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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
April 7, 2018

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Association Between US State Medical Cannabis Laws and Opioid Prescribing
   in the Medicare Part D Population
Legal Marijuana States Have Lower Opioid Use, New Studies Show
Evening Light Exposure Suppresses Melatonin in Preschoolers
What Terms Should Clinicians Use to Discuss Weight Problems with Adolescents?
Weight Reduction in Childhood Associated with Reduced Risk for Type 2 Diabetes
Gliptins Might Be Associated with IBD
Use of Acid-Suppressive Drugs, Antibiotics in Infancy Linked to Increased Allergy Risk
Inducing Immune Tolerance in Multiple Sclerosis
Cortical Lesions in Multiple Sclerosis and Inflammatory Cytokines in CSF
Long-Term Risk for Secondary ADHD After Traumatic Brain Injury
Do Black Patients Need a Longer Course of Ledipasvir plus Sofosbuvir for HCV Infection?
Good News for Rheumatoid Arthritis Patients Who Like to Eat Fish2
Do Probiotics Prevent C. difficile-Associated Diarrhea in Patients Receiving Antibiotics?
Vaginal Estrogen: Revisiting Conventional Wisdom
How Prevalent Is Depression Among Reproductive-Aged U.S. Women?
The ACA, Prenatal Care, and Preterm Birth
Which Adverse Pregnancy Outcomes Increase with Maternal Age?

Association Between US State Medical Cannabis Laws and Opioid Prescribing in the Medicare Part D Population
Abstract: Opioid-related mortality increased by 15.6% from 2014 to 2015 and increased almost 320% between 2000 and 2015. Recent research finds that the use of all pain medications (opioid and nonopioid collectively) decreases in Medicare Part D and Medicaid populations when states approve medical cannabis laws (MCLs). The association between MCLs and opioid prescriptions is not well understood.
Conclusions: In this study, we investigated whether medical cannabis access was associated with prescription opioid prescribing in Medicare Part D. We found that overall opioid prescribing in Part D was lower when states permit access to medical cannabis. When examining data by individual drug classes, we found that prescriptions for hydrocodone and morphine had statistically significant negative associations with medical cannabis access via dispensaries; while not statistically significant, there were also negative associations between dispensary MCLs and fentanyl and “other opioid” use. Combined with previously published studies suggesting cannabis laws are associated with lower opioid mortality, these findings further strengthen arguments in favor of considering medical applications of cannabis as one tool in the policy arsenal that can be used to diminish the harm of prescription opioid.
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Legal Marijuana States Have Lower Opioid Use, New Studies Show
by Tom Angell Forbes April 2, 2018
Letting people legally access marijuana appears to reduce reliance on addictive opioids, two new studies published by the American Medical Association find.
"Medical cannabis laws are associated with significant reductions in opioid prescribing in the Medicare Part D population," concludes one paper from researchers at the University of Georgia, Athens. "This finding was particularly strong in states that permit dispensaries, and for reductions in hydrocodone and morphine prescriptions."
The second study, from scientists at the University of Kentucky and Emory University, noted that "marijuana is one of the potential nonopioid alternatives that can relieve pain at a relatively lower risk of addiction and virtually no risk of overdose." It found that laws allowing medical cannabis or recreational marijuana "have the potential to lower opioid prescribing for Medicaid enrollees, a high-risk population for chronic pain, opioid use disorder, and opioid overdose."
"Marijuana liberalization may serve as a component of a comprehensive package to tackle the opioid epidemic," the researchers conclude.
The two papers, released Monday by JAMA Internal Medicine, a publication of the AMA, looked at use of opioids such as fentanyl by people enrolled in Medicare and Medicaid, with both examinations finding that states with legal marijuana access saw lower reliance on the pharmaceutical drugs.
And the easier the access to legal marijuana, the lower the rate of opioid prescribing.
"States with active dispensaries saw 3.742 million fewer daily doses filled; states with home cultivation only [laws] saw 1.792 million fewer filled daily doses," one of the studies, which focused on medical cannabis laws, found.
The other new paper shows that while medical marijuana is associated with reduced opioid prescriptions, recreational laws have an even greater effect.
"State implementation of medical marijuana laws was associated with a 5.88% lower rate of opioid prescribing," the authors wrote. "Moreover, the implementation of adult-use marijuana laws, which all occurred in states with existing medical marijuana laws, was associated with a 6.38% lower rate of opioid prescribing."
