky. But “only some have published peer-reviewed evidence regarding efficacy.” Direct head-to-head comparisons of the devices are needed.

“I really didn’t think the low-energy light worked; I always thought it was just a myth,” said Sharona Yashar, MD, a dermatologist in private practice in Culver City, California. About 20% of her patients have alopecia, she reported.

The fact that both Dr Sadick and Dr Hordinsky “use it and recommend it is good information to me,” Dr Yashar told Medscape Medical News.

Dr Sadick reports financial relationships with Actavis, Allergan, Almirall, Anacor, Auxilium, Bayer, Biorasi, BTG PLC, Carma Laboratories, Cassiopea SpA, Celgene, Cutera, Cynosure, DUSA Pharmaceuticals, Eclipse Medical, Eli Lilly, Endo International, EndyMEd Medical, Eternogen, Ferndale Laboratories, Galderma, Gerson Lehrman Group, Hydropeptide, Merz Aesthetics, Neostrata, Novartis, Nutraceutical Wellness, Palomar Medical Technologies, Prescriber’s Choice, Regeneron, Roche, Samumed, Slender Medical, Solta Medical, Storz Medical, Suneva Medical, Valeant, Vanda, Vascular Insights, and Venus Concept. Dr Hordinsky reports financial relationships with Allergan, Astellas, Concert, Incyte, and Procter & Gamble. Dr Yashar has disclosed no relevant financial relationships.

American Academy of Dermatology (AAD) 2017 Summer Meeting. Presented July 27, 2017.

Follow Medscape Dermatology on Twitter @MedscapeDerm and Maureen Salamon @maureensalamon

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Jeda Musim Datang di Waktu yang Pas bagi Hamilton

Jeda Musim Datang di Waktu yang Pas bagi Hamilton

Setelah GP Hongaria, kompetisi F1 akan jeda sekitar sebulan. Lewis Hamilton menjadikan momen jeda musim ini sebagai kesempatan untuk “mengisi ulang baterai”.


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ACTH vs TCH for Breast Cancer in Real-World Setting

ACTH vs TCH for Breast Cancer in Real-World Setting

Trastuzumab (Herceptin, Roche/Genentech) in combination with chemotherapy remains the standard of care for the adjuvant treatment of HER2+ breast cancer, but there is still a question over which chemotherapy regimen is best.

The two most commonly used regimens in the United States are ACTH (doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab) and TCH (docetaxel, carboplatin, and trastuzumab). No clinical trials have been designed to compare the two. However, the two chemotherapies have been compared in a real-world study by researchers at the University of North Carolina at Chapel Hill, using outcomes for patients aged 65 years and older from the Surveillance, Epidemiology, and End Results (SEER)–Medicare database.

The study was published online July 21 in the Journal of Clinical Oncology.

In this retrospective, claims-based dataset, there were no significant differences in breast cancer–specific survival, nor in the number of serious adverse events or hospitalizations between the patients who received ACTH and those who received TCH.

However, significantly fewer women who received ACTH completed the full course of adjuvant trastuzumab therapy — 77% for ACTH vs 88% for TCH (P = .001).

There was also a change in choice of chemotherapy during recent years — ACTH usage has dropped for this older population of patients with early-stage breast cancer, from 88% in 2005 to only 15% in 2011.

Comparing ACTH and TCH in Older Women

“Although there are more and more choices for women with HER2+ breast cancer in the adjuvant setting, physicians are often faced with choosing between ACTH and TCH, two trastuzumab-based regimens that are considered standard,” corresponding author Katherine E. Reeder-Hayes, MD, of the University of North Carolina at Chapel Hill, told Medscape Medical News.

“Comparative-effectiveness studies [such as this one comparing ACTH with TCH] can fill a crucial knowledge gap when clinical trial data have limited applicability to a patient population or when a comparative trial is unlikely to be conducted,” Dr Reeder-Hayes and colleagues write in their discussion.

They note the difference in the patient population in their real-world study (in which 80% of the women were aged 65 to 74 years) and in previous clinical trials, in which women were on average aged 49 years, were mainly white, and had few comorbidities. In clinical trials, only approximately 15% of women were older than 60 years, and older women with cardiac conditions were excluded from these studies, the researchers note.

“Prior research has shown surprisingly low rates of adjuvant trastuzumab use among older, particularly minority women with HER2-positive breast cancer, possibly because of these data limitations,” the team writes. Many of these women receive nonstandard regimens and do not complete therapy.

Approached for comment, Daniel F. Hayes, MD, Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Comprehensive Cancer Center, was not surprised with the increased uptake of TCH. “These data are consistent with good medical care for many patients in this dataset [older than 65 years],” he told Medscape Medical News.

Dr Hayes is not related to Dr Reeder-Hayes and was not associated with the study.

He explained that a number of prospective clinical studies have been directed toward reducing treatment for patients who do not need it or will not benefit from it, while ensuring that those who do need it receive appropriate therapy.

He explained that the advent of multigene panels such as Oncotype DX and similar assays has permitted identification of patients with node-negative, estrogen receptor–positive, and HER2-negative cancers, whose prognoses are so favorable that even in cases in which chemotherapy is efficacious, so few patients can benefit that, overall, the toxicities outweigh those benefits. “Thus, medical care is determined based on risk of cancer recurrence rather than just one size fits all,” he said.

In light of this, from what is known from clinical studies about the reduction in risk for recurrence associated with ACTH and TCH, as well as the risk for toxicities, especially cardiac dysfunction and the risk for secondary malignancies associated with ACTH, the increased use of TCH from 2005 to 2011 is not surprising, he remarked.

He echoed what the authors note — that ACTH was approved for use in 2006 (at which time its uptake was 88%), and TCH was approved 2 years later, in 2008. “The increased use of TCH over this period is not surprising, especially after the results of the BCIRG [Breast Cancer International Research Group] 006 study,” Dr Hayes said.

The BCIRG 006 study compared ACTH and TCH with the ACT chemotherapy regimen (doxorubicin + cyclophosphamide followed by docetaxel), which served as control. However, because this is the only trial with separate arms for the two regimens, clinicians looked to BCIRG 006 to provide evidence as to whether anthracyclines should be used at all for patients with HER2+ breast cancer.

There was a perception that the risk-benefit ratio favored TCH over the anthracycline-containing ACTH, Dr Hayes indicated. On the basis of this trial, the TCH regimen was approved for the adjuvant treatment of HER2+ breast cancer and became an acceptable regimen.

BCIRG 006 was not powered to show whether ACTH was better than TCH; however, there was a small difference in efficacy that favored ACTH (a 3% absolute improvement in disease-free survival through 5 years) in both node-negative and node-positive disease, Dr Hayes explained. “TCH was less effective, although not statistically significantly so, but was slightly less toxic,” he said.

“The perception that TCH is as good as ACTH may not be true, since there is a numerical superiority for the latter, but, again, it is not statistically significant,” he said.

However, doxorubicin (ie, an anthracycline) may be associated with greater risk when used in older patients, such as those from the SEER-Medicare database, than in younger women. Moreover, several studies have suggested that cardiac risk associated with trastuzumab, given after AC (doxorubicin + cyclophosphamide), is most common in older women. “Therefore, it is not surprising, nor inappropriate, that use of TCH is common in this age group,” Dr Hayes said. He did note that that in some subsequent clinical trials, and in his own practice, cyclophosphamide has been substituted for carboplatin in combination with docetaxel and trastuzumab, which may reduce toxicities.

“It is important to use a risk-based assessment of whether to add an anthracycline to the chemotherapy regimen in these patients,” Dr Hayes said. There is a perception that an anthracycline is toxic in older patients, he explained. “With many older women having preexisting heart failure or other risk factors for heart disease, such as diabetes, anthracyclines may pose a liability. But in an otherwise healthy woman, especially if she has a worse prognosis (such as positive axillary lymph nodes), I still think ACTH is a preferred regimen,” he told Medscape Medical News.

Study Details

The real-world study conducted by Dr Reeder-Hayes and colleagues searched the Medicare database and identified women for whom there was a claim for trastuzumab within 1 year of their diagnosis, who had undergone cancer surgery within 6 months of diagnosis, and who did not receive neoadjuvant therapy. Chemotherapy-related toxicities were identified from inpatient and outpatient claims within 6 months of beginning chemotherapy.

The full cohort analysis included 1077 women (ACTH: 365; TCH: 712). To reduce bias, the researchers used propensity score matching, a statistical method that matches a patient from one cohort with a corresponding patient in the second cohort on the basis of pretreatment characteristics. Factors in matching included demographic information and disease stage characteristics. After propensity score matching, the study population was reduced to 208 women in each group.

Data for the propensity score–matched cohort were commensurate with those reported for the full cohort. For the full study cohort, neutropenia (57% vs 45%) and anemia (59% vs 46%) were significant for ACTH vs TCH but not for the propensity-matched cohort. Similarly, the incidence for heart failure was numerically higher but was not statistically significant for ACTH (7.2% vs 3.9%). Fewer than 1% of patients in each cohort had claims related to postchemotherapy acute myeloid leukemia.

For the overall cohort, hospital stays related to adverse events were also similar between the groups (21% for ACTH vs 24% for TCH). Hospital services that included emergency visits and observation visits were also similar (34% for ACTH vs 36.5% for TCH).

The difference in 5-year overall survival was not significant between the two cohorts: 88% for ACTH vs 93% for TCH. For the matched subset, a similar finding was reported (90% for ACTH vs 92% for TCH). Five-year breast cancer–specific survival was also similar between the two groups: 90% for ACTH vs 96% for TCH. For the matched subset, corresponding rates were 92% and 96%, respectively. When analysis took into consideration patients who had completed trastuzumab therapy, there was no significant difference between the ACTH and TCH groups.

