Folic Acid Supplementation to Prevent Neural Tube Defects: US Preventive Services Task Force Reaffirmation Recommendation Statement.

Importance: Neural tube defects are among the most common congenital malformations in the US, with an estimated 3000 pregnancies affected each year. Many of these neural tube defects are caused by low folate levels in the body. Objective: The US Preventive Services Task Force (USPSTF) commissioned a reaffirmation evidence update on the benefits and harms of folic acid supplementation. Population: Persons who are planning to or could become pregnant. Evidence Assessment: The USPSTF concludes that, for persons who are planning to or could become pregnant, there is high certainty that folic acid supplementation has a substantial net benefit to prevent neural tube defects in their offspring. Recommendation: The USPSTF recommends that all persons planning to or who could become pregnant take a daily supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid. (A recommendation).

Vitamin, Mineral, and Multivitamin Supplementation to Prevent Cardiovascular Disease and Cancer: US Preventive Services Task Force Recommendation Statement.

Importance: According to National Health and Nutrition Examination Survey data, 52% of surveyed US adults reported using at least 1 dietary supplement in the prior 30 days and 31% reported using a multivitamin-mineral supplement. The most commonly cited reason for using supplements is for overall health and wellness and to fill nutrient gaps in the diet. Cardiovascular disease and cancer are the 2 leading causes of death and combined account for approximately half of all deaths in the US annually. Inflammation and oxidative stress have been shown to have a role in both cardiovascular disease and cancer, and dietary supplements may have anti-inflammatory and antioxidative effects. Objective: To update its 2014 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a review of the evidence on the efficacy of supplementation with single nutrients, functionally related nutrient pairs, or multivitamins for reducing the risk of cardiovascular disease, cancer, and mortality in the general adult population, as well as the harms of supplementation. Population: Community-dwelling, nonpregnant adults. Evidence Assessment: The USPSTF concludes with moderate certainty that the harms of beta carotene supplementation outweigh the benefits for the prevention of cardiovascular disease or cancer. The USPSTF also concludes with moderate certainty that there is no net benefit of supplementation with vitamin E for the prevention of cardiovascular disease or cancer. The USPSTF concludes that the evidence is insufficient to determine the balance of benefits and harms of supplementation with multivitamins for the prevention of cardiovascular disease or cancer. Evidence is lacking and the balance of benefits and harms cannot be determined. The USPSTF concludes that the evidence is insufficient to determine the balance of benefits and harms of supplementation with single or paired nutrients (other than beta carotene and vitamin E) for the prevention of cardiovascular disease or cancer. Evidence is lacking and the balance of benefits and harms cannot be determined. Recommendation: The USPSTF recommends against the use of beta carotene or vitamin E supplements for the prevention of cardiovascular disease or cancer. (D recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the use of multivitamin supplements for the prevention of cardiovascular disease or cancer. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the use of single- or paired-nutrient supplements (other than beta carotene and vitamin E) for the prevention of cardiovascular disease or cancer. (I statement).

Estimating the Theoretical Cost Implications of Funding New Drugs Considered Not to Be Cost-Effective.

This study aims to estimate the theoretical excess expenditure that would be incurred by the Irish state-payer, should drugs be reimbursed at their original asking ("list") price rather than at a price at which the drug is considered cost-effective. In Ireland, all new drugs are evaluated by the National Centre for Pharmacoeconomics. For this study, drugs that were submitted by pharmaceutical companies from 2012 to 2017 and considered not cost-effective at list price were reviewed. A total of 43 such drugs met our inclusion criteria, and their pharmacoeconomic evaluations were further assessed. The price at which the drug could be considered cost-effective (cost-effective price) at the upper cost-effectiveness threshold used in Ireland (€ 45 000/quality adjusted life-year) was estimated for 18 drugs with an available cost-effectiveness model. Then, for each drug, the list price and cost-effective price (both per unit) were both individually applied to 1 year of national real-world drug utilization data. This allowed the estimation of the expected expenditures under the assumptions of list price paid and cost-effective price paid. The resulting theoretical excess expenditure, the expenditure at list price minus the expenditure at the cost-effective price, was estimated to be €108.2 million. This estimate is theoretical because of the confidentiality of actual drug prices. The estimation is calculated using the list price and likely overestimates the actual excess expenditure, which would reduce to zero if cost-effective prices are agreed. Nevertheless, this estimate illustrates the importance of a process to assess the value of new drugs so that potential excess drug expenditure is identified.

