• Cannabis Use Increasing in Parents with Children at Home
• Is Sleep Deprivation Related to Alzheimer Disease?
• AAN Guidelines for Multiple Sclerosis: Starting, Switching, Stopping Disease
Modifying Therapies
• How Does Hormone Therapy Affect Breast Cancer Risk After Oophorectomy in
BRCA1 Mutation Carriers?
• Does What You Eat Affect When You Reach Menopause?
• Consequences of the FDA Warnings About Power Morcellation
• How Effective Is Oseltamivir for Treatment of Influenza in Children?
• Nitrofurantoin vs. Fosfomycin for Uncomplicated UTIs
• Cost Benefit of Removing the Penicillin Allergy Label from Nonallergic Patients
• DMPA: The Advantages of Self-Administration
Cannabis Use Increasing in Parents with Children at Home
By Amy Orciari Herman, Edited by Susan Sadoughi, MD, and André Sofair, MD, MPH
Cannabis use is on the rise among adults with children in the home, placing those children at risk for the detrimental health effects of secondhand cannabis smoke exposure, according to a Pediatrics study.
Using data from the National Survey on Drug Use and Health, researchers examined trends in cigarette smoking and cannabis use from 2002 through 2015. The analysis included roughly 170,000 adults with children under age 18 years living at home.
Current cigarette smoking decreased over the study period (from 28% to 20% of respondents), while current cannabis use increased (5% to 7%). Cannabis use was more common among cigarette smokers. For example, in 2015, 17% of cigarette smokers reported current cannabis use, while 4% of nonsmokers did so.
The researchers cite data suggesting that secondhand cannabis smoke "carries health risks similar to, or worse than" secondhand tobacco smoke. They conclude: "Parents may benefit from education about protecting children from marijuana products, paraphernalia, waste, and smoke."
LINK(S): Pediatrics article (Free), Pediatrics online-first page (if above link doesn't work yet)
(Free)
Top of Page
Proc Natl Acad Sci U S A 2018 Apr 24; 115:4483
Is Sleep Deprivation Related to Alzheimer Disease?
Acute sleep deprivation is shown to increase β-amyloid burden in the hippocampus and thalamus, but causality has not been definitively established.
β-amyloid is considered a brain metabolic “waste product.” High levels are associated with cognitive impairment, and it is a primary constituent of Alzheimer plaque. Impaired sleep is also a risk factor for Alzheimer disease (AD). Although studies in animals indicate that β-amyloid clearance occurs during sleep and that deprivation may lead to higher brain levels, whether sleep deprivation causes a higher β-amyloid burden, thereby leading to AD in humans, is not known.
In this study, researchers performed 18F-florbetaben positron emission tomography (PET) in 20 healthy controls and compared β-amyloid levels after a night of total sleep deprivation and a full night's sleep. β-amyloid levels were higher in the hippocampus, a region showing early changes in AD, with a moderate effect size; higher levels were also observed in the parahippocampus and thalamus. Increases in β-amyloid levels were associated with increases in negative mood according to Likert scales obtained during the PET scans. Higher-risk genotype was associated with higher subcortical β-amyloid burden, but not with increases in β-amyloid following deprivation.
COMMENT: This is the first study to demonstrate that sleep deprivation increases β-amyloid in the human brain, a risk factor for Alzheimer disease. The causal link between β-amyloid deposition and development of AD is not definitively established (Brain 2016; 139:23), and therapies that reduce β-amyloid levels do not reverse the disease in its late stages. However, AD has a long incubation period, and definitive clinical trials of compounds that reduce β-amyloid have yet to be done in early stages of the disease and in asymptomatic individuals; experts still hypothesize that β-amyloid may be an important causal agent. Although these findings do not prove that sleep deprivation causes AD, they highlight the importance of sleep to optimal brain health.
CITATION(S): Shokri-Kojori E et al. β-amyloid accumulation in the human brain after one night of sleep deprivation. Proc Natl Acad Sci U S A 2018 Apr 24; 115:4483.