Dr Reeder-Hayes has disclosed no relevant financial relationships. Dr Hayes receives research funding from AstraZeneca, Eli Lilly, Janssen, Pfizer, and Puma. He has stock options in OncImmune and Inbiomotion and is named as a primary inventor on two patents issued to the University of Michigan. One of those patents is licensed to Janssen, for which he receives royalties.

J Clin Oncol. Published July 21, 2017. Abstract

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Jeda Musim Datang di Waktu yang Pas bagi Hamilton

Jeda Musim Datang di Waktu yang Pas bagi Hamilton

Budapest – Setelah GP Hongaria, kompetisi Formula 1 akan jeda sekitar sebulan. Lewis Hamilton menjadikan momen jeda musim ini sebagai kesempatan untuk “mengisi ulang baterai”.

Setelah 11 seri berlalu, Hamilton menempati posisi kedua di klasemen F1 dengan perolehan 188 poin. Pebalap Mercedes itu tertinggal 14 poin di belakang jagoan Ferrari, Sebastian Vettel.

Melebarnya jarak Hamilton dan Vettel tak lepas dari hasil GP Hongaria pada akhir pekan lalu. Di Hungaroring, Vettel tampil sebagai pemenang, sementara Hamilton cuma finis di posisi keempat.

Peluang Hamilton untuk menyalip Vettel masih sangat terbuka karena ada sembilan seri tersisa pada musim ini. Namun, seri berikutnya baru akan digelar pada 27 Agustus mendatang di Sirkuit Spa, Belgia.

“Saya tentunya berpikir ini (jeda musim) datang di waktu yang bagus,” ujar Hamilton di Sky Sports.

“Ini benar-benar berat, baik secara fisik, mental, dan emosional, untuk semua orang di dalam tim. Saya hanya bicara atas nama saya, tapi ini pastinya musim yang sulit hingga sekarang.

“Jeda ini akan sangat bagus buat semua orang agar bisa menghabiskan waktu bersama keluarga dan apapun yang mereka lakukan. Mengisi ulang dan kembali dalam kondisi yang semoga segar lagi.

“Saya benar-benar yakin kami punya kemampuan untuk memenangi kejuaraan ini, tapi untuk melakukannya akan butuh usaha 100 persen dari semua orang. Saya hanya menyemangati tim saya agar kembali kuat dan saya akan berusaha untuk kembali dalam kondisi lebih kuat lagi,” kata juara dunia tiga kali itu.

(mfi/cas)

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Brain Patterns May Predict Psychiatric Problems in Adulthood

Brain Patterns May Predict Psychiatric Problems in Adulthood

After age 30 years, underdevelopment of the brain network that controls inhibition is tied to self-reported psychological problems, including depression and anxiety, new research shows.

Investigators at the University of Toronto, Canada, found that among younger individuals, a neural signature of superior inhibition emerged in both static and dynamic connectivity analyses.

However, in individuals older than 30 years, superior inhibition was more apparent in static connectivity patterns linked to increased reward or cognitive profile. In that group, those who did not show a strong later adulthood pattern of specialized brain mechanisms for dealing with novel social challenges were more likely to report anxiety, depression, and difficulties with attention and aggression.

“We wanted to identify neural markers as well as age windows when one can actually detect subtle signs of impairment that may predict subsequent psychopathology,” Dr Petrican told Medscape Medical News.

“Our finding that may have clinical relevance is dealing with so-called late-inhibition profile, a delayed development of more specialized brain mechanisms for dealing with complex social and cognitive situations, and to look for brain change as well as associated cognitive problems that may be shared across psychopathologies, such as depression and anxiety,” she said.

The study was published online July 17 in the Journal of Neuroscience.

Fine Tuning the Brain

“The brain’s functional architecture changes across different contexts and life stages,” the authors write. An increasing body of research points to the importance of the brain’s intrinsic functional architecture for “optimal adaptation across the lifespan.”

The brain’s functional architecture evolves and changes longitudinally as a “reflection of development and accumulated behavioral changes,” as well as cross-sectionally as “a function of the various demands faced by an individual.”

Characterizing these changes is valuable in advancing understanding of the “distinct mechanisms through which a specific predisposition impacts behavior in distinct circumstances and life changes,” the authors note.

“We were interested both in how cognition can regulate emotional reaction and how they can work symbiotically,” Dr Petrican said.

“There has been a great deal of work on why it is important to control emotions — specifically, negative emotions, but even positive emotions — and oftentimes, people who are good at controlling emotions also do well on tasks that tap cognitive/executive control,” she added.

A core feature of this strength is the “ability to attend to relevant information in the present moment and tune out irrelevant information.” But “high cognitive control” used for memory tasks may not be the same as that used when “controlling emotions in social situations,” she explained.

Cognitive control “moderately correlates with fluid IQ, which helps people respond to novel situations and does not necessarily draw on previous knowledge,” she said.

“We wanted to see what brain mechanisms enable people with high cognitive control to respond to mental challenges — memory — vs responding to stimuli that evoke a sense of reward. Do individuals high on control recruit different mechanisms on tasks such as memory, vs emotionally relevant information?”

A second component of the research was to observe whether cognitive control underwent changes over time. The researchers chose to study individuals who were in their twenties and to mid thirties because prior evidence suggests that neural substrates of neural control continue to develop during this period.

“Although most existing investigations assume that the functional neural architecture is stable across time, there is accumulating evidence that the brain demonstrates significant temporal fluctuations, not only in activity but also in connectivity patterns,” the authors write.

“It is a matter of fine-tuning,” Dr Petrican said. “These brain mechanisms start to respond in a more differentiated, specialized, refined manner at that age.”

Predicting Poorer Function

To investigate these situational effects on the neural architecture of inhibition, the researchers engaged the study participants in two tasks that involve inhibition but are nevertheless “likely to illuminate distinguishable mechanisms.”

The first was a cognitive task involving a working memory assignment that required continual updating of information, a context demanding inhibitory control.

The second utilized social and financial rewards derived from a theory-of-mind and a decision-making task. In total, the researchers measured working memory, social cognition, and incentive processing.

Participants (n = 359) were drawn from the Human Connectome Project (HCP) and had already completed behavioral and fMRI assessment. Of the sample, 174 were men and 185 were women. The majority (n = 301) were right-handed. Participants with a mental health disorder and structural abnormalities, as revealed by MRI structural scans, were excluded.

To evaluate inhibitory control, the National Institutes of Health Flanker Inhibitory Control and Attention test, completed on day 2 of the participants’ HCP schedule, measured the ability of the participants to focus on a given target stimulus while inhibiting attention to stimuli flanking it.

To measure psychological functioning, participants completed the Achenbach Adult Self-Report (ASR) for persons aged 18 to 59 uears on the day of their session 1 fMRI appointment. The ASR consists of several subscales designed to elicit reactions of participants to a problem: the Anxious/Depressed, the Withdrawn, the Somatic Complaints, the Thought Problem, the Attention, the Aggressive Behavior, the Rule Breaking, and the Intrusive Behavior Problem Subscales.

Functional MRI tests focused on working memory and social cognition (theory of mind). Participants also completed an incentive processing test, in which they were required to guess the number on a mystery card in order to win or lose money.

The researchers found that superior inhibitory control on the flanker task predicted faster responses on both high- and low-reward value trials (Spearman’s rhos of 0.20 and 0.16 respectively; P < .005 for both) and in both working memory conditions (Spearman’s rhos of 0.19 and 0.24; P < .001 for both).

“The whole-brain connectivity measures documented similarities and differences in the dynamic and stable neural architecture of inhibition across two task contexts, varying in cognitive load and reward value,” the authors write.

From a dynamic point of view, “a context-free signature emerged as stronger segregation of internal cognition (DMN, or default mode) and environmentally driven control (salience [SAL], cingulo-opercular [CON]) systems,” they report.

Across both contexts, younger individuals who had superior inhibition demonstrated greater temporal cohesion in the DMN, the CON, and the SAL. As a function of increasing inhibitory control over time, the nodes within each of these three networks were increasingly more likely to interact with one another rather than with nodes from other networks.

When the researchers conducted stable connectivity analyses, they found context-free (greater DMN segregation) signatures of inhibition. They also found context-specific signatures of inhibition (greater frontoparietal [FPC] segregation for higher cognitive load; greater attentional and environmentally driven control system segregation for greater reward value).

Superior inhibition in more mature adulthood “was typified by reduced segregation in the DMN, with increasing reward value and increased ventral attention.” However, there was reduced CON and subcortical system segregation with increasing cognitive load.

The researchers utilized a two-level hierarchical linear model in which standardized scores on the eight ASR subscales were nested within individuals. Several other variables, such as handedness and years of education, were included in the analysis. However, the “robust standard error results” revealed a significant two-way interaction only between age and scores on the late inhibition connectivity profile.

On further statistical analysis, they found that the association between scores on the late inhibition profile and psychological problems started becoming significant (P < .05) for individuals older than 30 years of age. (Those participants were >0.4232 standard deviations older than the average age of the sample.) At that region-of-significance boundary, the association between scores on the late inhibition profile and psychological problems was negative (b = -0.0657, SD = 0.0334, t = -1.972).

The effect of this interaction “can be interpreted as evidence that expression of the late inhibition-linked neural profile after the age of 30 shields against psychological problems (ie, adults over 30 who express this profile more strongly show fewer psychological problems than those over 30 who show a weaker expression of this profile),” the authors write.

Failure to evidence this neural profile after the age of 30 “predicted poorer life functioning.”

Boosting Cognitive Control

“Our results suggest that distinguishable neural mechanisms underlie individual differences in cognitive control during different young adult stages and across tasks, thereby underscoring the importance of better understanding the interplay among dispositional, developmental and contextual factors in shaping adaptive versus maladaptive patterns of thought and behavior,” the authors conclude.

