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Content 7

 

The Doctor and the Pharmacist

Radio Show Articles:
June 3, 2017

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Gut Microbiome Affects Two Nervous System Diseases
Later School Start Times Associated with Better Sleep and Academic Performance
A New Way to Measure Childhood Obesity
FDA Approves Edaravone for Amyotrophic Lateral Sclerosis
Better Diets Protect Against Left-Sided Colon Cancer
Do Mothers' Eating Disorders Affect Their Newborns and Infants?
Alternate-Day Fasting Is No Better Than a Typical Reduced-Calorie Diet
Lower-pH Vaginal Gel Didn't Tip the Balance Farther Toward Better Sex
Does Ovarian Function's Protective Power Extend to Heart Failure?
Endometrial Cancer and Breast-Feeding: Add Another Benefit to the Inventory
Hepatitis C Infection Is on the Rise in U.S. Women and Children
Exercise Limitation After Acute Pulmonary Embolism
Is Formal Physical Therapy Necessary After Hip Replacement?

Proc Natl Acad Sci U S A 2017 May 15
Gut Microbiome Affects Two Nervous System Diseases
Macular degeneration and cerebral cavernous malformations can be slowed by controlling the gut microbiome in mice.
The gut microbiome is being linked to diseases throughout the body, including the nervous system. The latest two associations have just been reported.
Epidemiologic data have suggested a link between high–glycemic index (HG) diets and age-related macular degeneration (AMD). Using a mouse model for AMD, investigators confirmed that HG diets made AMD worse and that switching mice to low–glycemic index (LG) diets promptly arrested progression of AMD. This strong association depended on changes in the gut microbiome induced by the dietary changes. Specifically, the change from an HG to an LG diet increased the numbers of Bacteroidales species, which led to production of bacterial metabolites that protected against development of AMD.
Cerebral cavernous malformations (CCMs) can cause strokes and seizures. A new study in a mouse model of brain CCMs shows that lipopolysaccharide (LPS) produced by gram-negative bacteria can penetrate the gut mucosa during inflammatory states and can enter the circulation. When LPS reaches the brain, it stimulates a particular receptor (TLR4) on the endothelial wall, and this triggers morphologic changes that evolve into CCMs. Natural polymorphisms that promote expression of the TLR4 gene (in mice and humans) are linked to higher numbers of CCMs. Antibiotic treatments that target gram-negative bacteria in CCM mice prevent formation of CCMs; antibiotics targeting gram-positive bacteria do not have this effect.
COMMENT: These two reports are just the latest evidence that the health of the nervous system can be influenced strongly by the gut microbiome. Whether prophylaxis or treatments based on this knowledge will be effective in humans remains to be determined.
CITATION(S): Rowan S et al. Involvement of a gut-retina axis in protection against dietary glycemia-induced age-related macular degeneration. 
Proc Natl Acad Sci U S A 2017 May 15; [e-pub].
(http://dx.doi.org/10.1073/pnas.1702302114)
Tang AT et al. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature2017 May 18; 545:305.
(http://dx.doi.org/10.1038/nature22075)
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J Adolesc Health 2017 May 3
Later School Start Times Associated with Better Sleep and Academic Performance
Eighth graders starting school before 8 a.m. had decreased sleep duration, lower grades, and lower rates of homework completion.
Research on the impact of later school start times on sleep hygiene and academic performance among middle school students is limited by small samples. Investigators took advantage of variable school start times in a large middle school district (165,000 students) to evaluate potential associations. Three cohorts of eighth grade students (33,000 total; 50% female, 42% white) self-reported how much sleep they got on weeknights, their grades, and their academic effort (“How often do you finish your homework?”). School start times were categorized as earliest (7:20–7:30 a.m.), early (7:40–7:55 a.m.), and latest (8:00–8:10 a.m.).
Students could report sleep duration of as little as <4 to as much as ≥9 hours. The probability of getting A's was highest among those sleeping 8 or more hours and lowest for those getting fewer than 7 hours. Compared with students in the latest-start schools, students in the earliest-start schools were 31% less likely to sleep 8 hours, and those in the early-start schools were 17% less likely. Path analysis revealed that compared to students in latest-start schools, and controlling for survey year, gender, race, and free-lunch status, those in the earliest-start schools were significantly less likely to get good grades. This analysis also showed that school start times before 8 a.m. negatively affected homework completion — but indirectly, through their impact on sleep duration.