(https://doi.org/10.1073/pnas.1721694115)
Top of Page
Neurology Neurology 2018 Apr 24; 90:777
AAN Guidelines for Multiple Sclerosis: Starting, Switching, Stopping Disease Modifying Therapies
These guidelines update the goals of multiple sclerosis treatment and thresholds to switch or stop therapy.
Sponsoring Organization: The Guideline Development, Dissemination, and Implementation Subcommittee of the AAN convened a panel of multiple sclerosis (MS) experts. They developed 30 recommendations on the use of disease modifying therapies (DMTs).
Target Population: People with relapsing or progressive forms of MS or clinically isolated syndromes
Background and Objective: Numerous new disease modifying therapies have high efficacy but potentially serious adverse effects. Deciding when to start, switch, or stop these drugs can be challenging.
Key Points:
Starting
- An office visit is recommended to counsel and discuss the benefits and risks of the medications to prevent relapses and new MRI lesions, considering adherence, comorbidities, and family planning.
- Treatment should be considered for those with clinically isolated syndrome, relapsing MS, and primary progressive MS (PPMS). Annual MRIs for 5 years are recommended for those not initiating a DMT.
- Clinicians should monitor for side effects, adverse events, adherence, and disease activity with a follow-up visit at least annually. Treatment expectations and a monitoring plan should be established.
- The panel defines natalizumab, fingolimod, ocrelizumab, and alemtuzumab as higher-efficacy therapies, which should be prescribed for people with highly active MS. Mitoxantrone is not recommended due to safety concerns. Azathioprine or cladribine may be considered for those without access to other therapies.
- Natalizumab should not be routinely considered when John Cunningham virus (JCV) antibody index is above 0.9. Natalizumab discontinuation strategy and risks should be considered. Washout should be no longer than 8 to 12 weeks with natalizumab or fingolimod.
- Ocrelizumab should be offered to PPMS patients unless risks outweigh benefits.
Switching
- Breakthrough disease activity should be assessed routinely. A medication switch should be considered for adherent patients who have taken the medication for sufficient time to allow biological and clinical efficacy.
- A switch should be considered for ≥1 relapse, ≥2 new MRI lesions, or 1 year of worsening disability, and should be done for intolerable side effects.
Stopping
- Women should discontinue DMT before conception unless benefits outweigh risks.
- In patients with secondary progressive MS (SPMS), treatment discontinuation should be done under supervision and may be advised for SPMS patients who have 2 years of no relapses or MRI activity and are wheelchair bound (<5 meters ambulation with assistance).
COMMENT: These guidelines reflect the general practice and standards of care for the past 5+ years. While these guidelines do not provide an algorithm or recommendations on specific therapies, they do define high-efficacy therapies and highly active disease (including disease for which high-efficacy therapies should be first line treatments or as part of an escalation approach), recommend switching for subclinical disease activity, and emphasize the therapeutic relationship between doctor and patient, ongoing discussion about balancing risks of MS and risks of therapies, and the number of available treatment choices. The recommendations on JCV index with natalizumab, high-efficacy therapy wash out and disease reactivation concerns, family planning, and stopping therapy in SPMS are all important concepts for clinicians to consider.
CITATION(S): Rae-Grant A et al. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis. Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 2018 Apr 24; 90:777.
(https://doi.org/10.1212/WNL.0000000000005347)
Top of Page
JAMA Oncol 2018 Apr 19
How Does Hormone Therapy Affect Breast Cancer Risk After Oophorectomy in BRCA1 Mutation Carriers?
In a prospective study, estrogen-alone therapy — but not combination therapy — appeared to protect against breast cancer.
Prophylactic bilateral oophorectomy lowers risk for ovarian cancer in women with BRCA1 mutations; however, carriers may be reluctant to use menopausal hormone therapy (HT) after oophorectomy out of concern that HT might elevate their risk for breast cancer. In a multicenter international cohort study, 872 women with BRCA1mutations and no history of breast cancer were followed prospectively for a mean of 7.6 years following oophorectomy.