U.S. Sen. Kirsten Gillibrand (D-NY) recently suggested that pharmaceutical companies oppose marijuana legalization for selfish reasons.
"To them it's competition for chronic pain, and that's outrageous because we don't have the crisis in people who take marijuana for chronic pain having overdose issues," she said. "It's not the same thing. It's not as highly addictive as opioids are."
The results of the new studies add to a growing body of research indicating that legal marijuana access is associated with reduced opioid issues.
In 2014, for example, a previous JAMA study showed that states with medical cannabis laws have roughly 25 percent lower opioid overdose rates.
A separate analysis published in February concluded that "legally protected and operating medical marijuana dispensaries reduce opioid-related harms," suggesting that "some individuals may be substituting towards marijuana, reducing the quantity of opioids they consume or forgoing initiation of opiates altogether."
And previous work by Ashley and David Bradford of the University of Georgia, who authored one of the new studies released on Monday, showed broad reductions in Medicare and Medicaid pain prescriptions when state medical cannabis laws went into effect. Their new paper builds on that by zeroing in on opioid painkillers and showing that the type of state marijuana law has an effect on the reduction in prescriptions.
"The type of [medical cannabis law] matters," David Bradford said in an email. "Dispensaries have the biggest effect."
The other paper, by the Kentucky and Emory researchers, tabulated reductions in opioid prescriptions associated with changes in laws, finding that medical cannabis policies lead to 39.41 fewer opioid prescriptions per 1,000 enrollees annually and that the effect for recreational legalization was even larger.
"Furthermore, the implementation of adult-use marijuana laws was associated with a 9.78% lower Medicaid spending on prescription opioids, equivalent to an annual saving of $1,815 Medicaid spending per 1,000 enrollees," the study found. "The implementation of medical and adult-use marijuana laws was also associated with a lower rate of Medicaid-covered prescriptions for nonopioid pain medications of 8.36% and 8.69%, respectively."
The research teams behind both new studies said that medical cannabis shows promise as a partial solution to opioid issues.
"Combined with previously published studies suggesting cannabis laws are associated with lower opioid mortality, these findings further strengthen arguments in favor of considering medical applications of cannabis as one tool in the policy arsenal that can be used to diminish the harm of prescription opioids," the Bradfords' Georgia team wrote. "Furthermore, a growing consensus suggests that cannabis can be used to effectively manage pain in some patients. If initial licit prescriptions for opioids can be reduced, then there is a plausible theoretical pathway to anticipate that opioid misuse and abuse could also fall."
When legal marijuana is available, some patients appear to be more likely to choose it instead of prescription pain pills that can lead to addiction or overdose.
"Most opioid use disorder and overdose cases occurred in patients with legitimate prescriptions from health care professionals for pain management. Marijuana liberalization, therefore, may have benefited these patients by providing them with legal protection and access to marijuana as an alternative relief from their pain conditions," the Kentucky and Emory team wrote. "The widespread public support will bring medical marijuana laws to more and more states for years to come, which may help decrease the use of prescription opioids in pain management and the adverse consequences, such as opioid use disorder and overdose."
Those researchers also noted that "marijuana may help ease opioid withdrawal symptoms."
"Thus, marijuana liberalization potentially reduced prescription opioid use on 2 fronts, serving as a substitute for opioid pain medications, and as a complement to opioid use disorder treatment," the wrote. "The potential of adult-use marijuana laws to reduce the use and consequences of addictive opioids deserves consideration, especially in states that have been hit hard by the opioid epidemic.
Tom Angell publishes Marijuana Moment news and founded the nonprofit Marijuana Majority. Follow Tom on Twitter for breaking news and subscribe to his daily newsletter.
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Physiol Rep 2018 Mar; 6:e13617
Evening Light Exposure Suppresses Melatonin in Preschoolers
Dim indoor light conditions might be helpful in getting young kids ready for bed.
Researchers postulate that young children's eyes might transmit more light to retinal photoreceptors compared with older children and adults, thereby making them more susceptible to light- and dark-induced effects on melatonin secretion.