COMMENT: These results were drawn from a single school district with a large, diverse student body, which helps control for potential confounders (differences in demography, grading systems, teaching style, etc.). If you have a child in middle school or are involved in middle school healthcare, these data can help convince school administrators of the benefits of later start times. Your children will likely thank you as well.
CITATION(S): Lewin DS et al. Variable school start times and middle school student's sleep health and academic performance. J Adolesc Health 2017 May 3;
[e-pub]. (http://dx.doi.org/10.1016/j.jadohealth.2017.02.017)
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JAMA Pediatr 2017 May 15;
A New Way to Measure Childhood Obesity
Triponderal-mass index was more stable than body-mass index throughout adolescence.
Because body weight in children and adolescents is not proportional to height squared as it is in adults, providers classify youth as normal weight versus overweight or obese based on body-mass index (BMI) percentile for each age (BMI-z score) instead of BMI score (weight in kg/height in meters2). However, even BMI-z scores are problematic, given the rapid growth and normal changes in body-fat percentage that occur during adolescence.
To further characterize inaccuracies of BMI scores and identify better measures of body fat, investigators analyzed cross-sectional data on 2285 youth (ages 8–17 years; 55% male). The data were obtained from the 1999–2006 National Health and Nutrition Examination Survey (NHANES), which included dual-energy x-ray absorptiometry (DXA) measurements of body composition. Body-fat indices — including triponderal mass index (TMI; mass/height3) — were correlated with percent body fat calculated from DXA readings.
Results were as follows:

COMMENT: The BMI-z scores in use now were calculated from data that are 40 to 50 years old. The authors note that BMI for age thresholds calculated from the newer NHANES data performed as well as TMI. Nonetheless, TMI would be easier to use because a single value (16 kg/m3 for boys and 16.8 kg/m3 for girls) would suffice to classify all children 8 to 17 years old as overweight or obese. Further studies in larger and more ethnically and racially diverse samples are needed before we can say whether TMI will replace BMI measurement. But if these data hold up, TMI may be just the right amount of information.
CITATION(S): Peterson CM et al. Tri-ponderal mass index vs body mass index in estimating body fat during adolescence. JAMA Pediatr 2017 May 15; [e-pub].
(http://dx.doi.org/10.1001/jamapediatrics.2017.0460)
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U.S. Food and Drug Administration, May 5, 2017
FDA Approves Edaravone for Amyotrophic Lateral Sclerosis
Patient selection will be critical for making effective use of this treatment.
On May 5, 2017, the FDA granted approval of Radicava (edaravone) for treatment of patients with amyotrophic lateral sclerosis (ALS). The approval is based on a phase III, double-blind, placebo-controlled 24-week trial (MCI 186-19 trial; NCT01492686 at http://clinicaltrials.gov). The trial was restricted to Japanese ALS patients with disease duration <2 years, forced vital capacity ≥80%, and ALS Functional Rating Scale–Revised (ALSFRS-R) score ≥24 points. Researchers randomized 137 patients to either placebo (68 patients) or 60 mg edaravone (69 patients) infused intravenously daily for 14 days, followed by 14 days drug-free; subsequent treatment cycles were 10 daily infusions out of 14 days, followed by 14 days drug-free, for up to 6 cycles. The primary outcome was change in ALSFRS-R score from baseline.
The mean change in ALSFRS-R was −5.01 with edaravone versus −7.50 with placebo, a significant difference of 2.49 points. No serious adverse effects were reported. The most common side effects were bruising and gait disturbance. Concomitant use of riluzole was permitted; the two groups did not differ in riluzole use.
COMMENT: Edaravone is a potent radical scavenger previously used in stroke trials. Although the ALS community is excited about the prospect of a new therapy, there are several areas of concern. The approval is based on evidence from a preselected subgroup of patients, and a prior trial with broader inclusion criteria (MCI 186-16) failed to reach statistical significance for the same primary outcome. The FDA approval decision did not provide guidance for patient selection, but selection will be necessary to deliver efficacious, cost-effective, rational therapy. Confirmation of efficacy in patients with broader genetic backgrounds is pending, and collection of real-world evidence on efficacy and safety is in the best interest of all. This trial demonstrates what is already known in the neurodegenerative field: Earlier therapy is more efficient. Therefore, we need sustained efforts to increase awareness, expedite neurologic consultation, and, importantly, discover imaging and fluid biomarkers to identify subgroups of ALS patients for targeted therapies.