Among participants, 43% used HT after oophorectomy (mean duration of use, 3.9 years); of these, 69% used estrogen-alone therapy (ET) and 19% used estrogen plus progestogen (EPT). Overall, HT users were younger at oophorectomy than nonusers (mean age, 43 vs. 48; P<0.001). During follow-up, rates of invasive breast cancer were similar in users and nonusers (10.3% and 10.7%, respectively; P=0.86). In analysis by HT type, 10-year actuarial risk for breast cancer was lower with ET than with EPT (12% vs. 22%, respectively; P=0.04), and this difference was more marked among women who underwent oophorectomy before age 45 (9% vs. 24%; P=0.009).
COMMENT: In premenopausal women, bilateral oophorectomy without HT is associated with severe vasomotor symptoms, osteoporosis, cardiovascular disease, and cognitive decline. In this study, the clear reduction in breast cancer risk associated with ET (compared with EPT) after oophorectomy suggests that hysterectomy — which precludes the need for progestogen therapy — should be considered as part of risk-reducing gynecologic surgery for BRCA1 carriers who have completed childbearing. Lastly, these findings in high-risk women parallel those of the Women's Health Initiative trial (performed in the general population of menopausal women), which showed that, while EPT modestly raises risk for breast cancer, ET reduces such risk (NEJM JW Womens Health Nov 2013 and JAMA 2013; 310:1353).
CITATION(S): Kotsopoulos J et al. Hormone replacement therapy after oophorectomy and breast cancer risk among BRCA1mutation carriers. JAMA Oncol 2018 Apr 19; [e-pub].
(https://doi.org/10.1001/jamaoncol.2018.0211)
Top of Page
J Epidemiol Community Health 2018 Apr 30
Does What You Eat Affect When You Reach Menopause?
According to a large U.K. study, some dietary components may be associated with earlier or later natural menopause.
To find out if dietary intake influences the timing of natural menopause, investigators analyzed data from the U.K. Women's Cohort Study, a large, long-term study of diet's health effects. Among some 14,000 participants, 914 (age range, 40–64) reported still menstruating at baseline and having ceased (without surgery or pregnancy) 4 years later. Mean age at menopause was 50.5 and mean body-mass index was 23.9 kg/m2(9.6% were obese). Most women were married, parous, and working at professional or managerial jobs. Only 8% smoked, and mean alcohol consumption was low. A validated food frequency questionnaire was used to assess daily intake of 217 foods. About 38% of participants reported following vegetarian diets.
In a model adjusted for baseline age, alcohol consumption, physical activity, smoking, and social class, higher intake of refined pasta and rice was associated with earlier age at menopause (−1.5 years per daily portion) and consumption of oily fish and fresh legumes was associated with later menopausal age (+3.3 and +0.9 years per daily portion, respectively). Higher intake of vitamin B6 and zinc was associated with later menopausal age and vegetarian diets with earlier age.
COMMENT: The authors did not report participants' ethnicity, which could have affected dietary choices as well as menopausal timing. Moreover, I find it difficult to apply studies of specific dietary health effects to clinical practice. Association does not prove causation, and counseling women to consume or avoid specific nutrients in the interests of specific health endpoints may not actually alter their diets or produce the desired outcomes. For now, I will simply continue to encourage healthful dietary practices.
CITATION(S): Dunneram Y et al. Dietary intake and age at natural menopause: Results from the UK Women's Cohort Study. J Epidemiol Community Health 2018 Apr 30; [e-pub].
(http://dx.doi.org/10.1136/jech-2017-209887)
Top of Page
MM: The FDA seems to make recommendations without sufficient evidence at a frequency that is alarming. Whether it is a process that has limited invasive qualities - such as that described in the following article - or the prohibition of the use of dietary supplements as primary ingredients (eg.: glutathione, methylcobalamin) when making compounded preparations, the FDA appears to not always be working in the best interests of the general population but may be unduly influenced by outside individuals or groups that have their own interests at the foreground. Here it could be surgeons who are looking for greater compensation by using more invasive surgical procedures. In the case of the FDA's prohibition of using dietary supplements possessing legitimate, peer-reviewed and legally recognized dietary supplement monographs, against the intent of the US Congress, in the compounding process to benefit those who are physically compromised by conventionally prepared products from Big Pharma, the influence seems even more obvious.