Management of Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia: AUA GUIDELINE PART I-Initial Work-up and Medical Management.

PURPOSE: Benign prostatic hyperplasia (BPH) is a histologic diagnosis describing proliferation of smooth muscle and epithelial cells within the prostatic transition zone. The prevalence and severity of lower urinary tract symptoms (LUTS) in aging men are progressive and impact the health and welfare of society. This revised Guideline provides a useful reference on effective evidence-based management of male LUTS/BPH. See the accompanying algorithm for a summary of the procedures detailed in the Guideline (figures 1 and 2[Figure: see text][Figure: see text]). MATERIALS AND METHODS: The Minnesota Evidence Review Team searched Ovid MEDLINE, Embase, Cochrane Library, and AHRQ databases to identify eligible English language studies published between January 2008 and April 2019, then updated through December 2020. Search terms included Medical Subject Headings (MeSH) and keywords for pharmacological therapies, drug classes, and terms related to LUTS or BPH. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, information is provided as Clinical Principles and Expert Opinions (table 1[Table: see text]). RESULTS: Nineteen guideline statements pertinent to evaluation, work-up, and medical management were developed. Appropriate levels of evidence and supporting text were created to direct both primary care and urologic providers towards streamlined and suitable practices. CONCLUSIONS: The work up and medical management of BPH requires attention to individual patient characteristics, while also respecting common principles. Clinicians should adhere to recommendations and familiarize themselves with standards of BPH management.

Interventions to Prevent Perinatal Depression: US Preventive Services Task Force Recommendation Statement.

Importance: Perinatal depression, which is the occurrence of a depressive disorder during pregnancy or following childbirth, affects as many as 1 in 7 women and is one of the most common complications of pregnancy and the postpartum period. It is well established that perinatal depression can result in adverse short- and long-term effects on both the woman and child. Objective: To issue a new US Preventive Services Task Force (USPSTF) recommendation on interventions to prevent perinatal depression. Evidence Review: The USPSTF reviewed the evidence on the benefits and harms of preventive interventions for perinatal depression in pregnant or postpartum women or their children. The USPSTF reviewed contextual information on the accuracy of tools used to identify women at increased risk of perinatal depression and the most effective timing for preventive interventions. Interventions reviewed included counseling, health system interventions, physical activity, education, supportive interventions, and other behavioral interventions, such as infant sleep training and expressive writing. Pharmacological approaches included the use of nortriptyline, sertraline, and omega-3 fatty acids. Findings: The USPSTF found convincing evidence that counseling interventions, such as cognitive behavioral therapy and interpersonal therapy, are effective in preventing perinatal depression. Women with a history of depression, current depressive symptoms, or certain socioeconomic risk factors (eg, low income or young or single parenthood) would benefit from counseling interventions and could be considered at increased risk. The USPSTF found adequate evidence to bound the potential harms of counseling interventions as no greater than small, based on the nature of the intervention and the low likelihood of serious harms. The USPSTF found inadequate evidence to assess the benefits and harms of other noncounseling interventions. The USPSTF concludes with moderate certainty that providing or referring pregnant or postpartum women at increased risk to counseling interventions has a moderate net benefit in preventing perinatal depression. Conclusions and Recommendation: The USPSTF recommends that clinicians provide or refer pregnant and postpartum persons who are at increased risk of perinatal depression to counseling interventions. (B recommendation).

Interventions to Prevent Falls in Community-Dwelling Older Adults: US Preventive Services Task Force Recommendation Statement.