Dr Petrican notes that she does not know of any studies that suggest ways of enhancing the brain mechanisms associated with superior cognitive control. “It is an open question, so I cannot offer recommendations, I can only speculate.”

She suggested, “perhaps exposure to a more diverse range of social situations may help with developing more specialized neural mechanisms for dealing more efficiently with those circumstances.”

Additionally, “exposure to mental challenges and more years of education can also provide benefit in increasing cognitive control by leading to more specialized brain mechanisms for dealing with cognitive challenges.”

This work was supported by the Canadian Institutes of Health Research and the Canada Research Chairs program. The authors have disclosed no relevant financial relationships.

J Neurosci. Published online July 17, 2017. Abstract

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Ditantang McGregor, Mayweather Diharapkan Tak Kecewakan Dunia Tinju

Ditantang McGregor, Mayweather Diharapkan Tak Kecewakan Dunia Tinju

London – Mempertimbangkan pengalaman keduanya, Floyd Mayweather sangat diunggulkan untuk mengalahkan Conor McGregor. Tapi, kalau sampai kalah, Mayweather disebut akan membuat dunia tinju kecewa.

Tak mengherankan kalau Mayweather jadi favorit dalam pertarungan tinju melawan McGregor di Las Vegas, Amerika Serikat, 26 Agustus 2017 mendatang. Petinju berusia 40 tahun itu pernah menyandang gelar juara di lima kelas berbeda dan belum sekali pun kalah di sepanjang kariernya.

Sebaliknya, McGregor masih sangat hijau di dunia tinju profesional karena dia lebih terkenal sebagai seorang petarung UFC. Meski usianya lebih muda 11 tahun daripada Mayweather, dia belum pernah menjalani duel tinju pro.

Mantan petinju Inggris yang sekarang menjadi komentator untuk Sky Sports, Carl Froch, juga sangat menjagokan Mayweather. Dia menyebut duel ini sebagai misi mustahil bagi McGregor.

“Siapa pun yang tahu soal tinju tak akan memberi peluang untuk Conor McGregor,” ujar Froch kepada Sky Sports News.

“Saya benar-benar memperkirakan Floyd Mayweather akan menang, tapi dia lebih baik tidak mengecewakan dunia tinju. Saya berharap dia memenanginya untuk dunia tinju, tapi ini adalah event yang luar biasa dan saya tak sabar menyaksikannya,” katanya.

“McGregor harus mendaratkan sesuatu, sebuah pukulan, yang cukup keras dan menyakitkan sejak awal agar punya peluang menang. Tapi, siapa pun yang tahu tinju tak akan memberinya peluang,” ujar Froch.

“Ini adalah sebuah Mission: Impossible,” katanya.

(mfi/cas)

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Most Patients Don't Use EHR Portals, GAO Finds

Most Patients Don't Use EHR Portals, GAO Finds

Hard to navigate and find information. Too many passwords to remember for too many systems. Down for maintenance.

No, these aren’t gripes that physicians have about electronic health records (EHRs). They’re what many patients say about accessing their medical information online through a portal that typically comes with an EHR system, according to a study issued in March by the Government Accountability Office (GAO). These complaints help explain why only 30% of Medicare beneficiaries who could have visited an EHR portal in 2015 actually did so.

Granted, these finding are slightly dated. And seniors may not be the heaviest computer users out there. Still, the study shows that patients and physicians share some of the same frustrations about digital medicine.

In numerous surveys, the general public has expressed a high demand to communicate with clinicians online. A Medscape survey in 2016 found that 63% of patients believed an online portal into their EHR improves the relationship with their physician.

The federal government also thinks these portals are beneficial, and it  promotes them. To comply with the Medicare incentive program for EHR meaningful use in 2015, for example, physicians had to give at least 50% of their patients the ability to electronically access health information, such as test results and current medications, in a timely manner, and at least one patient had to actually do it. Sharing digital data with patients remains a requirement of Medicare’s Merit-based Incentive Payment System, which incorporated elements of the meaningful-use program.

The prodding from Washington, DC, has been effective. Ninety-nine percent of the 194,000 clinicians who successfully participated in the meaningful-use program in 2015 gave at least half of their patients online access to their health records (the remaining 1% were exempted from the requirement for various reasons).

However, of the patients with a pipeline into their chart, only 30% logged in.  The percentage was even lower for physicians in rural areas (21%) and for practices with 10 members or fewer (20%). In contrast, the rate of online patient access hit 38% for physicians in group practices with more than 50 members.

Patient-Friendliness of EHR Portals Varies Widely

To better understand this dimension of telehealth, the GAO interviewed 33 patients who have electronically delved into their medical records. These individuals said the technology had its benefits, such as the ability to review their physician’s instructions, track lab results to spot a change in their condition, and share information with other clinicians. However, they also cited frustrations:

• Having multiple physicians means using multiple EHR portals. Patients told the GAO that it’s difficult to manage all the different passwords and master each portal’s interface.

• Some patients complained about the time and effort needed to set up access to their physician’s portal.

• It’s not always clear how to download or transmit health information.

• Information is sometimes incorrect — and hard to correct.

• Technical difficulties, such as downtime for maintenance, or a portal not being optimized for a mobile device, can put data out of reach.

• Some portals are clunkier than others when it comes to navigating and finding information.

The GAO took this last complaint seriously. Noting that user interfaces vary from portal to portal, the GAO broke down patient access rates for each of the 10 most frequently used EHR vendors in the meaningful-use program. The agency found that for physicians aligned with one particular vendor — not identified — only 10% of their patients took advantage of the EHR portal. With another vendor, that percentage shot up to 48%.

“Our analysis…confirms that the type of portal itself may affect the extent to which patients access their available health information,” the GAO report stated.

Patients also complained that they could not collect all their health data information — scattered in various EHR systems— and put it at their fingertips in a single longitudinal record. The GAO noted that clinicians can acquire software programs to aggregate data from various EHRs, but they’re not in high demand. There also are personal health record (PHR) programs that patients can buy to round up data from their physicians’ digital charts, but they’re not widely used, owing to a variety of technological limitations, including lack of EHR standardization. “Relatively few hospitals and healthcare professionals we surveyed reported having the ability to submit information to PHR products,” the GAO said.

But if someone builds a better PHR, will patients come? The Department of Health and Human Services (HHS) hopes so. As part of its work to connect patients to their health information, the department’s Office of the National Coordinator for Health Information Technology (ONC) recently issued a cash-prize challenge to software designers to develop a PHR that could easily siphon data from different EHRs. First place and $50,000 went to a company called PatientLink Enterprises.

The GAO noted ONC’s efforts to make patient portals more of a success story but said that ONC hasn’t developed ways to measure success. HHS told the GAO that it concurred with the agency’s recommendation to create such performance metrics.

The GAO report is available on the agency’s website.

Follow Robert Lowes on Twitter @LowesRobert

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New Antiemetic Guidelines Issued by ASCO

New Antiemetic Guidelines Issued by ASCO

The American Society of Clinical Oncology (ASCO) has fully updated its antiemetic guideline for patients with cancer receiving chemotherapy and radiation therapy for the first time since 2015. The update is published online in the Journal of Clinical Oncology.

Most notably, the guideline provides new evidence-based information on the use of olanzapine (Zyprexa Relprevv, Eli Lilly) as well as neurokinin-1 (NK1) receptor antagonists and dexamethasone. The guidance discusses using medical marijuana to control nausea and vomiting.

The guide includes a table detailing the estimated prices (per dose and per treatment cycle) of the antiemetic agents (generic and branded).

Olanzapine, which is an antipsychotic medication, should be added to standard antiemetic regimens for adults who receive chemotherapy with a high risk for emesis or who experience breakthrough nausea and vomiting. High-risk regimens include those using cisplatin or the combination of cyclophosphamide and an anthracycline.

The evidence for olanzapine comes from a large double-blind, randomized, phase 3 study that compared the drug with placebo in patients who received the standard triple-drug antiemetic regimen of an NK1-receptor antagonist, a 5-HT3-receptor antagonist, and dexamethasone.

Last year, trial results were published online in the New England Journal of Medicine. “This drug made a difference, it really did,” lead author, Rudolph M. Navari, MD, PhD, from the Indiana University School of Medicine–South Bend, told Medscape Medical News at that time.  “The study was strikingly positive and the drug was tolerable and showed no significant side effects.”

Mark Kris, MD, from Memorial Sloan Kettering Cancer Center in New York City, called the results “amazing” last year in an online commentary. “What is even more amazing is that this drug is sitting in your pharmacy. It literally costs pennies,” said Dr Kris, who is also co-chair of the ASCO expert panel that developed and authored the guideline update.

For olanzapine, the quality of evidence is high and the strength of recommendation is strong, according to the ASCO guideline authors, including the other co-chair, Paul Hesketh, MD, from the Lahey Clinic in Burlington, Massachusetts.

In another key update, the ASCO guideline authors recommend that an NK1 receptor antagonist should be added to the standard antiemetic regimen (the combination of 5-HT3 receptor antagonist and dexamethasone) for adults receiving carboplatin-based chemotherapy or high-dose chemotherapy, and children receiving chemotherapy with a high risk for nausea and vomiting.

NK1 receptor antagonists include aprepitant (Emend, Merck) and casopitant (Rezonic, GlaxoSmithKline) and rolapitant (Varubi, Tesaro).

This recommendation was actually issued last year in an abbreviated update from ASCO and is now included in the new full update.

The quality of evidence for the addition of an NK1 receptor antagonist is high and the strength of recommendation is strong, according to the guideline authors.