JAMA Surg 2018 Apr 11
Consequences of the FDA Warnings About Power Morcellation
Complications of hysterectomy for fibroids increased in association with diminishing use of minimally invasive surgical approaches.
In April 2014, the FDA issued a statement discouraging use of laparoscopic power morcellation in hysterectomy for uterine fibroids; this was followed by a warning in November 2014 against use of uterine power morcellation because of risk for dissemination of malignant tissue. In response, many hospitals banned power morcellation. In a retrospective cohort study to assess the effects of these FDA statements on 30-day complications associated with hysterectomy and on surgical approach, investigators analyzed data from 603 hospitals involving 75,500 women [mean age, 48] undergoing hysterectomy for benign indications and a subset of 25,600 women undergoing hysterectomy specifically for uterine fibroids. Minimally invasive surgery included total laparoscopic hysterectomy, laparoscopic supracervical hysterectomy, and laparoscopic-assisted vaginal hysterectomy.
Overall frequency of major and minor complications did not change following the FDA warning. However, in the subset of women undergoing hysterectomy for fibroids, major complications increased after the warning from 1.9% to 2.4% (adjusted odds ratio, 1.23; P=0.02) and minor complications increased from 2.7% to 3.3% (adjusted OR, 1.21; P=0.01). Notably, open abdominal hysterectomy in these women rose from 37.2% to 43.0% and minimally invasive surgery fell from 56.1% to 49.7% (P<0.001).
COMMENT: The authors suggest it's important to balance the harms of surgical complications against the much lower odds that a uterine fibroid contains a malignancy. Indeed, occult malignancy is uncommon in women undergoing hysterectomy or myomectomy for benign conditions (NEJM JW Womens Health May 2018 and Obstet Gynecol 2018 Apr; 131:642). I reiterate the need for careful preoperative evaluation to exclude a malignancy, and I agree that decisions about surgical approach should be guided by the surgeon's experience and recommendations combined with the informed preferences of each patient.
CITATION(S): Multinu F et al. Practice patterns and complications of benign hysterectomy following the FDA statement warning against the use of power morcellation. JAMA Surg 2018 Apr 11; [e-pub].
(http://dx.doi.org/10.1001/jamasurg.2018.0141)
Top of Page
MM:THIS COMMENT RELATES TO THE FOLLOWING TWO ARTICLES:
Simpler may be better. The adage of KISS (Keep It Simple) may certainly be true when it comes to antibiotic (AB's) use. Overuse of AB's has been running rampant around the world for more than 50 years and nowhere is this more prominent than in the USA. This has led to the presence of superbugs that can predominate. Especially true is the presence of these in our children. One developing fear is that this can occur in other lines of drugs that serve to allegedly combat other biological invaders. We have already seen this happen with fungal infections that have become highly resistant to our historic anti-fungals, such as nystatin, and we can expect the haphazard use of anti-viral agents, such as ostelamir, to create super-viruses. This does not serve the public well to address a minor shortening duration of a viral infection from 36 to 18 hours. In the lon run we are potentially endangering ourselves and our children and grandchildren by using these products injudiciously.
Clin Infect Dis 2018 May; 66:1492
How Effective Is Oseltamivir for Treatment of Influenza in Children?
A meta-analysis shows reductions in illness duration and incidence of otitis media.
Oseltamivir, a neuraminidase inhibitor, has been shown to benefit adults with influenza, but its safety and efficacy are not as well demonstrated in children.
Researchers performed a meta-analysis of data from five randomized, placebo-controlled trials (one unpublished) that examined the safety and efficacy of oseltamivir treatment in over 2500 children aged <18 years with either proven influenza or influenza-like illness. Two studies included only children with asthma, and four of the five trials enrolled children within 48 hours of symptom onset. Findings include the following:
- For patients with documented influenza infection, treatment with oseltamivir resulted in:
- A 34% reduction in risk for developing otitis media
- A non–statistically significant decrease in risk for lower respiratory tract complications
- Children treated with oseltamivir had a higher frequency of emesis compared with those receiving placebo.