To quantify the magnitude of evening light–induced melatonin suppression in young children, researchers conducted a highly controlled 7-day protocol in 10 preschoolers (aged 3–5 years). On days 1 through 5, children followed a strict sleep–wake schedule, which was verified through an actigraph and daily diary. On the afternoon of day 6, children were exposed to 3 hours of dim light conditions (~15 lux; windows were covered and low-wattage bulbs used), and saliva melatonin levels were collected. On day 7, dim light conditions continued, until 1 hour before bedtime when children were exposed to 1 hour of bright light (they played on a light table of ~1000 lux), when saliva melatonin levels were again collected.
Compared with melatonin levels during dim light on day 6, during bright light exposure, melatonin levels were suppressed by an average of 88%; these effects persisted at least 50 minutes following light exposure, and melatonin levels stayed suppressed to <50% of dim-light levels in 7 of the 10 children.
COMMENT: The melatonin suppression found in these preschoolers is much stronger than that in older children or adults, suggesting that dim indoor light exposure may be helpful in getting young children ready for bedtime. Although light from digital devices is only ~30 to 50 lux, these data support the American Academy of Pediatrics recommendation that children not use electronic devices in the hour before going to bed. These results may not be generalizable to children with behavioral problems, developmental delays, or chronic illnesses, who were excluded and often present with dysregulated sleep cycles.
CITATION(S): Akacem LD et al. Sensitivity of the circadian system to evening bright light in preschool-age children. Physiol Rep 2018 Mar; 6:e13617. (https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.13617)
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Pediatr Obes 2018 Mar 24
What Terms Should Clinicians Use to Discuss Weight Problems with Adolescents?
Adolescents enrolled in a national weight loss camp most disliked the terms extremely obese, obese, curvy, large, fat, and heavy.
The American Academy of Pediatrics recommends that clinicians use nonstigmatizing terms to discuss weight issues with adolescents. To determine what terms adolescents prefer to hear from their providers, investigators conducted an online survey among approximately 150 adolescents aged 13 to 18 attending a national weight loss camp. Response rates were 74% of boys and 36% of girls. Respondents rated the acceptability of 16 words providers might use to describe excess weight using a 5-point scale (1=never use this word; 3=not sure; 5=prefer this word).
At least 40% of adolescents disliked the terms extremely obese, obese, curvy, large, fat and heavy (all scale values < 3). At least 44% preferred the terms weight problem, plus size, chubby, BMI (body-mass index), weight, high BMI, and unhealthy weight (mean scale values, 3.2–3.6). Adolescents with BMI between the 85th and 95th percentiles most preferred overweight, higher body weight, weight, and high BMI (mean scale values, 3.5–3.6), and those with BMI >95th percentile most preferred weight problem, unhealthy weight, chubby, and plus size (3.8–4.5). Adolescents with the highest level of weight bias internalization gave highest ratings to weight problem, chubby, plus size, BMI, and high BMI (mean scale values >3.5).
COMMENT: Despite the methodological limitations of this study, these are the only data currently available and are consistent with findings in adults. I was surprised that “chubby” and “plus size” were acceptable to some teens, but this was mostly among the most obese teens and those with a greater degrees of weight bias internalization; the authors speculate that for these teens, these terms seemed less threatening than obese and extremely obese. Even so, I would recommend avoiding them and use the highly rated terms that are most neutral and can be tied to the concept of health (e.g., BMI, high BMI, weight problem, unhealthy weight).
CITATION(S):Puhl RM and Himmelstein MS. Adolescent preferences for weight terminology used by health care providers. Pediatr Obes 2018 Mar 24; [e-pub].
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N Engl J Med 2018 Apr 5; 378:1302
Weight Reduction in Childhood Associated with Reduced Risk for Type 2 Diabetes
A heightened risk for type 2 diabetes in adulthood was eliminated in overweight boys who achieved a normal weight by puberty and sustained it into early adulthood.
To determine whether the risk for type 2 diabetes mellitus (DM) in adulthood can be mitigated by weight reduction in overweight and obese children, researchers examined type 2 DM incidence at ages 30 to 60 years in a longitudinal study of 62,000 Danish men from boyhood. Evaluations occurred at age 7 years, at 13 years, and as young adults (ages 17–26). Results were as follows:

COMMENT: These data provide a glimmer of hope. Boys who are overweight and obese can reduce their risk for type 2 DM with sustained weight reduction. Now we need to find effective ways to help overweight and obese children and adolescents accomplish weight reduction.