Dr. Ilieva is Assistant Professor of Neurology, Johns Hopkins University, Baltimore, Maryland.
CITATION(S): FDA approves drug to treat ALS [press release]. Silver Spring, MD: U.S. Food and Drug Administration, May 5, 2017. (https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm557102.htm)
The Writing Group on behalf of the Edaravone (MCI-186) ALS 19 Study Group.Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: A randomised, double-blind, placebo-controlled trial. Lancet Neurol 2017 May 15; [e-pub].
(http://dx.doi.org/10.1016/S1474-4422(17)30115-1)
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Gastroenterology 2017 Apr 17
Better Diets Protect Against Left-Sided Colon Cancer
Risk is reduced for individuals in the highest versus lowest healthy-eating quintile.
Previous studies of the relationship between diet and colorectal cancer (CRC) have largely involved only white patients. Now, investigators have examined this association in a multi-ethnic cohort, including whites, African Americans, Japanese Americans, Latinos, and native Hawaiians. To assess diet quality, the researchers used four quality indices that have been extensively studied for their association with disease risk.
CRC risk was reduced for men and women in the highest versus lowest healthy-eating quintiles across all four diet-quality indices. Healthy diets were beneficial for all ethnic and racial groups, although the benefits were less for African Americans. Improvements in CRC risk were confined to the left colon and rectum in all groups.
COMMENT: Randomized controlled trials of high-fiber diets after colonoscopy have failed to show reductions in recurrent adenomas on follow-up colonoscopy. However, epidemiologic data such as these support a recommendation to patients that eating a healthier diet reduces CRC risk and, as has been repeatedly shown, reduces all-cause mortality.
Note to readers: At the time NEJM JW reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.
CITATION(S): Park SY et al. High-quality diets associate with reduced risk of colorectal cancer: Analyses of diet quality indexes in the multiethnic cohort. Gastroenterology 2017 Apr 17; [e-pub].
(http://dx.doi.org/10.1053/j.gastro.2017.04.004)
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J Child Psychol Psychiatry 2017 Apr 28
Do Mothers' Eating Disorders Affect Their Newborns and Infants?
Infants of eating-disordered mothers had various autonomic, language, and motor impairments during their first year of life.
Maternal nutrition is known to be important for healthy babies. To learn about the effects of mothers' eating disorders (EDs) on their children during the first year of life, researchers recruited 37 women with active EDs, 39 women with past EDs, and 61 healthy controls during their first or second trimester (mothers were in their early 30s).
Data at 8 days postpartum were available on newborns of 15 women with active EDs, 20 with past EDs, and 28 healthy controls. Compared with infants in the control group, those in the active-ED group showed autonomic instability. At 1 year postpartum (active-ED group, 18 infants; past-ED group, 19; control group, 28), infants in the past-ED group had impaired language and motor development compared with those in the control group. Statistical models controlled for maternal age, education, child's sex, birthweight, depression, and anxiety but not for maternal body-mass index, weight gain during pregnancy, or birthweight for gestational age.
COMMENT: This small investigation did not control for many factors that could have influenced outcomes (e.g., weight gain during pregnancy; NEJM JW Gen Med Nov 15 2007 and Obstet Gynecol 2007; 110:745). Still, the findings are consistent with studies showing adverse effects of maternal malnutrition, which can extend across generations (e.g., after the Dutch famine during World War II).
Eating-disordered patients are usually women before or during their childbearing years. These patients can be difficult to engage in treatment and often have considerable denial about their medical condition. Perhaps, educating these young women about potential risks to their babies posed by their eating disorders would increase motivation for treatment.
CITATION(S): Barona M et al. Neurobehavioural and cognitive development in infants born to mothers with eating disorders. J Child Psychol Psychiatry 2017 Apr 28; [e-pub].
(http://dx.doi.org/10.1111/jcpp.12736)
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JAMA Intern Med 2017 May 1
Alternate-Day Fasting Is No Better Than a Typical Reduced-Calorie Diet
Weight loss and several measures of cardiovascular risk were similar in both groups.