Importance: Falls are the leading cause of injury-related morbidity and mortality among older adults in the United States. In 2014, 28.7% of community-dwelling adults 65 years or older reported falling, resulting in 29 million falls (37.5% of which needed medical treatment or restricted activity for a day or longer) and an estimated 33 000 deaths in 2015. Objective: To update the 2012 US Preventive Services Task Force (USPSTF) recommendation on the prevention of falls in community-dwelling older adults. Evidence Review: The USPSTF reviewed the evidence on the effectiveness and harms of primary care-relevant interventions to prevent falls and fall-related morbidity and mortality in community-dwelling older adults 65 years or older who are not known to have osteoporosis or vitamin D deficiency. Findings: The USPSTF found adequate evidence that exercise interventions have a moderate benefit in preventing falls in older adults at increased risk for falls and that multifactorial interventions have a small benefit. The USPSTF found adequate evidence that vitamin D supplementation has no benefit in preventing falls in older adults. The USPSTF found adequate evidence to bound the harms of exercise and multifactorial interventions as no greater than small. The USPSTF found adequate evidence that the overall harms of vitamin D supplementation are small to moderate. Conclusions and Recommendation: The USPSTF recommends exercise interventions to prevent falls in community-dwelling adults 65 years or older who are at increased risk for falls. (B recommendation) The USPSTF recommends that clinicians selectively offer multifactorial interventions to prevent falls in community-dwelling adults 65 years or older who are at increased risk for falls. Existing evidence indicates that the overall net benefit of routinely offering multifactorial interventions to prevent falls is small. When determining whether this service is appropriate for an individual, patients and clinicians should consider the balance of benefits and harms based on the circumstances of prior falls, presence of comorbid medical conditions, and the patient's values and preferences. (C recommendation) The USPSTF recommends against vitamin D supplementation to prevent falls in community-dwelling adults 65 years or older. (D recommendation) These recommendations apply to community-dwelling adults who are not known to have osteoporosis or vitamin D deficiency.

Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: US Preventive Services Task Force Recommendation Statement.

Importance: Because of the aging population, osteoporotic fractures are an increasingly important cause of morbidity and mortality in the United States. Approximately 2 million osteoporotic fractures occurred in the United States in 2005, and annual incidence is projected to increase to more than 3 million fractures by 2025. Within 1 year of experiencing a hip fracture, many patients are unable to walk independently, more than half require assistance with activities of daily living, and 20% to 30% of patients will die. Objective: To update the 2013 US Preventive Services Task Force (USPSTF) recommendation on vitamin D supplementation, with or without calcium, to prevent fractures. Evidence Review: The USPSTF reviewed the evidence on vitamin D, calcium, and combined supplementation for the primary prevention of fractures in community-dwelling adults (defined as not living in a nursing home or other institutional care setting). The review excluded studies conducted in populations with a known disorder related to bone metabolism (eg, osteoporosis or vitamin D deficiency), taking medications known to be associated with osteoporosis (eg, long-term steroids), or with a previous fracture. Findings: The USPSTF found inadequate evidence to estimate the benefits of vitamin D, calcium, or combined supplementation to prevent fractures in community-dwelling men and premenopausal women. The USPSTF found adequate evidence that daily supplementation with 400 IU or less of vitamin D and 1000 mg or less of calcium has no benefit for the primary prevention of fractures in community-dwelling, postmenopausal women. The USPSTF found inadequate evidence to estimate the benefits of doses greater than 400 IU of vitamin D or greater than 1000 mg of calcium to prevent fractures in community-dwelling postmenopausal women. The USPSTF found adequate evidence that supplementation with vitamin D and calcium increases the incidence of kidney stones. Conclusions and Recommendation: The USPSTF concludes that the current evidence is insufficient to assess the balance of the benefits and harms of vitamin D and calcium supplementation, alone or combined, for the primary prevention of fractures in community-dwelling, asymptomatic men and premenopausal women. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of the benefits and harms of daily supplementation with doses greater than 400 IU of vitamin D and greater than 1000 mg of calcium for the primary prevention of fractures in community-dwelling, postmenopausal women. (I statement) The USPSTF recommends against daily supplementation with 400 IU or less of vitamin D and 1000 mg or less of calcium for the primary prevention of fractures in community-dwelling, postmenopausal women. (D recommendation) These recommendations do not apply to persons with a history of osteoporotic fractures, increased risk for falls, or a diagnosis of osteoporosis or vitamin D deficiency.

Influence of Intramyocardial Adipose Tissue on the Accuracy of Endocardial Contact Mapping of the Chronic Myocardial Infarction Substrate.