CITATION(S): Bjerregaard LG et al. Change in overweight from childhood to early adulthood and risk of type 2 diabetes. N Engl J Med 2018 Apr 5; 378:1302.
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BMJ 2018 Mar 21; 360:k872
Gliptins Might Be Associated with IBD
An observational study showed that gliptin use is associated with excess risk for inflammatory bowel disease in patients with type 2 diabetes.
Patients with inflammatory bowel disease (IBD) have low serum concentrations of dipeptidyl peptidase-4 (DPP-4) enzyme, which is associated inversely with disease activity. Researchers conducted a population-based cohort study of >140,000 U.K. adults with type 2 diabetes to investigate whether DPP-4 inhibitors (gliptins) are associated with excess risk for IBD (eg. Januvia, Onglyza, Galvus).
Among patients who initiated noninsulin antidiabetes drugs, 208 new IBD events occurred during average follow-up of 3.6 years. In an analysis adjusted for multiple potential confounders, gliptins were associated with significant excess risk for IBD compared with other antidiabetes drugs (53 vs. 34 events per 100,000 person-years; hazard ratio, 1.8). Relative risk peaked at 3 to 4 years (HR, 2.5) and dropped thereafter. Numbers needed to harm were about 2300 and 1200 during 2 and 4 years, respectively. Gliptin use compared with insulin was associated with excess risk for IBD (HR, 2.3), whereas use of other noninsulin antidiabetes drugs was not (insulin use is not associated with excess risk for IBD).
COMMENT: In this observational study, which might be subject to residual confounding, gliptins were associated with excess risk for IBD in patients with type 2 diabetes. However, absolute risk was small, and the number needed to harm was large. The authors advise that clinicians be aware of this association, avoid using gliptins in patients with elevated risk for IBD (e.g., family history), and carefully assess patients who take gliptins and who develop symptoms associated with IBD (e.g., abdominal pain, diarrhea).
CITATION(S): Abrahami D et al. Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: Population based cohort study. BMJ 2018 Mar 21; 360:k872.
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Use of Acid-Suppressive Drugs, Antibiotics in Infancy Linked to
Increased Allergy Risk

By Kelly Young, Edited by David G. Fairchild, MD, MPH, and Jaye Elizabeth Hefner, MD
Use of acid-suppressive medications and antibiotics early in infancy is associated with elevated risk for developing allergic diseases in childhood, an observational study in JAMA Pediatrics finds.
Using a military healthcare database, researchers identified 790,000 children free of allergic conditions at age 6 months. Children who received prescriptions for histamine-2 receptor antagonists (H2RAs) or proton pump inhibitors (PPIs) in the first 6 months of life were at greater risk for all allergic diseases studied except seafood allergy during a median 4.6 years' follow-up. The increased risk was highest for food allergies (adjusted hazard ratios, 2.18 for H2RAs and 2.59 for PPIs), and the relationship was dose-dependent.
Antibiotics were also tied to increased risk for most allergies, with asthma risk being most elevated (adjusted HR, 2.09).
The authors write: "This study provides further impetus that antibiotics and acid-suppressive medications should be used during infancy only in situations of clear clinical benefit."
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Neurology 2018 Feb 21
Inducing Immune Tolerance in Multiple Sclerosis
The number of MRI lesions was reduced in an open-label pilot study of peptide therapy for relapsing multiple sclerosis.
Peptide therapy to reduce multiple sclerosis (MS) severity through antigen tolerization is an interesting approach to the disease, as it proposes to target the root of MS without suppressing the immune system. Although the target antigen is presumed to be a myelin component, the exact component is not known. Researchers conducted two open-label, manufacturer-funded studies using an investigational peptide, ATX-MS-1467, in patients with relapsing MS. ATX-MS-1467 consists of four epitopes of myelin basic protein that reduced disease severity in animal models. Participants were aged 18 to 65, had HLA-DRB1*15 positivity, and had recent history of relapses. In the first study, 43 participants received the full dose (intradermally or subcutaneously) every other week for 8 weeks. In the second study, 37 patients received intradermal injections every other week for 16 weeks.
Gadolinium-enhancing lesions were reduced by 73% from baseline to week 16 in the first study and by about one third from baseline to the end of treatment in the second study. Adverse effects were common but mild to moderate.