Among the many approaches to dieting, alternate-day fasting has become increasingly popular. In this controlled trial, 100 obese but otherwise healthy adults (mean body-mass index, 35 kg/m2; mean age, 44; mostly women) were randomized to alternate-day fasting, daily calorie restriction, or a control group. Baseline energy expenditure was measured during a 1-month run-in phase. Alternate-day participants were instructed to consume 25% of their calculated energy needs on fast days and 125% of their needs on alternating “feast” days; reduced-calorie participants were told to lower their daily calorie intake to 75% of energy needs. Control participants were asked to maintain their weight and, on study completion, received free dietary counseling and gym memberships.
At the end of the 1-year study, the dropout rate was slightly higher in the alternate-day group than in the reduced-calorie and control groups (38% vs. 29% and 26%, respectively). During the first 6 months, mean reduction in calorie intake from baseline energy needs was 21% in the alternate-day group and 24% in the reduced-calorie group. In intent-to-treat analysis, mean weight loss at 12 months was about 5% in both intervention groups, compared with a slight weight gain in the control group. The alternate-day and reduced-calorie groups also did not differ on several cardiovascular and metabolic risk factors.
COMMENT: Alternate-day fasting appears to offer no advantage over typical reduced-calorie diets in adherence, calorie reduction, or weight loss.
CITATION(S): Trepanowski JF et al. Effect of alternate-day fasting on weight loss, weight maintenance, and cardioprotection among metabolically healthy obese adults: A randomized clinical trial. JAMA Intern Med2017 May 1; [e-pub].
(http://dx.doi.org/10.1001/jamainternmed.2017.0936)
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Obstet Gynecol 2017May; 129:970
Lower-pH Vaginal Gel Didn't Tip the Balance Farther Toward Better Sex
In breast cancer survivors, both pH-balanced and neutral gels substantially attenuated dyspareunia and improved sexual function.
Estrogen deficiency can lead to dyspareunia with attendant impairment of sexual function. Investigators in South Korea tested whether vaginal gel balanced to pH 4.0 (achieved by addition of lactate) would affect dyspareunia and sexual dysfunction differently than placebo gel (pH 7.2; constituents not specified). A total of 136 breast cancer survivors (median age, 49) were randomized to use either gel three times weekly and at intercourse for 8 weeks.
Both dyspareunia and sexual function substantially improved in both groups. Among women who received the pH-balanced gel, vaginal pH decreased and vaginal maturation index increased significantly. Both gels were well tolerated.
COMMENT: Sexual dysfunction in breast cancer survivors is associated with lower quality of life, but concern about systemic absorption of vaginal estrogen therapy prevents its use in this population. Thus, the search continues for the most appropriate vaginal lubricant. These findings suggest that a pH balanced (i.e., more acidic) vaginal gel is not superior to one with neutral pH. Consistent use is the likely key to realizing either gel's benefit.
CITATION(S): Kim YH et al. Effect of a pH-balanced vaginal gel on dyspareunia and sexual function in breast cancer survivors who were premenopausal at diagnosis: A randomized controlled trial. Obstet Gynecol 2017May; 129:970.
(http://dx.doi.org/10.1097/AOG.0000000000001988)
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J Am Coll Cardiol 2017 May 15
Does Ovarian Function's Protective Power Extend to Heart Failure?
Shorter reproductive duration was associated with higher risk for heart failure.
Previous reports suggest that early menopause is associated with excess risk for cardiovascular disease (CVD). To evaluate associations between reproductive function and risk for heart failure (HF), investigators analyzed data from a subgroup of 28,516 women (54% non-Hispanic white, 31% black, 12% Hispanic) enrolled in the Women's Health Initiative (WHI). In this cohort, mean age at menarche was 13; at menopause, 47; and at enrollment, 63; no CVD was present at baseline. The analysis was adjusted for factors including body mass index, hypertension, and diabetes.
At a mean follow-up of 13 years, incident HF resulting in hospitalization had occurred in 1494 participants. Total reproductive duration was inversely associated with risk for incident HF (multivariable hazard ratio per year of reproductive function, 0.99; P=0.02). This association was more robust in women with natural (i.e., spontaneous) menopause than in those with surgical menopause. No significant effect modification was noted with race/ethnicity.