BACKGROUND: Recent studies have demonstrated that intramyocardial adipose tissue (IMAT) may contribute to ventricular electrophysiological remodeling in patients with chronic myocardial infarction. Using an ovine model of myocardial infarction, we aimed to determine the influence of IMAT on scar tissue identification during endocardial contact mapping and optimal voltage-based mapping criteria for defining IMAT dense regions. METHOD AND RESULTS: In 7 sheep, left ventricular endocardial and transmural mapping was performed 84 weeks (15-111 weeks) post-myocardial infarction. Spearman rank correlation coefficient was used to assess the relationship between endocardial contact electrogram amplitude and histological composition of myocardium. Receiver operator characteristic curves were used to derive optimal electrogram thresholds for IMAT delineation during endocardial mapping and to describe the use of endocardial mapping for delineation of IMAT dense regions within scar. Endocardial electrogram amplitude correlated significantly with IMAT (unipolar r=-0.48±0.12, P<0.001; bipolar r=-0.45±0.22, P=0.04) but not collagen (unipolar r=-0.36±0.24, P=0.13; bipolar r=-0.43±0.31, P=0.16). IMAT dense regions of myocardium reliably identified using endocardial mapping with thresholds of <3.7 and <0.6 mV, respectively, for unipolar, bipolar, and combined modalities (single modality area under the curve=0.80, P<0.001; combined modality area under the curve=0.84, P<0.001). Unipolar mapping using optimal thresholding remained significantly reliable (area under the curve=0.76, P<0.001) during mapping of IMAT, confined to putative scar border zones (bipolar amplitude, 0.5-1.5 mV). CONCLUSIONS: These novel findings enhance our understanding of the confounding influence of IMAT on endocardial scar mapping. Combined bipolar and unipolar voltage mapping using optimal thresholds may be useful for delineating IMAT dense regions of myocardium, in postinfarct cardiomyopathy.

Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain: A Clinical Practice Guideline From the American College of Physicians.

Description: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on noninvasive treatment of low back pain. Methods: Using the ACP grading system, the committee based these recommendations on a systematic review of randomized, controlled trials and systematic reviews published through April 2015 on noninvasive pharmacologic and nonpharmacologic treatments for low back pain. Updated searches were performed through November 2016. Clinical outcomes evaluated included reduction or elimination of low back pain, improvement in back-specific and overall function, improvement in health-related quality of life, reduction in work disability and return to work, global improvement, number of back pain episodes or time between episodes, patient satisfaction, and adverse effects. Target Audience and Patient Population: The target audience for this guideline includes all clinicians, and the target patient population includes adults with acute, subacute, or chronic low back pain. Recommendation 1: Given that most patients with acute or subacute low back pain improve over time regardless of treatment, clinicians and patients should select nonpharmacologic treatment with superficial heat (moderate-quality evidence), massage, acupuncture, or spinal manipulation (low-quality evidence). If pharmacologic treatment is desired, clinicians and patients should select nonsteroidal anti-inflammatory drugs or skeletal muscle relaxants (moderate-quality evidence). (Grade: strong recommendation). Recommendation 2: For patients with chronic low back pain, clinicians and patients should initially select nonpharmacologic treatment with exercise, multidisciplinary rehabilitation, acupuncture, mindfulness-based stress reduction (moderate-quality evidence), tai chi, yoga, motor control exercise, progressive relaxation, electromyography biofeedback, low-level laser therapy, operant therapy, cognitive behavioral therapy, or spinal manipulation (low-quality evidence). (Grade: strong recommendation). Recommendation 3: In patients with chronic low back pain who have had an inadequate response to nonpharmacologic therapy, clinicians and patients should consider pharmacologic treatment with nonsteroidal anti-inflammatory drugs as first-line therapy, or tramadol or duloxetine as second-line therapy. Clinicians should only consider opioids as an option in patients who have failed the aforementioned treatments and only if the potential benefits outweigh the risks for individual patients and after a discussion of known risks and realistic benefits with patients. (Grade: weak recommendation, moderate-quality evidence).

Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A Clinical Practice Guideline From the American College of Physicians.