In another recommendation, the authors say that clinicians should administer dexamethasone only on day 1 for adults who receive anthracycline and cyclophosphamide chemotherapy.

Medical marijuana is not recommended in the new guidance, for either prevention or treatment of nausea and vomiting in patients with cancer receiving chemotherapy or radiation therapy. The evidence “remains insufficient,” say the authors.

However, the authors point out that ASCO guidance continues to recommend the US Food and Drug Administration–approved cannabinoids dronabinol or nabilone to treat nausea and vomiting that are resistant to standard antiemetic therapies.

The guideline authors are a panel of experts from medical oncology, radiation oncology, nursing, pharmacy, and health services research, as well as a patient representative.

The team conducted a systematic review of the medical literature published between November 2009 and June 2016.

“Tremendous progress has been realized over the last 25 years in the prevention of chemotherapy-induced nausea and vomiting with the introduction of new classes of antiemetic agents,” said Dr Kris in a press statement. “The full benefit of these treatment advances will only be realized, however, if evidence-based guidelines are fully implemented.”

Dr Hesketh has financial ties to UpToDate. Dr Kris has ties to AstraZeneca, ARIAD, Genentech. and Puma Biotechnology. Multiple other authors have financial ties to industry.

J Clin Oncol. Published online July 31, 2017. Abstract 

Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick

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Opioid Commission: Declare a State of Emergency, Mr President

Opioid Commission: Declare a State of Emergency, Mr President

The White House commission charged with advising the Trump administration on the country’s opioid epidemic is calling on President Donald J. Trump to declare a state of emergency to quickly and aggressively address this crisis.

Some 142 Americans die every day from a drug overdose, said Chris Christie, chairman of the President’s Commission on Combating Drug Addiction and the Opioid Crisis, in a press briefing.

The declaration of a national emergency is “the single-most important recommendation,” Christie said.

The commission’s interim report, addressed to President Trump, said such a declaration would “empower your cabinet to take bold steps and would force Congress to focus on funding and empowering the Executive Branch even further to deal with this loss of life.”

The report, released July 31, had been expected earlier, but Christie said it was delayed by the need to sift through some 8000 comments that were received after the commission held its first public meeting in mid-June.

The report made a number of recommendations, including some that would mandate physician education. Others would encourage and boost medication-assisted treatment (MAT) and increase availability of the overdose reversal agent naloxone.

The commission also urged an immediate change in Medicaid policy — one that would essentially require the federal government to pay for more addiction treatment, at a time when Congress has been looking at paring back Medicaid.

The healthcare community will play an increasingly crucial role in addressing the opioid epidemic, commission member Bertha Madras, PhD, told reporters.

“We are going to need an evolution or even a revolution in how the health care system addresses substance use issues,” said Dr Madras,  professor of psychobiology at Harvard Medical School, Boston, Massachusetts.

“Revolutionary” Approach Needed

Physicians need much more training in identifying people with substance use issues and to learn how to manage those individuals, she said. The healthcare system also frequently overlooks the fact that mental health problems are what she called a “massive contributor” to substance use disorders.

“If there isn’t an integration of mental and physical health in a revolutionary new way, we aren’t going to be able to address the entirety of the problem in a systematic and coordinated fashion,” Dr Madras said.

The report’s recommendations call for mandatory training for those who prescribe opioids, which includes understanding risk factors for substance use disorders. This, the commission says, could be accomplished by amending the Controlled Substances Act to require all Drug Enforcement Administration (DEA) registrants to take a course in “the proper treatment of pain.”

The report urged adoption of the American Society of Addiction Medicine’s (ASAM) suggestion that all clinicians who apply for DEA registration to prescribe controlled substances be required to demonstrate competency in safe prescribing, pain management, and substance use identification.

Christie said the commissioners agree with the ASAM proposal and that it should also be applied to clinicians who seek renewal of their DEA registration.

The American Medical Association has repeatedly said that prescriber education should be voluntary, not mandatory.

The President’s commission is also recommending that states allow naloxone dispensing via standing orders and that clinicians be required to prescribe the overdose antidote along with high-risk opioid prescriptions.

The commission further recommends the US Department of Health and Human Services (HHS) Secretary be granted the ability to negotiate reduced pricing on naloxone so that the drug is available to all governmental agencies and law enforcement.

In addition, it directed HHS and other federal agencies to find a way to identify individuals who have overdosed and been revived with naloxone, so that their primary care or other healthcare providers can be identified.

Mandatory Use of PDMPs

Christie said the Commission also believes clinicians should be required to check a state’s prescription drug monitoring database before prescribing an opioid.

Currently, 49 states have prescription drug monitoring programs (PDMPs). But the information in those databases is of no use if doctors aren’t required to use them, Christie said.

The commission also recognizes that databases are not as useful as they could be because currently states share information. The report urges the president to direct Veterans Affairs and HHS to lead an effort to have all state and federal PDMPs share information by July 1, 2018.

Information should also be shared among clinicians and families, the commission said. It recommended that patient privacy laws be amended to ensure that a patient’s substance use history can be shared by clinicians with other healthcare providers and family members. 

“Sharing this information is appropriate in light of the crisis we are suffering,” Christie said.

One of the Commission’s top recommendations was to rapidly expand treatment capacity, by allowing states to immediately seek waivers from a regulation that prohibits Medicaid reimbursement for services provided in inpatient facilities that have more than 16 beds.

“This is the single fastest way to increase treatment availability across the nation,” the report said.

The report also urges the Trump administration to find a way to create a federal incentive to boost access to MAT. All FDA-approved modes of MAT should be offered at every licensed MAT facility, and the decision should be based on what’s best for the individual, “not on what is best for the provider,” the report notes.

The commission called for the federal government to find a way to reduce reimbursement hurdles for MAT.

The commission’s other recommendations include:

* That President Trump direct the Department of Labor to aggressively enforce the Mental Health Parity and Addiction Equity Act. Penalties should be levied on violators.

* That more funding and manpower be provided to Customs and Border Protection, the Federal Bureau of Investigation, and the DEA to quickly develop ways to detect fentanyl, and that legislation be supported to stop opioids from being trafficked through the United States mail.

The five-member commission was established by executive order and signed by President Trump on March 29. The panel is due to issue a final report in October.

That report will focus on creating addiction prevention strategies and will take a close look at patients’ “satisfaction with pain” measure, which the federal government currently uses as a means of evaluating physicians.

“We believe this may very well have proven to be a driver for the incredible amount of prescribing of opioids,” said Christie.

He noted that in 2015 enough opioids were prescribed so that every American could be medicated for three weeks. “It’s an outrage,” said Christie.

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Artificial Sweeteners Linked to Higher BMI, Cardiometabolic Risk

Artificial Sweeteners Linked to Higher BMI, Cardiometabolic Risk

WINNIPEG, MB — A new meta-analysis and systematic review finds mixed evidence to support use of artificial sweeteners for weight loss and suggests routine consumption may be associated with long-term weight gain and an increased risk of cardiometabolic disease^[1].

“People are generally consuming nonnutritive sweeteners (NNS) believing they are a ‘healthy choice,’ but this may not be true,” study author Dr Meghan Azad (University of Manitoba, Winnipeg) told theheart.org | Medscape Cardiology in an email.

“More important, our results send a strong message to researchers and research funding bodies that more studies are needed to understand the long-term health impacts of artificial sweeteners.”

The lack of studies looking at long-term effects is surprising, given that more than 40% of adult Americans regularly consume NNS, such as aspartame, sucralose, and stevia, she said. In addition, studies measuring NNS in blood and urine show that many people who report not using NNS are unknowingly consuming these sweeteners in foods.

The study, published July 17, 2017 in CMAJ, pooled results from seven randomized controlled trials with 1003 participants (median follow-up 6 months) and 30 cohort studies with 405,907 participants (median follow-up 10 years).

In participants who were obese or overweight, two longer trials showed significant weight loss with NNS over 16 to 24 months and three shorter trials showed no effect with NNS use over 6 months. Both of the longer-term trials, however, were industry sponsored, and all five trials were at high risk of bias, the authors noted.

Two trials involving mildly hypertensive patients who were taking stevioside capsules and one in overweight participants showed no significant effect on BMI over 6 to 24 months (mean difference -0.37 kg/m²; 95% CI -1.10 to 0.36).

Large cohort studies with longer follow-up, however, showed that high NNS intake was significantly associated with modest long-term gains in body weight, BMI, and waist circumference.

In addition, high NNS intake was associated with higher risks of hypertension (hazard ratio [HR] 1.13, 95% CI 1.06–1.20), stroke (risk ratio [RR] 1.14, 95% CI 1.04–1.26), cardiovascular events (RR 1.32, 95% CI 1.15–1.52), and incident type 2 diabetes (RR 1.14, 95% CI 1.05–1.23).

Notably, there were no data from the trials to confirm these observations, and the increased risk for type 2 diabetes found in nine cohort studies was attenuated (RR 1.07, 95% CI 0.97–1.18) after imputing missing studies, suggesting potential publication bias, the authors write.

Dr Lawrence Cheskin (Johns Hopkins Weight Management Center, Baltimore, MD) said, “Even though they point to some observational studies and say there is more diabetes, there’s no experimental evidence that that occurs in humans. Nor heart disease.”

He said that artificial sweeteners don’t directly cause heart disease. “It may be associated with people who have somewhat higher risks of heart disease because they’re heavier and have bad habits and are drinking diet soda to make up for the other things they’re doing that aren’t so good,” he speculated.

In addition to the confounding factor of selection bias, Cheskin pointed out that the seven randomized trials were in small numbers of people followed for relatively short periods of time and looked only at certain types of sweeteners available at the time and in beverages, not in other foods. In four of the trials, participants using NNS were also on a weight-loss program.