COMMENT: This modestly elevated risk for HF in women with shorter reproductive duration could reflect the excess risk for coronary heart disease (CHD) accompanying early menopause. This finding is also consistent with reports that bilateral oophorectomy raises CHD risk (BMJ 2017 Feb 6; 356:j372) — and with WHI clinical trial data showing lower incidence of CHD when hormone therapy was initiated in recently menopausal women (JAMA 2013; 310:1353). As the authors and editorialist note, more research is needed to fully understand the mechanisms underlying these findings (in particular, estrogen's cardioprotective effect).
CITATION(S): Hall PS et al. Reproductive factors and incidence of heart failure hospitalization in the Women's Health Initiative. J Am Coll Cardiol 2017 May 15; [e-pub].
(http://dx.doi.org/10.1016/j.jacc.2017.03.557)
Scott NS.Understanding hormones, menopause, and heart failure: Still a work in progress. J Am Coll Cardiol 2017 May 15; [e-pub].
(http://dx.doi.org/10.1016/j.jacc.2017.03.561)
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Obstet Gynecol 2017 Jun; 129:1059
Endometrial Cancer and Breast-Feeding: Add Another Benefit to the Inventory
Breast-feeding each newborn for >3 months was associated with lower risk for endometrial cancer.
Exclusive breast-feeding induces ovarian quiescence and decreases estrogen secretion. These changes may contribute to the mechanism linking breast-feeding and lower risk for breast and ovarian cancer. To investigate whether this relation extends to endometrial cancer, investigators pooled individual data from 3 cohort studies and 14 case-control studies including 8981 parous women with endometrial cancer and 17,241 parous controls. In both groups, about two thirds of women reported histories of breast-feeding.
Ever breast-feeding was associated with 11% lower risk for endometrial cancer (pooled odds ratio, 0.89; 95% CI, 0.81–0.98). Although lifetime cumulative breast-feeding of ≤3 months and mean breast-feeding duration of ≤3 months per newborn did not affect risk for endometrial cancer, mean duration of breast-feeding up to 9 months was associated with steadily decreasing risk.
COMMENT: For newborns, breast milk is an optimal food because it contains unique oligosaccharides that promote healthy gut bacterial flora including proliferating Bifidobacterium longum biovar infantis, as well as antimicrobial agents (e.g., lactoferrin, secretory IgA). Breast-fed infants have lower risk for gastroenteritis, respiratory illness, otitis media, and urinary tract infections — and their mothers have lower risk for diabetes mellitus, breast cancer, and ovarian cancer. The finding that breast-feeding each newborn for >3 months is associated with decreased risk for endometrial cancer highlights yet another potential health benefit of breast-feeding.
CITATION(S): Jordan SJ et al. Breastfeeding and endometrial cancer risk: An analysis from the Epidemiology of Endometrial Cancer Consortium. Obstet Gynecol 2017 Jun; 129:1059.
(http://dx.doi.org/10.1097/AOG.0000000000002057)
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Ann Intern Med 2017 May
Hepatitis C Infection Is on the Rise in U.S. Women and Children
About 30,000 reproductive-aged women are reported to have HCV infection each year.
Until recently, the bulk of hepatitis C virus (HCV) infections occurred in persons born between 1945 and 1965 (baby boomers); thus, a one-time screening has been recommended for this group. To examine trends in younger women, investigators analyzed data on HCV cases in women and children reported to the National Notifiable Diseases Surveillance System (2006–2014) as well as those tested by Quest Laboratories (2011–2014).
The reported number of reproductive-aged women with HCV rose from 16,000 in 2006 to 31,000 in 2014. Among some 580,000 pregnant women who were tested, 0.73% had HCV. In addition, 0.76% of tested children had HCV. Infection rates varied with age and peaked at 1.62% in those aged 2 to 3 years.
COMMENT: As the authors speculate, the increasing number of HCV infections in younger women likely reflects the current opioid injection epidemic. While transmission to the neonates is infrequent, those born to women with high viral loads and concurrent HIV infection are at increased risk. Because routine testing in this age group — or in pregnancy — is not currently recommended, these numbers reflect only the testing performed when a high-risk history is elicited; therefore, we really do not know the extent of the problem. Population-based studies will be needed to evaluate HCV's scope and to devise screening strategies.