COMMENT: These two studies demonstrate early tolerability and safety for this novel treatment. The effect on MRI lesions is interesting, but the lack of a placebo group does not permit interpretation of whether it represents the natural decrease in enhancing lesions over time. Additional studies are required to demonstrate efficacy according to disability endpoints.
CITATION(S): Chataway J et al. Effects of ATX-MS-1467 immunotherapy over 16 weeks in relapsing multiple sclerosis. Neurology 2018 Feb 21; [e-pub].
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Ann Neurol 2018 Mar 8
Cortical Lesions in Multiple Sclerosis and Inflammatory Cytokines in CSF
Meningeal demyelination is associated with TNF, IFNγ, and CXCL13 in cerebrospinal fluid.
Patients with multiple sclerosis (MS) are more likely to have early onset aggressive disease if they have grey matter damage and meningeal demyelination. Whether these changes can be identified by markers in cerebrospinal fluid (CSF), especially early in the disease course, is unknown.
To find out, investigators tested postmortem samples from 27 patients with progressive MS and identified patients with either low or high densities of meningeal inflammation. Those with high meningeal inflammation had frequent aggregates of CD20+ B cells and CD3+ T cells in the subarachnoid space. Patients with high meningeal inflammation had worse disability (earlier age of wheelchair use and death) than the low-inflammation group. Gene expression for several inflammatory cytokines was present in the meninges of the high meningeal inflammation group (TNF, IFNγ, IL2, IL22, CXCL9, CXCL10, CXCL13, CXCL20, CCL22). Those with low meningeal inflammation had a different cytokine gene profile (IL9, IL17, IL22). CSF also contained elevated levels of protein for most of the cytokines between the high and low groups.
The investigators also conducted CSF profiling on 35 recently diagnosed MS patients, divided into high and low MRI cortical lesion burden (≥10 or <2 lesions). Higher cortical lesion load was associated with increased CSF neurofilament light chain protein levels and inflammatory CSF cytokine protein levels. A separate set of 38 untreated MS patients had a similar pattern of neurofilament and cytokine levels according to cortical lesion burden. Three cytokines in the postmortem and recently diagnosed patient groups were predictive of cortical lesion number (TNF, IFNγ, CXCL13).
COMMENT: These investigators demonstrated that CSF could accurately reflect inflammatory and demyelinating changes within the cortex in both end-stage MS patients (at autopsy) and recently diagnosed MS patients (on MRI). The CSF findings suggest a process that is more inflammatory and destructive in those with than in those without cortical lesions. These inflammatory CSF markers may someday be important for determining early disease prognosis and selecting an optimal MS therapy.
Note to readers: At the time we reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.
CITATION(S): Magliozzi R et al. Inflammatory intrathecal profiles and cortical damage in multiple sclerosis. Ann Neurol 2018 Mar 8; [e-pub].
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JAMA Pediatr 2018 Mar 19
Long-Term Risk for Secondary ADHD After Traumatic Brain Injury
Secondary attention-deficit/hyperactivity disorder in children was more common after TBI than after orthopedic injury, with new onset occurring up to 7 years later.
Traumatic brain injury (TBI) has been associated with risk for developing secondary attention-deficit/hyperactivity disorder (SADHD) in the short-term, but studies with longer follow-up are lacking. In addition, risk factors for developing SADHD are incompletely understood.
Researchers followed 187 children aged 3 to 7 years without prior ADHD who were admitted to one of four hospitals for either TBI (81 patients) or orthopedic injury (OI; control group; 106 patients). Incidence of SADHD and multiple possible risk factors were assessed by parental report at five follow-up visits (at 6 months, 12 months, 18 months, and approximately 3 years and 7 years after injury).
At final follow-up, SADHD was significantly more common in children with severe TBI than in those with OI (62% vs. 15%; hazard ratio 3.6). Incidence rates of SADHD rose with increasing severity of TBI (OI, 0.03 events per person-year; complicated mild TBI, 0.06; moderate TBI. 0.06; severe TBI, 0.19). Most children experiencing TBI developed SADHD within the first 18 months postinjury, but a few children in each severity group had new-onset SADHD identified at the last two follow-up visits. Lower maternal education and higher family dysfunction were associated with SADHD, while age at injury and child sex were not.
COMMENT: This study supports previous findings, reinforcing that clinicians should monitor for signs of ADHD onset in the years after TBI severe enough to require hospitalization. The link between SADHD and low maternal education, as well as family dysfunction, suggests that the family environment should be considered and addressed (as possible) by clinicians following children with TBI and their families, even several years after injury.