For its part, the Academy of Nutrition and Dietetics, the largest organization of food and nutrition professionals in the US, says NNS play a role in weight and blood glucose control.

“I think there’s certainly nothing in this paper that would reverse that recommendation,” Cheskin said. “It doesn’t add truth, it just adds a few more observational studies.”

Dr Matthew Pase (Boston University School of Medicine, MA) commented, “I don’t think the evidence is very strong with regard to the harder cardiovascular outcomes. Certainly there needs to be more research done there.”

His own group recently reported that participants in the Framingham Heart Study who drank one or more cans of artificially sweetened diet soda daily vs those who never drank diet soda were at three times increased risk of stroke or dementia.

“But obviously this was an observation, and like the observational studies we’re discussing, it’s hard to know what’s driving the association,” he said. “Is it due to reverse causality: do people who are unhealthy simply gravitate toward artificial sweeteners or do artificial sweeteners actually have some detrimental effect on health?”

Pase said that NNS consumption should be tracked from an early age in cohort and observational studies rather than in already-unhealthy people and that more mechanistic and animal studies are needed to understand the mechanisms that could contribute to the negative effects of NNS seen in observational studies.

Azad said much of her research is focused on the gut microbiome and that recent studies have shown artificial sweeteners can disrupt the gut microbiome in rats and adult humans. Thus, “routinely consuming artificial sweeteners may be selecting for an ‘obesogenic’ microbiome.”

There is also some evidence that routine consumption may confuse and “reprogram” metabolism in a way that favors weight gain, insulin resistance, and glucose intolerance, she said.

Consuming NNS may also promote a sweet tooth or give consumers a sense of “permission” to eat higher-calorie foods because they “saved” on calories with their diet drink, for example.

The Calorie Control Council, an association representing the low- and reduced-calorie food and beverage industry, said in a statement the study paints low-calorie sweeteners with “too broad a brush” and that the “researchers admit that less than 50% of the cohort studies controlled for ethnicity or socioeconomic status, which are both known risk factors for obesity and cardiometabolic illness.”

Azad reported no relevant financial relationships. Disclosures for the coauthors are listed in the paper. Cheskin reported serving on the scientific advisory boards of Medifast and Pressed Juicery. Pase is funded by the National Health and Medical Research Council.

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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Drug Resistant Tuberculosis on the Rise in Eastern Europe

Drug Resistant Tuberculosis on the Rise in Eastern Europe

An epidemic of drug-resistant tuberculosis (TB) is mounting in Eastern Europe, and without intervention on multiple fronts there is little hope the spread will slow.

For several years, we have been hearing that there is “a need for urgent action,” said Daria Podlekareva, MD, PhD, from Rigshospitalet at the University of Copenhagen.

It needs to be addressed now, she told Medscape Medical News.

However, cultural and political issues mean that it is “not always easy to adopt international guidelines or initiate research projects,” she said at the International AIDS Society 2017 Conference in Paris.

“It’s difficult to go into Eastern Europe and initiate projects and do studies,” she explained. “Some Eastern Europe countries are still behind an iron wall.”

It can be easier to conduct research into infectious disease in other places — even African countries — than in most formerly Soviet Union countries.

To help curb the epidemic in Eastern Europe, the World Health Organization (WHO), the Stop TB Partnership, and the European Union should collaborate to encourage governments to recognize TB as a public health emergency and to implement international programs and standards of care, said Dr Podlekareva.

Eastern Europe Is a “Perfect Storm” for TB

TB continues to be a major public health issue, according to the 2017 WHO report — Tuberculosis Surveillance and Monitoring Report in Europe 2017 — released in March. Most of the 323,000 new TB cases and the 32,000 deaths due to TB in the WHO European Region in 2015 occurred in Eastern Europe and Central Asia.

Eastern Europe is a “perfect storm” for the spread of TB because it has high rates of incarceration, HIV infection, and injection drug use, and it has disintegrated healthcare systems, suboptimal TB diagnosis and treatment, and poor adherence rates, Dr Podlekareva said.

In addition, nearly half of all TB cases are multidrug-resistant, which requires longer, more expensive treatment than drug-susceptible TB, and leads to more adverse effects. Treatment is also less accessible in the region.

And because rates of HIV infection are on the rise in Eastern Europe, where antiretroviral therapy coverage is low, the fast progression of immunosuppression leads to increases in the rate of TB and HIV coinfection.

More Likely to Die From TB in Eastern Europe

In an international cohort study on the management of concurrent HIV and TB, Dr Podlekareva and her colleagues found that TB-related deaths were significantly more common in Eastern Europe than in Western Europe or Latin America (Lancet HIV. 2016;3:e120-e131).

In that study, 1406 consecutive HIV-positive patients aged 16 years or older with a tuberculosis diagnosis were followed up for 12 months at one of 62 HIV and tuberculosis clinics in 19 countries.

The prognosis was far worse for the 834 patients treated in Eastern Europe than for the 317 treated in Western Europe or the 255 treated in Latin America.

Of the 264 (19%) deaths in the study cohort, 188 (71%) were related to tuberculosis.

Table. Probability of Death

Cause of Death	Eastern Europe, %	Western Europe, %	Latin America, %	P- Value
All	29	4	11	<.0001
TB	23	1	4	<.0001

 

“Latin America and Eastern Europe have comparable economies, as middle-or poor-resource settings,” Dr Podlekareva said. But “Latin American patients did better — much better — than the Eastern European patients.”

In Eastern Europe, diagnosis is often made on the basis of clinical judgment, not laboratory confirmation, she pointed out. And treatment is often suboptimal, including very few active drugs. Moreover, disintegrated healthcare systems in Eastern Europe are detrimental to treatment, and care centers for TB and HIV are not combined. Plus, opiate-substitution therapy — an effective treatment for drug dependence — is limited or prohibited in most regions.

“Nearly 40% of our cohort had multidrug-resistant TB,” Dr Podlekareva reported.

Eastern Europe does not have to invent its own solutions; it can adopt “what we already know,” she told Medscape Medical News. Experience from the 1980s HIV epidemic in Western countries can be a guide. There are thousands of publications on the strategies and standards of care that work.

Prisons and Drugs Contribute

In Russia, illicit drug use is a criminal offense, and “methadone treatment is prohibited,” Dr Podlekareva said. “In Eastern European countries, like the Ukraine and Belarus, there are some drug-treatment programs, but they are not widely used as a standard of care.”

With no methadone support and very few social supports for injection drug users, access to treatment, adherence, and retention in care are a challenge.

Clinicians need to ramp up their efforts to convince patients to get treated. “There is a need for clinicians to be more willing to work together, to support these patients,” she said. “When we ask why a patient is not on antiretroviral therapy, they say the patient refused it, but I think it’s the clinician’s task to convince the patient.”

When injection drug users are thrown in jail, as they are in Russia, TB transmission proliferates, Dr Podlekareva explained. A previous study showed that intrapopulation transmission in prisons, population-to-prison transmission, intraprison transmission, and prison-to-population transmission have driven overall population-level differences in TB incidence, prevalence, and mortality rates in countries of the former Soviet Union (Proc Natl Acad Sci USA. 2008;105:13280-13285)

/The number of people with drug-resistant TB is increasing more than 20% every year./

She is not alone in her assessment. “The problem in Eastern Europe will not go away, especially multidrug-resistant TB, if the infrastructure is not improved,” said Christoph Lange, MD, from the tuberculosis unit of the German Center for Infection Research and Research Center Borstel in Germany.

“Patients have been getting treatment on and off,” so new strains of multidrug-resistant TB are emerging, he told Medscape Medical News. “People are now getting infected with drug-resistant strains,” and most Eastern European countries are not equipped to treat multidrug-resistant TB.

Dr Lange said that in the past year he has seen five Armenian patients with multidrug-resistant TB looking for treatment at his clinic. He referred to them as “health-seeking migrants,” and said, “we expect to see more.”

“The number of people with drug-resistant TB is increasing more than 20% every year,” he reported. The current targets of elimination are not credible and they don’t work under the current circumstances; health organizations and governments have to acknowledge that.

“Instead of having the goal of elimination, we need to work toward low incidence,” Dr Lange said. “We have to redefine our goals and address what is most endangering public health.”

Drs Podlekareva and Lange have disclosed no relevant financial relationships.

International AIDS Society (IAS) 2017 Conference. Presented July 2017.

Follow Medscape on Twitter @Medscape and Ingrid Hein @ingridhein

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Minat pada Griezmann Dianggap Simeone sebagai Sanjungan

Minat pada Griezmann Dianggap Simeone sebagai Sanjungan

Pemain Atletico Madrid, Antoine Griezmann, diminati oleh banyak klub. Pelatih Los Colchoneros,Diego Simeone, menganggapnya sebagai sebuah sanjungan.


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Hundreds of U.S. Counties at Risk for No Obamacare Insurer in 2018

Hundreds of U.S. Counties at Risk for No Obamacare Insurer in 2018

NEW YORK (Reuters) – With Republican efforts to dismantle Obamacare in disarray, hundreds of U.S. counties are at risk of losing access to private health coverage in 2018 as insurers consider pulling out of those markets in the coming months.

Republican senators failed this week to repeal and replace Obamacare, former President Barack Obama’s signature healthcare reform law, creating new uncertainty over how the program providing health benefits to 20 million Americans will be funded and managed in 2018. In response, Republican President Donald Trump on Friday again suggested that his administration would let the Obamacare program “implode.” He has weakened enforcement of the law’s requirement for individuals to buy insurance, threatened to cut off funding and sought to change plan benefits through regulations.