CITATION(S): Ly KN et al. Hepatitis C virus infection among reproductive-aged women and children in the United States, 2006 to 2014. Ann Intern Med 2017 May 9; [e-pub].
(http://dx.doi.org/10.7326/M16-2350)
DeMaria A Jr et al. Hearing from the silent epidemic. Ann Intern Med 2017 May 9; [e-pub].
(http://dx.doi.org/10.7326/M17-0927)
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Chest 2017 May; 151:1058
Exercise Limitation After Acute Pulmonary Embolism
One year after PE, exercise limitation probably was caused by deconditioning and not by persistent physiological abnormalities.
During the months after successfully treated acute pulmonary embolism (PE), some patients report exercise limitation or persistent exertional dyspnea. In this Canadian study that involved 100 patients with acute uncomplicated PE, researchers performed physiologic assessments at 1, 6, and 12 months; the goal was to determine whether circulatory impairment, ventilatory impairment, or muscle deconditioning contributed to persistent symptoms at 1 year. Patients with previous PE and those with major comorbidities were excluded.
On cardiopulmonary exercise testing, mean peak oxygen uptake (VO2) increased significantly between 1 and 12 months, but nearly half the patients still exhibited abnormally low peak VO2 (<80% of predicted) at 12 months. Patients with low peak VO2 at 12 months reported poorer quality of life and more dyspnea than did patients with normal peak VO2. However, these two groups did not differ significantly in pulmonary function test results, oxygen desaturation with exercise, diffusing capacity, echocardiographic measurements, or degree of pulmonary vascular obstruction on repeated imaging.
COMMENT: One year after acute PE, physiologic measurements of circulatory and ventilatory function were not obviously impaired in patients with abnormal cardiopulmonary exercise test results. The authors tentatively conclude that muscle deconditioning — perhaps caused by anxiety about resuming normal physical activity after PE — likely is responsible for ongoing dyspnea and exercise limitation in some patients. This makes sense to me; I wonder if another contributing factor is fear of exercise-related bleeding complications in patients who are receiving anticoagulation indefinitely. One unavoidable limitation of this study is that no pre-PE measurements of exercise capacity were available.
CITATION(S): Kahn SR et al. Functional and exercise limitations after a first episode of pulmonary embolism: Results of the ELOPE prospective cohort study. Chest 2017 May; 151:1058.
(http://dx.doi.org/10.1016/j.chest.2016.11.030)
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J Bone Joint Surg Am 2017 Apr 19; 99:648
Is Formal Physical Therapy Necessary After Hip Replacement?
For selected patients, unsupervised home exercises are as effective as formal therapy.
Physical therapy after total hip arthroplasty (THA) can be administered in inpatient settings, outpatient settings, or at home. But is formal physical therapy necessary for everyone? In this randomized trial, orthopedists randomized 120 patients undergoing THA either to formal physical therapy (2 weeks in the home, followed by as long as 8 weeks in an outpatient facility) or to unsupervised home exercises (taught to the patient before discharge from the hospital). Patients who were undergoing revision of prior THA or those requiring skilled nursing were excluded.
In intent-to-treat analysis, outcomes on several standardized scales of pain and function were virtually identical in the two groups at 1, 6, and 12 months. Ten patients in the unsupervised home-exercise group who did not meet progress goals at 2 weeks crossed over to formal outpatient physical therapy. However, 20 patients crossed over from the formal outpatient group to unsupervised home exercise, often because of out-of-pocket expenses or difficulty traveling to outpatient facilities.
COMMENT: This study shows convincingly that formal posthospitalization physical therapy after hip replacement is unnecessary for selected patients with good home support. In this intent-to-treat analysis, the crossovers between groups don't negate the value of the study: Most crossovers went from more-intensive to less-intensive intervention, and patients whose initial progress is suboptimal with informal home exercise still can opt for formal physical therapy.
CITATION(S): Austin MS et al. Formal physical therapy after total hip arthroplasty is not required: A randomized controlled trial. J Bone Joint Surg Am 2017 Apr 19; 99:648.
(http://dx.doi.org/10.2106/JBJS.16.00674)

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