CITATION(S): Narad ME et al. Secondary attention-deficit/hyperactivity disorder in children and adolescents 5 to 10 years after traumatic brain injury. JAMA Pediatr 2018 Mar 19; [e-pub].
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Clin Gastroenterol Hepatol 2018 Mar 10
Do Black Patients Need a Longer Course of Ledipasvir plus Sofosbuvir
for HCV Infection?

Observational data do not support the current recommendation for a 12-week regimen in black patients who meet criteria for an 8-week regimen.
An 8-week regimen of ledipasvir plus sofosbuvir (LDV/SOF) is approved for treatment of genotype 1 hepatitis C virus (HCV) infection in certain patients (treatment-naive, no cirrhosis, no human immunodeficiency virus infection, HCV RNA <6 million IU/mL). However, based on concern over lower treatment response among black patients and despite limited evidence, a guideline from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America recommends a 12-week regimen in black patients who are eligible for the 8-week regimen.
To investigate this issue further, in an observational study, researchers assessed sustained virologic response at 12 weeks after treatment ended (SVR12) in over 2600 HCV-infected patients (including approximately 450 black patients) who were eligible for an 8-week LDV/SOF regimen. Seventy-six percent received treatment for 8 weeks and 24% for 12 weeks. The researchers also evaluated factors that could potentially affect SVR rates.
The SVR12 rate was 96% with either 8 or 12 weeks of therapy, both overall and in black patients. Potential predictors of nonresponse, such as diabetes, obesity, and male gender, did not affect SVR12 rates.
COMMENT: This observational study suggests that potent direct-acting anti-HCV regimens seem to overcome traditional predictors of nonresponse, even when taken for only 8 weeks. These findings also demonstrate that 8 weeks of LDV/SOF is highly effective in black patients, for whom clinicians should consider prescribing this shorter course.
Note to readers: At the time we reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.
CITATION(S): Marcus JL et al. No difference in effectiveness of 8 vs 12 weeks of ledipasvir and sofosbuvir for treatment of hepatitis C in black patients. Clin Gastroenterol Hepatol 2018 Mar 10; [e-pub].
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Arthritis Care Res (Hoboken) 2018 Mar; 70:327
Good News for Rheumatoid Arthritis Patients Who Like to Eat Fish
A small study shows fish consumption might help alleviate RA symptoms.
Many ω-3 fatty acids downregulate proinflammatory cytokines; therefore, researchers have evaluated their effect in patients with rheumatoid arthritis (RA). Fish oil supplements, when added to traditional nonbiologic triple therapy, can produce higher rates of remission and lower counts of tender joints. To examine whether dietary fish intake also attenuates RA disease activity, investigators studied a subset of 176 RA patients from a larger cohort study. Participants were categorized by frequency of fish consumption (ranging from less than once monthly to twice weekly or more often and excluding fried fish, nonfried shellfish, and fish in mixed dishes). A single trained, blinded assessor evaluated disease activity scores (DAS) in 28 joints using DAS28-CRP scores (which reflect both clinical findings and C-reactive protein [CRP] levels).
Participants who ate fish more than twice weekly had significantly lower DAS28-CRP scores than those who ate fish less than once monthly. For each additional serving of fish weekly, DAS28-CRP was reduced significantly. Results were similar after adjusting for several demographic and clinical variables.
COMMENT: Rheumatologists often recommend fish oil supplementation for their RA patients, a practice that is supported by at least one randomized trial (NEJM JW Gen Med Feb 1 2015 and Ann Rheum Dis 2015; 74:89). This new study — although small, observational, and subject to potential confounding — suggests that eating fish also can help alleviate RA symptoms. Some clinicians also recommend fish oil supplements for patients with osteoarthritis (especially knee osteoarthritis), but strong evidence to support that practice is lacking.
CITATION(S): Tedeschi SK et al. Relationship between fish consumption and disease activity in rheumatoid arthritis. Arthritis Care Res (Hoboken) 2018 Mar; 70:327. (http://dx.doi.org/10.1002/acr.23295)
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Cochrane Database Syst Rev 2017 Dec 19; 12:CD006095.
Do Probiotics Prevent C. difficile-Associated Diarrhea in Patients
Receiving Antibiotics?