Anthem Inc, Cigna Corp, Health Care Service Corp and Molina Healthcare, four of the biggest health insurers selling Obamacare plans, said they are weighing whether to pull out of more markets for 2018 rather than face financial losses. They have until Sept. 27 to finalize their plans.

So far, 40 U.S. counties are expected to have no insurer offering individual coverage next year, but that number could rise by the hundreds, according to U.S. government data, Kaiser Family Foundation analysis and insurer disclosures. More than 1,300 counties, primarily in 15 states, currently have only one insurer participating in 2018. Anthem and HCSC are the last man standing in one-third of those counties and states – putting those areas in particular at risk.

“Right now the number of counties at immediate risk of having no insurers in 2018 is small, but it could easily grow significantly if a couple major insurers decide to exit,” Larry Levitt, health economist at the Kaiser Family Foundation, said.

Many insurers have been waiting for an answer from Trump or lawmakers on whether they will continue to fund $8 billion in annual government subsidies. Without assurances, many insurers plan to raise rates an additional 20 percent by an Aug. 16 deadline for premium prices. Others say that the many unknowns will make the business too risky.

The last-minute drama has left millions of Americans questioning whether they will have medical coverage next year.

Julie Grady, a 59-year-old small business owner in Carson City, Nevada, is currently covered by Blue Cross Blue Shield of Nevada, part of Anthem, which has already decided to leave the exchanges in her county and most of the state. Carson City will have no insurer on the exchanges next year.

Grady’s pays a reduced premium of $70 per month and a deductible under $1,000 for her plan, which is part of the Affordable Care Act, commonly called Obamacare. Grady is looking at being uninsured, as she was before the law.

“I would have to go without health insurance,” she said. “I would just stay healthy, hike, eat well. I’d be in trouble if something catastrophic happened. I would lose everything.”

ANTHEM CONSIDERING 2018 PLANS

Anthem, the second-largest U.S. health insurer, sells Blue Cross Blue Shield plans in 14 states. It has already decided to pull out of most individual markets in Nevada, Ohio, Indiana and Wisconsin in 2018. Earlier this week, Chief Executive Officer Joe Swedish said he was still weighing 2018 participation in its other states. In states like Colorado, Georgia, Kentucky, Missouri, and Virginia, Anthem sells plans in more than 250 counties where it is the only insurer, and they could be left “bare” next year, according to government data.

Health Care Services Corp is a Blue Cross Blue Shield licensee in five states and is the only Obamacare individual insurer in more than 90 Texas counties, more than 75 Oklahoma counties, and half a dozen Illinois counties. It confirmed on Friday that it has submitted products for its five states but is still weighing next year.

“We’re working through the regulatory filing process and hope to fully participate…in 2018, however no final decisions have been made,” HCSC spokeswoman Kristen Cunningham said.

Molina, which has more than 1 million members in Obamacare plans, and Cigna, with more than 250,000 participants, have said they need more certainty from the government to decide on 2018 participation and would weigh their decisions up until the late September deadline.

State insurance regulators have worked hard in recent months to replace insurers who have left. In Nevada, for instance, Centene Corp and Aetna Inc entered in some counties that Anthem left after the insurance commissioner said he would favor these insurers for its Medicaid contract bids.

But they are unlikely to find replacements for new dropouts in these final weeks, particularly if the Trump administration signals it won’t fund $8 billion in subsidies for out-of-pocket medical costs.

“There is almost no chance they would step in to participate,” said Kurt Wrobel, a fellow at the Society of Actuaries and chief financial officer of the Geisinger Health Plan in Pennsylvania.

Some insurers say they will likely just raise rates and hope it works. Blue Cross Blue Shield of Michigan filed two sets of rates with the state department of insurance, one up to 32 percent higher if the fate of subsidies remains unclear.

“We don’t have any plans to pull out,” said Rick Notter, director of the individual business at BCBS Michigan. “But it would certainly help to have more certainty around what the market holds.”

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Siapkan Regenerasi, Satria Muda Rekrut Rivaldo

Siapkan Regenerasi, Satria Muda Rekrut Rivaldo

Playoff NBA

LeBron James Bawa Cavs Lumat Celtics

DETIKSPORT | Sabtu 20 Mei 2017, 10:53 WIB
Cleveland Cavaliers kembali menang di kandang Boston Celtics. Cavs, yang dimotori LeBron James, melumat Celtics dan unggul 2-0 di final Wilayah Timur.

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High-Normal Troponin Levels May Signal Risk for Fatal CVD

High-Normal Troponin Levels May Signal Risk for Fatal CVD

INNSBRUCK, AUSTRIA — Cardiac troponin levels that are high but still within the “normal” range appear to be a marker for increased cardiovascular disease (CVD) risk, especially fatal CVD events, results of a systematic review and meta-analysis suggest^[1].

Among 154,052 participants in 28 prospective, long-term studies of patients without a history of CVD, patients with the highest third of cardiac troponin levels detected by high-sensitivity cardiac troponin T or troponin I (hs-cTNT/cTNI) assays had a greater than 60% increase in risk for fatal CVD events, a nearly 60% greater likelihood of coronary heart disease (CHD), and a more than 40% rise in overall CVD compared with patients in the lowest third, reported investigators led by Dr Peter Willeit (Medical University of Innsbruck, Austria).

The association between troponin levels and fatal CVD persisted even after adjustment for other CVD risk factors.

“To shed more light on this preliminary finding, future research is needed that evaluates, in a direct comparison, whether the clinical utility of hs-cTnT and hs-cTnI measurements depends on the assay generation or on patient characteristics, including age, sex, and indicators of myocardial stress,” they write in the August 1, 2017 issue of Journal of the American College of Cardiology.

However, it’s still too early to tell whether the findings will have a significant effect on clinical practice, commented Dr Jennifer E Ho (Massachusetts General Hospital, Boston) in an accompanying editorial^[2].

“Although the use of hs-Tn assays in patients with suspected acute coronary syndrome may have been embraced early on, the clinical usefulness of hs-Tn assays when extended to asymptomatic populations without known cardiovascular disease is largely uncharted,” she writes.

PROSPER Plus 27

Willeit et al searched the medical literature for prospective studies reporting on associations between cardiac troponin concentrations and first-ever CVD outcomes, and identified 27 that met their criteria. Two independent reviewers then extracted study-specific estimates, controlling for conventional CVD risk factors.

The investigators then pooled the findings with de novo data from the Pravastatin in Elderly Individuals at Risk of Vascular Disease Study (PROSPER) and created a random effects meta-analysis. Increases were seen across a number of cardiovascular outcomes.

Relative Risks for CVD Events in Meta-analysis of 28 Studies

Outcome	Relative risk (top vs bottom third) (95% CI)
CVD	1.43 (1.31–1.56)
Fatal CVD	1.67 (1.50–1.86)
CHD	1.59 (1.38–1.83)
Stroke	1.35 (1.23–1.48)

For the end point of fatal CVD, the investigators found that the associations were significantly stronger for those studies measuring troponin T rather than troponin I (P=0.027) and in studies conducted in North American compared with other regions (P=0.010).

These associations occurred among populations with largely normal troponin values. For example, in PROSPER, which measured troponin T, 87.5% of the 4402 participants had detectable concentrations, with a median of 7 ng/L, and 85% of values were below the high-normal cutoff of 14 ng/L.

Now What?

The results indicate that binary classification of patients as being “troponin-positive” or “troponin-negative” are simplistic and may no longer be meaningful, Ho commented in her editorial.

“The days of ‘troponin-positive’ patients are likely to end, because hs-Tn assays will need to be considered quantitatively, and underlying etiologies for troponin release will need to be considered. For example, if hs-Tn is driven by cardiac remodeling, fibrosis, and stage B heart failure, prevention strategies could be distinct from hs-Tn release in the setting of atherosclerosis or uncontrolled hypertension,” she wrote.

In an interview with theheart.org / Medscape Cardiology, Ho said that high-sensitivity troponin assays have been shown in European trials to be valuable clinical aids when patients present with possible acute coronary syndrome and for ruling out MI early on with a rapid protocol.

“But with respect to measuring high-sensitivity troponins in the general population or in patients who are coming in for outpatient follow-up in the absence of chest pain, that, I think, is entirely unclear. We don’t know the clinical implications of measuring troponins in the general population and how that’s helpful in terms of taking care of our patients or modifying their risk for future cardiovascular events,” she said.

Dr Deepak Bhatt (Brigham & Women’s Hospital, Boston, MA), who was not involved in the study, likened the findings to earlier studies showing that serum cholesterol levels that are high but still within the so-called normal range confer greater CVD risk on patients than low or intermediate levels.

“On a population level what they found is definitely true, but how would one apply that as a physician to an individual patient? That’s where things get very tricky, because I think that just measuring this troponin and finding that it’s a bit higher but with the normal range isn’t necessarily actionable,” he said.

The US Food and Drug Administration recently granted 501(K) clearance to a high-sensitivity troponin T assay made by Roche Diagnostics.

The study was supported by the Austrian Research Promotion Agency (Agency FFG). Willeit and  coauthors reported no relevant financial relationships. Bhatt previously served on the advisory board of Medscape Cardiology and has received honoraria from WebMD (continued medical education steering committees), among others. Ho is supported in part by a National Institutes of Health grant and a Massachusetts General Hospital Hassenfeld Scholar Award. She reported no relevant financial relationships.

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Heavy Cannabis Use Associated With Depression, Suicidality

Heavy Cannabis Use Associated With Depression, Suicidality

Early and frequent use of cannabis is associated with major depressive disorder (MDD) as well as suicidal thoughts and behaviors, a large twin study suggests.

Investigators led by Arpana Agrawal, PhD, associate professor of psychiatry, Washington University in St. Louis, found that among monozygotic twins, those who used cannabis were more than 100 times more likely to meet criteria for MDD and report suicidal ideation than their genetically identical twin who had never used cannabis or who had used it less frequently.