- Reduction in duration of illness was greater for those with proven influenza infection, adolescents, those without asthma (illness duration reduction of 35 hours vs. 18 hours for all infected children), and for those who initiated oseltamivir therapy within 24 hours of symptom onset.
COMMENT: Oseltamivir should be initiated early in children with influenza symptoms. Early treatment reduced the duration of illness (by a day and a half in children without asthma) and reduced the occurrence of otitis media. These benefits appear to outweigh the elevated risk for emesis reported in treated children.
CITATION(S): Malosh RE et al. Efficacy and safety of oseltamivir in children: Systematic review and individual patient data meta-analysis of randomized controlled trials. Clin Infect Dis 2018 May; 66:1492.
(https://doi.org/10.1093/cid/cix1040)
Top of Page
JAMA 2018 May 1; 319:1781
Nitrofurantoin vs. Fosfomycin for Uncomplicated UTIs
In a multisite European study, nitrofurantoin won for treating women with urinary tract infections.
The newest guidelines for empirical treatment of women with uncomplicated urinary tract infections (UTIs) advise clinicians to choose among three venerable antibiotics: trimethoprim-sulfamethoxazole, nitrofurantoin, and fosfomycin. Although the latter two drugs — developed decades ago — have shown efficacy against most urinary pathogens, no recent head-to-head comparisons have been reported. In this open-label trial, researchers randomized 513 women from Switzerland, Poland, and Israel with symptoms of UTI and consistent urine dipstick results to fosfomycin (a single 3-g dose) or nitrofurantoin (100 mg thrice daily for 5 days). Pregnant women and those with signs of sepsis or upper urinary tract disease were excluded.
Following completion of treatment, the nitrofurantoin group was significantly more likely than the fosfomycin group to report symptom resolution (75% vs. 66% at 2 weeks and 70% vs. 58% at 4 weeks). Microbiological cure at 4 weeks also was more common in the nitrofurantoin group (74% vs. 63%), especially among women with Escherichia coli isolated from pretreatment urine. Side effects were similarly infrequent and consisted mostly of gastrointestinal complaints.
COMMENT: This study has several methodologic problems; for example, a positive culture wasn't required at baseline. Editorialists also wonder if the study's open-label design might have swayed its results — yet they conclude that “the verdict is in:” Nitrofurantoin is superior to fosfomycin on both clinical and microbiological grounds. Still, as the researchers note, nitrofurantoin is newly available over the counter in Poland — and E. coli resistance rates already are rising there. The authors' verdict will require periodic reexamination as antimicrobial resistance patterns evolve. Finally, note that fosfomycin is prescribed only rarely in the U.S. and is not stocked in many U.S. pharmacies.
CITATION(S): Huttner A et al. Effect of 5-day nitrofurantoin vs single-dose fosfomycin on clinical resolution of uncomplicated lower urinary tract infection in women: A randomized clinical trial. JAMA 2018 May 1; 319:1781.
(https://doi.org/10.1001/jama.2018.3627)
Datta R and Juthani-Mehta M. Nitrofurantoin vs fosfomycin: Rendering a verdict in a trial of acute uncomplicated cystitis. JAMA 2018 May 1; 319:1771.
(https://doi.org/10.1001/jama.2018.4654)
Top of Page
Pediatrics 2018 Apr 20; 141:e20173466
Cost Benefit of Removing the Penicillin Allergy Label from Nonallergic Patients
Besides avoiding broad-spectrum antibiotic use, “delabeling” children as penicillin-allergic resulted in significant antibiotic cost savings for families.
Most children with a reported allergy to penicillin are not actually allergic and could tolerate penicillin therapy. This is important because patients who report penicillin allergy spend more time in the hospital and have more exposure to broader-spectrum antibiotics.