A meta-analysis suggests that most inpatients — with specific exclusions — benefit from probiotic prophylaxis.
Hospitalization and antibiotic use are major independent risk factors for Clostridium difficile-associated diarrhea (CDAD), and probiotic prophylaxis can lessen CDAD's occurrence (NEJM JW Gastroenterol May 2017 and Gastroenterology 2017; 152:1889), but guidelines have not yet endorsed broad use of this preventive intervention.
In this meta-analysis of 31 randomized trials that involved >8500 patients (7000 were inpatients, 7800 were adults, 1100 were children, and 2500 had baseline CDAD risk >5%), significant effects on CDAD incidence for probiotics compared with control (placebo or no probiotic) were:

Adverse events (e.g., abdominal cramping, nausea, fever, flatulence, taste disturbance) were less likely with probiotics (14.3% vs. 17.0%; NNT, 37), and no episodes of severe probiotic-associated adverse effects (e.g., bacteremia, fungemia) were identified.
COMMENT; Moderate-quality evidence supports a significant protective effect of probiotics against CDAD. Probiotics should not be given to patients who are immunocompromised, are pregnant, are in intensive care, or have prosthetic heart valves or certain preexisting gastrointestinal disorders (e.g., inflammatory bowel disease, ostomy). For most other hospitalized patients who receive antibiotics during hospitalization, prescribing 20 to 50 billion colony forming units of probiotics daily (starting within 24–48 hours of antibiotic initiation) can prevent CDAD.
CITATION(S): Goldenberg JZ et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev 2017 Dec 19; 12:CD006095.
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JAMA Intern Med 2018 Mar 19
Vaginal Estrogen: Revisiting Conventional Wisdom
New trial questions our assumptions about managing genitourinary syndrome of menopause.
Declining estrogen levels underlie genitourinary syndrome of menopause (GSM, previously termed vulvovaginal atrophy), a common progressive condition that, if untreated, can impair sexual function and quality of life. Based on randomized placebo-controlled trials and clinical experience, current guidelines (NEJM JW Womens Health Feb 2014 and Obstet Gynecol 2014; 123:202) recommend low-dose vaginal estrogen for women with symptomatic GSM that has not responded to over-the-counter vaginal lubricants (used with sexual activity) and moisturizers (used regularly). To reevaluate this approach, NIH-funded investigators randomized 302 women (mean age, 61; 88% white; 85% partnered) with moderate-to-severe symptoms suggestive of GSM to 10-µg estradiol tablets (Vagifem) plus placebo vaginal gel (hydroxyethylcellulose), placebo vaginal tablets plus vaginal moisturizer gel (Replens), or placebo tablets plus placebo gel. Tablets were used daily for 2 weeks, then twice weekly. Gels were used every 3 days for the duration of the 12-week trial. Participants reported the severity of their most bothersome symptom (MBS).
The most common MBS was pain with vaginal penetration (60%), followed by vaginal dryness (21%). All treatments were associated with modest and similar reductions in MBS. Likewise, improvement in sexual function was similar between estradiol and placebo and between moisturizer and placebo.
COMMENT: As the authors and editorialists note, the robust response to placebo gel distinguishes this short-term trial from others (which used placebo creams and tablets, but not gels). Based on these findings, I plan to be more proactive in recommending lubricants and moisturizers. Long-term clinical trials assessing treatment of women with GSM have not been performed. Nonetheless, given our understanding of this common condition's pathophysiology (combined with clinical experience), my sense is that, over time, women with symptomatic GSM will be best served if treatment options include vaginal estrogen.
CITATION(S): Mitchell CM et al. Efficacy of vaginal estradiol or vaginal moisturizer vs placebo for treating postmenopausal vulvovaginal symptoms: A randomized clinical trial. JAMA Intern Med 2018 Mar 19; [e-pub]. (https://doi.org/10.1001/jamainternmed.2018.0116)
Huang AJ and Grady D. Rethinking the approach to managing postmenopausal vulvovaginal symptoms. JAMA Intern Med 2018 Mar 19; [e-pub].
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Obstet Gynecol 2018 Apr; 131:671
How Prevalent Is Depression Among Reproductive-Aged U.S. Women?
Cross-sectional national survey suggests major and minor depression afflict some 9% of nonpregnant women of childbearing age.