DESCRIPTION: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the comparative effectiveness of treatment with second-generation antidepressants versus nonpharmacologic treatments for major depressive disorder in adults. METHODS: This guideline is based on a systematic review of published, English-language, randomized, controlled trials from 1990 through September 2015 identified using several databases and through hand searches of references of relevant studies. Interventions evaluated include psychotherapies, complementary and alternative medicines (including acupuncture, ω-3 fatty acids, S-adenosyl-L-methionine, St. John's wort [Hypericum perforatum]), exercise, and second-generation antidepressants. Evaluated outcomes included response, remission, functional capacity, quality of life, reduction of suicidality or hospitalizations, and harms. The target audience for this guideline includes all clinicians, and the target patient population includes adults with major depressive disorder. This guideline grades the evidence and recommendations using ACP's clinical practice guidelines grading system. RECOMMENDATION: ACP recommends that clinicians select between either cognitive behavioral therapy or second-generation antidepressants to treat patients with major depressive disorder after discussing treatment effects, adverse effect profiles, cost, accessibility, and preferences with the patient (Grade: strong recommendation, moderate-quality evidence).

Restore: the journey toward self-forgiveness: a randomized trial of patient education on self-forgiveness in cancer patients and caregivers.

The present study evaluated "Restore: The Journey Toward Self-Forgiveness," a brief psycho-spiritual curriculum for encouraging self-forgiveness. This was a randomized, wait-list controlled trial including 83 cancer patients and caregivers. Restore encourages self-acceptance, self-improvement, and commitment using prayer/meditation, reflection, and expressive writing in a workbook format. Measures of self-forgiveness, acceptance, self-improvement, and optimism/pessimism were collected before and after participation. Using Analysis of Covariance to control initial levels, post-session levels showed that Restore participants scored higher than wait-list controls on self-forgiveness (F(1,78) = 9.85, p < .001), acceptance (F(1,77) = 4.84, p < .05), and self-improvement (F(1,79) = 5.28, p < .05) and lower than wait-list controls on pessimism (F(1,77) = 5.01, p < .05). Changes in acceptance, self-improvement, and pessimism mediate the Restore effect on self-forgiveness (Beta = -.08, p < .05). This is the first known brief, evidence-based program for facilitating self-forgiveness in patients with self-forgiveness issues.

Treatment assignment guesses by study participants in a double-blind dose escalation clinical trial of saw palmetto.

OBJECTIVES: This report assesses participant perception of treatment assignment in a randomized, double-blind, placebo-controlled trial of saw palmetto for the treatment of benign prostatic hyperplasia (BCM). DESIGN: Participants randomized to receive saw palmetto were instructed to take one 320 mg gelcap daily for the first 24 weeks, two 320 mg gelcaps daily for the second 24 weeks, and three 320 mg gelcaps daily for the third 24 weeks. Study participants assigned to placebo were instructed to take the same number of matching placebo gelcaps in each time period. At 24, 48, and 72 weeks postrandomization, the American Urological Association Symptom Index (AUA-SI) was administered and participants were asked to guess their treatment assignment. SETTINGS: The study was conducted at 11 clinical centers in North America. PARTICIPANTS: Study participants were men, 45 years and older, with moderate to low severe BPH symptoms, randomized to saw palmetto (N=151) or placebo (N=155). OUTCOME MEASURES: Treatment arms were compared with respect to the distribution of participant guesses of treatment assignment. RESULTS: For participants assigned to saw palmetto, 22.5%, 24.7%, and 29.8% correctly thought they were taking saw palmetto, and 37.3%, 40.0%, and 44.4% incorrectly thought they were on placebo at 24, 48, and 72 weeks, respectively. For placebo participants, 21.8%, 27.4%, and 25.2% incorrectly thought they were on saw palmetto, and 41.6%, 39.9%, and 42.6% correctly thought they were on placebo at 24, 48, and 72 weeks, respectively. The treatment arms did not vary with respect to the distributions of participants who guessed they were on saw palmetto (p=0.823) or placebo (p=0.893). Participants who experienced an improvement in AUA-SI were 2.16 times more likely to think they were on saw palmetto. CONCLUSIONS: Blinding of treatment assignment was successful in this study. Improvement in BPH-related symptoms was associated with the perception that participants were taking saw palmetto.

Primary radiofrequency ablation of ventricular tachycardia early after myocardial infarction: evaluation in an ovine model.