In a previous study, researchers found that 76% of children who presented to a pediatric emergency department (PED) reporting penicillin allergy were at low risk for allergy based on a symptom questionnaire. Of 100 children subsequently tested, none were found to be allergic (NEJM JW Pediatr Adolesc Med Aug 2017 and Pediatrics 2017; 140:e20170471).
In the current follow-up of those 100 nonallergic children, investigators assessed subsequent antibiotic use and safety outcomes, and estimated antibiotic cost savings from children's “delabeling” as penicillin-allergic. At a median of 1 year after penicillin allergy testing, researchers surveyed children's primary care providers (PCPs) and parents. Response rates were 81% among parents and 98% among PCPs. Results included the following:
- Eighty percent of parents reported that they notified their child's PCP of the negative penicillin allergy testing in the PED; only 16% of the PCPs reported that they were aware of the negative test.
- Forty-six antibiotic prescriptions were filled by 36 patients; 26 (57%) of the prescriptions were penicillin derivatives.
- No child developed a serious adverse reaction to a penicillin-derivative antibiotic; one child developed a rash 24 hours after starting amoxicillin.
- The estimated potential antibiotic cost savings (from purchasing penicillin derivatives versus higher-priced cefdinir) for the approximately 6700 patients per year who present to the PED with a reported penicillin allergy was US$192,223.00.
COMMENT: These data suggest that the delabeling of patients as penicillin-allergic would result in a significant savings in antibiotic costs for families. A rapid “test” to rule out penicillin allergy would be helpful. Delabeling is also a benefit to our patients and communities because it allows us to treat infections with narrow-spectrum antibiotics rather than resorting to the use of broad-spectrum antibiotics, thereby reducing the risk for the development of antibiotic-resistant bacteria.
CITATION(S): Vyles D et al. Antibiotic use after removal of penicillin allergy label. Pediatrics 2018 Apr 20; 141:e20173466.
(https://doi.org/10.1542/peds.2017-3466)
Top of Page
MM: This is a very exciting piece of information. Subcutaneous injections have become extremely easy, comfortable and safe for self-administration of a variety of medications. The ability to self administer takes away obstacles to use such as traveling to a clinician's office for administration and potentially decreases patient cost and cost to third party payors, including Medicare and Medicaid. I am hopeful that this approach to patient care and self-administration of a wider variety of medications and treatments will be seen and accepted more widely in healthcare.
Contraception 2018 Mar; 97:198
DMPA: The Advantages of Self-Administration
Do-it-yourself subcutaneous injectable contraception resulted in fewer pregnancies than clinic administration.
Depot medroxyprogesterone acetate (DMPA) has the potential to be a highly effective contraceptive, but returning to clinic every 12 to 14 weeks for the next injection is challenging for many women. Subcutaneous DMPA (available in the U.S. since 2004) is less painful and as effective as intramuscular DMPA and can be easily self-administered (NEJM JW Womens Health Jun 23 2014; [e-pub]; multiple citations). In a randomized trial involving 401 Planned Parenthood clients (age range, 16–44), researchers assessed 6- and 12-month continuation of subcutaneous DMPA with home self-administration versus clinic administration.
Continuous use of DMPA was significantly more likely with self-administration than clinic administration both at 6 months (87% vs. 69%) and 12 months (69% vs. 54%). One-year continuation was similar among teens compared with women older than 20 and was higher among prior DMPA users than new users (68% vs. 56%). Pregnancy within 1 year was less likely with self-administered than clinic-administered DMPA (0% vs. 1.5%).
COMMENT: Although patient-centered clinical practice requires us to offer the option of subcutaneous self-administration to those interested in DMPA, many women are now only offered intramuscular DMPA administered in clinic. Given this study's rigorous demonstration of the public health benefits and potential cost savings associated with self-administered subcutaneous DMPA, policy makers should hasten to facilitate changes in practice.
CITATION(S): Kohn JE et al. Increased 1-year continuation of DMPA among women randomized to self-administration: Results from a randomized controlled trial at Planned Parenthood. Contraception 2018 Mar; 97:198.
(https://doi.org/10.1016/j.contraception.2017.11.009)
Top of Page