This finding held true when the researchers adjusted for covariates. However, occasional use of cannabis was not associated with MDD and suicidal thoughts or behaviors.

“We need to carefully evaluate the relationship between various levels of cannabis use, from casual to heavy and problematic, and serious mental health outcomes, like depression and suicidal thoughts and behaviors,” Dr Agrawal told Medscape Medical News.

“We also need to examine all possible pathways that might lead to this association, such as shared genetic factors, and exclude them before ascribing causal effects,” she said.

The findings were published online July 24 in Lancet Psychiatry.

Role of Monozygous Twins

Previous research linked cannabis use and MDD and suicidal thoughts and behaviors. Daily cannabis use — especially during adolescence — has been associated with 6.8 odds of attempted suicide, the authors note.

Studying monozygous twins reared together is a useful avenue of exploration because cannabis use and suicidal thoughts and behaviors have been shown to be highly heritable. Because monozygotic twins share genetic and, typically, early familial influence, it follows that if a twin who uses cannabis shows an increased likelihood of MDD or suicidal thoughts and behaviors compared with their twin who does not use cannabis, “this residual association might be viewed as evidence supporting person-specific factors and causal mechanisms.

“Although prior research suggested that heavy cannabis use can increase likelihood of depression and suicidal thoughts, results were mixed, with some studies suggesting other factors, such as childhood neglect, that could explain the association,” Dr Agrawal said.

“We also know that genetics are an important factor that contributes to heavy cannabis use, depression, and suicidal ideation. We wanted to examine whether the association between heavy and early cannabis use and these mental health conditions would remain when we examined pairs of individuals who had the same genetic background — ie, identical twins — but with different levels of cannabis use,” she explained.

Beyond Genetics

To investigate these questions, the researchers conducted a retrospective study that drew on data from three studies that recruited twins from the Australian Twin Registry.

Sample 1 (n = 5846) included monozygotic and dizygotic twins (aged 24 to 90 years) who were born between 1902 and 1964. Those born between 1902 and 1940 were excluded because the use of cannabis was low in that age group. The cohort was invited to participate in a short telephone in Between 1992 and 1993.

Sample 2 (n = 6255) included twins aged 24 to 36 years who were born from 1964 to 1971 and were interviewed by telephone from 1996 to 2000. Sample 3 (n = 3299) included twins aged 27 to 32 years (born from 1972 to 1979) who were first interviewed from 2005 to 2009.

Respondents in all three studies were assessed using the Australian Semi-Structured Assessment for the Genetics of Alcoholism. All were interviewed about cannabis use and suicidal thoughts and behaviors, as well as MDD and all covariates.

Respondents who reported lifetime use of cannabis were asked about the age at first use and how many times they had used cannabis during their lifetimes. Use of cannabis before age 18 years (for sample 1) and before 17 years (samples 2 and 3) was defined as “early.” Those who used cannabis ≥100 times were designated as “frequent” users.

The researchers analyzed early and frequent use both within the pool of individuals who reported a lifetime history of cannabis use and within the full sample. Participants were also asked about suicidal ideation and suicide attempts.

Participants were regarded as experiencing the onset of MDD if they reported experiencing either recurring episodes of dysphoria or anhedonia. Cases involving MDD or suicidality that occurred prior to cannabis use were excluded from analysis.

Covariates included early alcohol use, early tobacco smoking, conduct disorder, childhood sexual abuse, and dysphoria or anhedonia before age 16 years (in the analysis of suicidal thoughts).

The researchers studied 13,986 twin individuals (6181 monozygotic and 7805 dizygotic, including opposite-sex). Monozygotic and same-sex dizygotic twin pairs were selected from this sample.

Mean age at onset of cannabis use was higher in sample 1 and was similar in samples 2 and 3 (21.1 years vs 18.9 years and 17.9 years, respectively). Early and frequent use were correlated (r = 0·46), with 44% of early users of cannabis also reporting frequent use, and 49% of frequent users also reporting use from a young age.

After temporal ordering, the researchers found that cannabis use was associated with both MDD and suicidal thoughts and behaviors, although these associations were no longer significant after accounting for covariates. For this reason, the researchers did not examine cannabis use in discordant twin models.

“Robust” Link

By contrast, both early and frequent cannabis use were “robustly associated” with MDD as well as suicidal thoughts and behaviors, with adjusted odds ratios (ORs) ranging from 1.28 to 2.38, after adjustment for covariates.

These significant associations persisted, even when the researchers excluded lifetime never-users of cannabis from the analysis. Frequent users were twice as likely to report suicidal ideation and attempt than were lifetime but less frequent users.

In analyses with and without never users, within-pair associations between early cannabis use, MDD, and suicidal thoughts and behaviors were significant within dizygotic twins but not monozygotic twins (OR 2.23 – 6.50 vs OR 1.17 – 2.00). This pattern of results is “consistent with shared genetic influences contributing to the association,” the authors suggest.

Within both dizygotic and monozygotic pairs, the associations between frequent cannabis use and MDD, suicidal ideation, and persistent ideation were significant.

Compared with their genetically identical twin who did not use cannabis as frequently, a monozygotic twin who reported frequent use was more likely to meet criteria for MDD and report suicidal ideation and persistent ideation (OR, 1.72, 2.71, and 3.14, respectively).

An OR of ≥1 in a monozygotic twin “suggests that factors other than those shared by members of identical twin pairs contribute to the association,” the authors state.

After accounting for covariates, twins who frequently used cannabis were at 2.35 to 2.47 odds of reporting suicidal ideation, as compared with their genetically identical twin who did not use cannabis as frequently or who had never used it at all. For users, the odds of MDD remained at 1.98 as compared with their identical twin who used cannabis less frequently.

“These results indicated that individual-specific factors other than these covariates contribute to the association between frequent cannabis use and MDD and suicidal ideation (but not persistent ideation),” the authors comment.

Compared to concordant unexposed twins, the prevalence of MDD and suicidal ideation in concordant exposed twins was greater, “suggesting a strong, main effect of frequent cannabis use on suicidal ideation.” In discordant twins, the exposed twins were more likely to report suicidal ideation and MDD than their identical but unexposed twin.

“Importantly, although there was minimal effect of the co-twin’s exposure status on an individual twin’s report of suicidal ideation, the rate of MDD was slightly higher in unexposed twins from discordant than concordant pairs,” the authors note.

“We speculate that familial factors may play a more important role in the relationship between depression and heavy cannabis use than for suicidal ideation because individuals who did not use cannabis heavily themselves, but their identical twin did, were slightly more likely to report depression than individuals who did not use cannabis heavily and also did not have a twin who did,” said Dr Arpana.

It appears that “having an identical twin increases one’s own chance of depression, even when one does not use cannabis heavily, possibly due to factors shared with that twin,” she added.

The authors note that when the associations between early and frequent cannabis use and MDD and suicidal thoughts and behaviors were examined within identical twin pairs, frequent use remained associated with MDD and suicidal ideation, “suggesting that factors beyond those shared by identical twins might contribute to the association.”

A Constellation of Factors

Commenting on the study for Medscape Medical News, Laura Huckins, PhD, postdoctoral fellow, Icahn School of Medicine at Mount Sinai, New York City, called the study “a very well-written paper in that the authors take into consideration that there are a whole constellation of mechanisms linking cannabis use to suicidal thoughts and behaviors.”

She was “pleased” that “all avenues were investigated thoroughly.”

Genetic, environmental, and neurobiological effects all play a role in the constellation of mechanisms, and “we always expect study findings to say ‘yes to all’ of these, as was found in this study,” said Dr Huckins, author of an accompanying editorial. “The risk is multifactorial.”

It is possible that the connection between frequent cannabis use and suicide risk is mediated by poor societal outcomes, and that removing stigma and criminality from cannabis smoking might improve these outcomes, she suggested.

“Societies where cannabis is legal see better mental health outcomes for those individuals and have lower levels of alcohol use, violent crime, and suicide rates for those who use cannabis.” Further research is needed to elucidate this mechanism.

Dr Agrawal added that the study findings have important implications for public health policy.

“The role of heavy cannabis use in potential mental health outcomes with serious morbidity, such as depression, should be carefully evaluated, as the results might inform how we frame future policies regarding cannabis use.”

The study was funded by the National Institute on Drug Abuse, the National Institutes of Health (NIH), and the Australian National Health and Medical Research Council. Dr Agrawal and a coauthor have received NIH funding and compensation for grant reviews for NIH outside the submitted work. Dr Huckins has disclosed no relevant financial relationships.

Lancet Psychiatry. Published online July 24, 2017. Abstract, Editorial

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U.S. Republicans Try to Pick Up the Pieces After Healthcare Defeat

U.S. Republicans Try to Pick Up the Pieces After Healthcare Defeat

WASHINGTON (Reuters) – The seven-year Republican quest to scrap Obamacare, a major campaign vow by President Donald Trump, lay in ruins on Friday after the Senate failed to dismantle the healthcare law, with congressional leaders now planning to move on to other matters.

John McCain, the maverick 80-year-old senator and 2008 Republican presidential nominee, cast the deciding vote in the dramatic early-morning showdown on the Senate floor as a bill to repeal key elements of Obamacare was defeated, 51-49, dealing Trump a crushing political setback.

McCain, who flew from Arizona this week after being diagnosed with brain cancer and was heading back for further treatment starting on Monday, joined fellow Republicans Susan Collins and Lisa Murkowski in voting with Senate Democrats unified against the legislation.

“It’s time to move on,” Senate Majority Leader Mitch McConnell, whose reputation as a master strategist was diminished, said on the Senate floor after the vote at roughly 1:30 a.m. (0530 GMT).