BACKGROUND: Ventricular tachycardia (VT) is a significant complication of myocardial infarction. Radiofrequency ablation for postinfarct VT is reserved for drug refractory VT or VT storms. Our hypothesis is that radiofrequency ablation in the early postinfarct period could abolish or diminish late recurrences of VT. METHODS AND RESULTS: Myocardial infarct was induced by balloon occlusion of the left anterior descending artery in 35 sheep. The 25 survivors underwent programmed ventricular stimulation and electroanatomical mapping 8 days postinfarct. Animals with inducible VT (12 out of 25 animals) underwent immediate radiofrequency ablation. Further VT inductions were performed 100 and 200 days postinfarct. At day 8, 3.0±0.9 VT morphologies per animal were inducible. All were successfully ablated with 24±6 applications of radiofrequency energy. All had ablations on the left ventricular endocardium, and 67% had ablations on the right ventricular aspect of the interventricular septum. All targeted arrhythmias were successfully ablated acutely. One animal was euthanized because of hypotension from a serious pericardial effusion. The other 11 survived and remained arrhythmia free on subsequent inductions on the 100th and 200th days (P<0.001). The 13 animals without inducible VT remained noninducible at the subsequent studies. A historical control arm of 9 animals with inducible VT at day 8 remained inducible at day 100. CONCLUSIONS: Radiofrequency ablation on the eighth day after infarction abolished inducibility of VT at late induction studies ≤200 days in an ovine model. Early identification and ablation of VT after infarction may prevent or reduce late ventricular arrhythmias but needs to be validated in clinical studies.

Evolution of ventricular tachycardia and its electrophysiological substrate early after myocardial infarction: an ovine model.

BACKGROUND: Sudden arrhythmic death after myocardial infarction (MI) is most frequent in the first month. Early programmed ventricular stimulation (within 1 week) post-MI has been able to identify long-term ventricular tachycardia (VT) occurrence. We aimed to determine the timing of development and stabilization of VT circuits after MI and how the evolution of the underlying substrate differs with VT inducibility. METHODS AND RESULTS: MIs were induced in 36 sheep. The 21 survivors underwent serial electroanatomic mapping and programmed ventricular stimulation. Animals were classified as VTpos (inducible VT) or VTneg (noninducible VT) at day 8. Forty-three percent of MI survivors were VTpos on day 8 (9/21), and all remained inducible on day 100 with 1.5 (1.0-2.0) and 1.0 (1.0-2.0) morphologies per animal on days 8 and 100, respectively. Twelve-lead electrocardiogram matched in 15 of 19 VTs between days 8 and 100. The earliest presystolic ventricular activations during VT circuits were in similar locations at the 2 time points. The 12 VTneg animals remained noninducible on day 100. There was no difference in voltage or velocity substrate with time or inducibility. The area with fractionated signals increased with time and VT inducibility. VTpos animals had more linear regions of slowed conduction forming conducting channels. CONCLUSIONS: The inducibility and earliest presystolic endocardial activation sites of VT as well as voltage and velocity substrate on day 8 predicted those on day 100 postinfarct, indicating early formation and stabilization of the arrhythmogenic substrate. VT inducibility was influenced by the distribution of conducting channels and increased complex fractionated signals.

Intramyocardial adiposity after myocardial infarction: new implications of a substrate for ventricular tachycardia.

BACKGROUND: Collagen has been attributed as the principal structural substrate of ventricular tachycardia (VT) after myocardial infarction (MI), even though adiposity of myocardium after MI is well recognized histologically. We investigated the effects of intramyocardial adiposity compared with collagen on electrophysiological properties, connexin43 expression, and VT induction after MI. METHODS AND RESULTS: Simultaneous left ventricular plunge-needle, noncontact mapping was performed in sheep without MI (MI-; n=5), with MI and inducible VT (MI+VT+; n=7), and with MI and no inducible VT (MI+VT-; n=8). Histological intramyocardial quantity of adipose and collagen and degree of discontinuity were coregistered with electrophysiological parameters (MI+; 290 specimens). Additional assessment of connexin43 expression was performed. Left ventricular scar contained a body mass-independent abundance of adipocytes (adipose:collagen=0.8). Increased adipose density and discontinuity contributed to a greater inverse correlation (r) with conduction velocity (r for adipose=0.39, r for discontinuity=0.45, r for collagen=0.26) and electrogram amplitude (r for adipose=0.73, r for contiguity=0.77, r for collagen=0.68) compared with collagen. Collagen density was similar between the MI+ groups (P>0.29). However, the MI+VT+ group demonstrated a significant (all P≤0.01) increase in adipose (8%) and discontinuity (qualitative) and decrease in conduction velocity (13%) and electrogram amplitude (21%) at MI borders compared with the MI+VT- group. In scar, myocytes adjacent to fibrofatty interfaces demonstrated increased connexin43 lateralization. A gradient increase in adipose was observed at sites that supported preferential presystolic VT activation and exhibited attenuation of excitation wavelength (P<0.001). CONCLUSIONS: Intramyocardial adiposity, in association with myocardial discontinuity within left ventricular scar borders, is a significant factor associated with altered electrophysiological properties, aberrant connexin43 expression, and increased propensity for VT after MI.