Studies of depression's prevalence have often lumped together postpartum and otherwise nonpregnant women. To get a better sense of the likelihood of depression among nonpregnant women of reproductive age, investigators analyzed National Health and Nutrition Examination Survey data from 2007–2014 in women aged 20–44 who had not been pregnant during the prior year. Participants were classified by depression status (none, major, and minor). Use of antidepressant medications was also assessed.
Among 3705 participants, major and minor depression were reported by 5% and 4%, respectively, and prevalence of any antidepressant use was 32% (major depression) and 20% (minor depression). In multivariable analysis, current smoking, hypertension, and government insurance were independently associated with major depression. Being black, having education below college level, currently smoking, and having asthma were independently associated with minor depression.
COMMENT: This report does not include data from adolescents. Furthermore, a substantial proportion of respondents did not provide data on depression status — and these respondents were more likely to be black, less educated, and low income (all determinants of depression risk). Finally, because the investigators specifically excluded pregnant and recently pregnant women, the prevalence of depression was lower than in other surveys. Nonetheless, these data should remind women's health clinicians to remain alert to the possibility of mood disorders among their patients, perform annual depression screening with the PHQ-2, and be proactive in providing or facilitating treatment of recognized depression.
CITATION(S): Guo N et al. Prevalence of depression among women of reproductive age in the United States. Obstet Gynecol 2018 Apr; 131:671.
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JAMA 2018 Feb 13; 319:579
The ACA, Prenatal Care, and Preterm Birth
Use of prenatal care rose and incidence of preterm birth fell with Affordable Care Act implementation.
The Affordable Care Act (ACA) allowed individuals to stay on their parents' insurance plans until age 26. To evaluate the effects of this policy on young women's receipt of prenatal care and birth outcomes, researchers conducted a retrospective cohort study using U.S. birth certificate data. They assessed birth outcomes before (i.e., 2009) and after (2011–2013) enactment of the ACA's dependent coverage provision among 1.4 million U.S. women aged 24 to 25 (who were potentially affected by this policy change) compared with women aged 27 to 28 (who were not affected by this policy change).
The ACA appears to have increased the proportion of privately insured births among unmarried women younger than 26, increased receipt of adequate prenatal care, and decreased rates of preterm birth. Incidence of low birth weight, neonatal intensive care unit admission, and cesarean delivery remained unchanged.
COMMENT: This study adds important evidence that the ACA has improved the health of our nation. Now just imagine if all Americans had timely, equitable, affordable access to healthcare whenever they needed it!
CITATION(S): Daw JR and Sommers BD. Association of the Affordable Care Act dependent coverage provision with prenatal care use and birth outcomes. JAMA 2018 Feb 13; 319:579.
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Obstet Gynecol 2018 Mar; 131:457
Which Adverse Pregnancy Outcomes Increase with Maternal Age?
In a Danish national study, excess risk in women 40 or older was driven mainly by fetal chromosomal abnormalities, miscarriage, and preterm birth.
Excess risk for fetal chromosomal abnormalities is well established in older mothers, but risks for other adverse pregnancy outcomes are less clearly defined. To determine risk estimates for such outcomes, investigators examined prospectively collected data on >350,000 pregnant women in Denmark from 2008 through 2014.
Overall risk for adverse outcomes (collectively defined as chromosomal abnormalities, congenital malformations, miscarriage, stillbirth, or preterm birth) was 5% (maternal age range, 20–34), 7% (age range, 35–39), and 11% (aged ≥40). The excess risk among women aged ≥40 was driven predominantly by increased probability of chromosomal abnormalities (odds ratio, 7), miscarriage (OR, 4), and preterm birth (OR, 2) compared with those aged 20–34. These risks were not substantially changed in analyses adjusted for body-mass index, smoking, parity, and assisted reproduction.
COMMENT: These findings — derived from a large sample of women with equitable and universal access to healthcare beginning in the first trimester — show that, aside from chromosomal abnormalities, risk for adverse pregnancy outcomes is relatively low even at advanced maternal ages. Although this is good news for women who are postponing pregnancy, extrapolating these findings to the U.S. is difficult: Baseline risk for adverse outcomes is higher, access to healthcare is not universal, and women's ability to decide whether to continue a pregnancy is significantly compromised in several states.
CITATION(S): Frederiksen LE et al. Risk of adverse pregnancy outcomes at advanced maternal age. Obstet Gynecol 2018 Mar; 131:457.

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