While House of Representatives Speaker Paul Ryan said fellow Republicans should not give up on healthcare, he cited other pressing issues that needed attention, including major tax-cut legislation sought by Trump.

“We have so much work still to do,” Ryan said in a statement.

The Senate’s healthcare failure called into question the Republican Party’s ability to govern even as it controls the White House, Senate and House of Representatives.

Trump has not had a major legislative victory after more than six months in office, and his administration is mired in investigations into contacts between his election campaign and Russia and high-level White House staff infighting. He had promised to get major healthcare legislation, tax cuts and a boost in infrastructure spending through Congress in short order.

Also on the legislative agenda are spending bills for the fiscal year beginning Oct. 1 to avoid a government shutdown and raising the U.S. debt limit.

Speaking in Brentwood, New York, on Long Island, Trump expressed dismay at the bill’s failure, saying, “I said from the beginning, let Obamacare implode and then do it (pass legislation). I turned out to be right. Let Obamacare implode.”

Trump, who earlier on Twitter said the three Republicans who voted no “let America down,” again took aim at lawmakers in his own party. “Boy, oh boy, they’ve been working on that one for seven years,” he said in Brentwood. “Can you believe that? The swamp. But we’ll get it done.”

Some lawmakers urged a bipartisan effort to buttress the existing healthcare system. With the partisan divide as wide as ever in Washington, it remained to be seen if a bipartisan approach can get off the ground.

McCain said the defeated bill did not offer meaningful reform and that its defeat presents “an opportunity to start fresh” on legislation crafted by lawmakers in both parties.

“I encourage my colleagues on both sides of the aisle to trust each other, stop the political gamesmanship and put the healthcare needs of the American people first,” McCain said.

Top congressional Democrats urged a bipartisan effort to fix problems in the Obamacare law without repealing it. “Change it, improve it, but don’t just take a knife and try to destroy it and put nothing in its place,” top Senate Democrat Chuck Schumer said.

While Ryan was able to secure House passage of a comprehensive bill to gut Obamacare in May, McConnell earlier in the week was unable to win passage of similarly broad healthcare legislation amid intraparty squabbling and competing demands by hard-line conservatives and moderates. On Friday morning, he failed to get even a stripped-down, so-called skinny bill over the finish line.

BACKLASH FEARED

Killing the Affordable Care Act, Democratic former President Barack Obama’s signature domestic policy achievement dubbed Obamacare, has been a passion for Republicans since its 2100 enactment over their unified opposition, and was a key campaign promise by Trump last year.

Republicans lawmakers, some of whom have been gleeful about razing Obama’s presidential legacy, now fear a backlash from their conservative political base that could affect the 2018 congressional elections.

For the moment, the Affordable Care Act, which extended health insurance to 20 million people and drove the percentage of uninsured people to historic lows, remains in place and must be overseen by an administration that is hostile to it.

This leaves health insurers unsure of how long the administration will continue to make billions of dollars in Obamacare payments that help cover out-of-pocket medical expenses for low-income Americans.

Schumer warned against any efforts to sabotage the law.

The leading lobby group for the insurance industry, America’s Health Insurance Plans, said it stood ready to work with Congress and the administration on healthcare improvements.

On Wall Street, shares of hospitals were mostly higher because of the dwindling prospects for big cuts in the Medicaid insurance program for the poor and disabled. Community Health Systems Inc rose 3.3 percent, HCA Healthcare Inc gained 0.5 percent and Tenet Healthcare Corp fell 0.6 percent.

Shares of health insurers, which had fought against the bill’s proposed repeal of the mandate that Americans obtain insurance, were up. Aetna Inc rose 0.9 percent, Anthem Inc gained 2.2 percent and Humana Inc rose 0.5 percent.

Republicans have long denounced Obamacare – which expanded Medicaid and created online marketplaces for individuals to obtain coverage – as an intrusion by government on people’s healthcare decisions.

Veteran House Republican Tom Cole said he thought there were “a number” of other Republican senators who were uncomfortable with the Senate’s healthcare legislation but were able to vote “yes” knowing McCain’s vote would kill it.

Republican Senator Lindsey Graham, a close friend of McCain, met on Friday with Trump to discuss Graham’s proposal to take tax money raised by Obamacare and send it back to the states in the form of healthcare block grants, the senator’s office said.

The skinny bill, released just three hours before voting began, would have retroactively repealed Obamacare’s penalty on individuals who do not obtain health insurance, repealed for eight years a penalty on certain businesses that do not provide employees with insurance and repealed a tax on medical devices until 2020.

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New Chronic Fatigue Syndrome Biomarkers in the Pipeline

New Chronic Fatigue Syndrome Biomarkers in the Pipeline

Patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) have different circulating levels of two cytokines when compared with healthy individuals, a study has found. In addition, the circulating levels of 17 cytokines correlate with disease severity.

“Although only two cytokines were found to be different ([transforming growth factor-β (TGF-β)] higher and resistin lower) in ME/CFS patients compared with controls, 17 cytokines correlated with ME/CFS severity,” the authors write. “Thirteen of these cytokines are proinflammatory and may contribute to many of the symptoms these patients experience for several years.”

Jose G. Montoya, MD, from Stanford University School of Medicine in California, and colleagues published the results of their cross-sectional study online July 31 in the Proceedings of the National Academy of Sciences.

“There’s been a great deal of controversy and confusion surrounding ME/CFS, even whether it is an actual disease,” senior author Mark Davis, PhD, professor of immunology and microbiology and director of Stanford’s Institute for Immunity, Transplantation and Infection, said in a news release. “Our findings show clearly that it’s an inflammatory disease and provide a solid basis for a diagnostic blood test.”

ME/CFS affects more than 1 million Americans and is characterized by unexplained chronic fatigue, as well as other symptoms including exertion intolerance, headaches, myalgias, and sleep and cognitive abnormalities. Although the pathogenesis of this disabling disorder remains incompletely understood, inflammation has long been considered to play a central role.

Surprisingly, however, traditional markers of inflammation that have been used in clinical practice, such as erythrocyte sedimentation rate and C-reactive protein, are rarely elevated in patients with ME/CFS. Nevertheless, studies have demonstrated changes in other inflammatory markers in this patient population.

For example, several studies have found increased numbers of circulating cytotoxic CD8⁺ cells expressing activation antigens in these patients; one study also described daily fluctuations of the pro-inflammatory adipokine leptin, and another study linked a distinct cytokine inflammatory profile with early disease.

The researchers therefore aimed to investigate whether patients with ME/CFS have an abnormal profile of circulating cytokines, and whether this profile correlates with disease severity and duration.

They analyzed blood samples from 192 ME/CFS patients and from 392 healthy individuals and performed immunological analyses of the samples, measuring the concentrations of 51 cytokines in each participant’s blood.

When comparing patients with ME/CFS with healthy individuals, the investigators found differences in the circulating levels of only two of the 51 cytokines: TGF-β was increased (P = .0052) in patients with ME/CFS, and resistin was decreased (P = .0052). In addition, levels of resistin were significantly lower in patients with mild (P = .0370) and severe (P = .0208) ME/CFS.

Pro-inflammatory Cytokines Elevated

Concentrations of 17 cytokines correlated with disease severity, showing a statistically significant upward linear trend across the sequence of mild, moderate, and severe manifestations of ME/CFS: CCL11 (P = .0069), CXCL1 (P = .0266), CXCL10 (P = .0100), G-CSF (P = .0110), GM-CSF (P = .0063), interferon γ (P = .0101), interleukin 4 (IL-4; P = .0103), IL-5 (P = .0073), IL-7 (P = .0063), IL-12p70 (P = .0069), IL-13 (P = .0069), IL-17F (P = .0103), leptin (P = .0100), leukemia inhibitory factor (P = .0100), nerve growth factor (P = .0069), stem cell factor (P = .0145), and TGF-α (P = .0367).

Thirteen of these were pro-inflammatory. Elevations in these pro-inflammatory cytokines not only highlight the strong immune component of the disease but also likely contribute to many of the symptoms experienced by patients with ME/CFS, the authors write.

Although the researchers also examined the relationship between cytokine concentration and fatigue duration, they found that only the level of CXCL9 (monokine induced by interferon γ) inversely correlated with fatigue duration (P = .0123).

As TGF-β is predominantly considered to be an anti-inflammatory cytokine, the researchers explain that the elevated levels of TGF-β elevation in patients with ME/CFS may reflect down-regulatory activity by these patients’ immune systems against continued inflammation. However, if this were true, TGF-β levels would be expected to correlate with ME/CFS severity, which was not the case in this study.

Thus, TGF-β may not always function to counteract inflammation. Instead, “its net effect may depend on the local immunological milieu at target tissues and the overall levels of TGF-β,” they say.

Resistin has significant pro-inflammatory activity and is reportedly a marker of inflammation in patients with systemic lupus erythematosus and Crohn’s disease. However, the authors are unclear why resistin levels showed an unusual trend, increasing in patients with mild to moderate ME/CFS, but decreasing in those with moderate to severe disease.

Acknowledging the cross-sectional design as one limitation of their study, the authors emphasize longitudinal studies are needed to determine whether patients with ME/CFS remain within their cytokine signature and disease severity category over time, or fluctuate among them.

“Future cytokine research in the peripheral blood of ME/CFS patients should embrace longitudinal designs and seek correlations with neuroradiology, neuroinflammation, and [cerebrospinal fluid]studies,” the authors add.

One of the authors reported being a member of the Scientific Advisory Board of the Open Medicine Foundation. Another author reported having previously published with one of the manuscript reviewers. The other authors have disclosed no relevant financial relationships.

Proc Natl Acad Sci U S A. Published online July 31, 2017. Article

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