Relationships among participant international prostate symptom score, benign prostatic hyperplasia impact index changes and global ratings of change in a trial of phytotherapy in men with lower urinary tract symptoms.

PURPOSE: We related changes in American Urological Association symptom index scores with bother measures and global ratings of change in men with lower urinary tract symptoms who were enrolled in a saw palmetto trial. MATERIALS AND METHODS: To be eligible for study men were 45 years old or older, and had a peak uroflow of 4 ml per second or greater and an American Urological Association symptom index score of 8 to 24. Participants self-administered the American Urological Association symptom index, International Prostate Symptom Score quality of life item, Benign Prostatic Hyperplasia Impact Index and 2 global change questions at baseline, and at 24, 48 and 72 weeks. RESULTS: In 357 participants global ratings of a little better were associated with a mean decrease in American Urological Association symptom index scores from 2.8 to 4.1 points across 3 time points. The analogous range for mean decreases in Benign Prostatic Hyperplasia Impact Index scores was 1.0 to 1.7 points and for the International Prostate Symptom Score quality of life item it was 0.5 to 0.8 points. At 72 weeks for the first global change question each change measure discriminated between participants who rated themselves at least a little better vs unchanged or worse 70% to 72% of the time. A multivariate model increased discrimination to 77%. For the second global change question each change measure correctly discriminated ratings of at least a little better vs unchanged or worse 69% to 74% of the time and a multivariate model increased discrimination to 79%. CONCLUSIONS: Changes in American Urological Association symptom index scores could discriminate between participants rating themselves at least a little better vs unchanged or worse. Our findings support the practice of powering studies to detect group mean differences in American Urological Association symptom index scores of at least 3 points.

Safety and toxicity of saw palmetto in the CAMUS trial.

PURPOSE: Extracts of the saw palmetto berry are used by many men in the United States as self-treatment for lower urinary tract symptoms due to benign prostatic hyperplasia. While the most recent data from double-blind clinical trials do not support efficacy superior to that of placebo, there are sparse data on saw palmetto toxicity. MATERIALS AND METHODS: A total of 369 patients were randomized in the CAMUS (Complementary and Alternative Medicine for Urological Symptoms) trial, of whom 357 were included in this modified intent to treat analysis. Participants were randomized to 320, 640 and 960 mg daily of an ethanolic saw palmetto extract or to an identical-appearing placebo in an escalating manner at 6-month intervals for a total of 18 months of followup. Adverse event assessments, vital signs, and blood and urine laboratory tests were obtained at regular intervals. RESULTS: There were no statistically significant differences between the groups in the rates of serious or nonserious adverse events, changes in vital signs, digital prostate examination findings or study withdrawal rates. Overall, there were no significant intergroup differences in laboratory test abnormalities, while differences in individual laboratory tests were rare and small in magnitude. No evidence of significant dose-response phenomena was identified. CONCLUSIONS: The saw palmetto extract used in the CAMUS trial showed no evidence of toxicity at doses up to 3 times the usual clinical dose during an 18-month period.

The effect of increasing doses of saw palmetto fruit extract on serum prostate specific antigen: analysis of the CAMUS randomized trial.

PURPOSE: Saw palmetto extracts are used to treat lower urinary tract symptoms in men despite level I evidence that saw palmetto is ineffective in reducing these lower urinary tract symptoms. We determined whether higher doses of saw palmetto as studied in the CAMUS (Complementary and Alternative Medicine for Urologic Symptoms) trial affect serum prostate specific antigen levels. MATERIALS AND METHODS: The CAMUS trial was a randomized, placebo controlled, double-blind, multicenter, North American trial conducted between June 5, 2008 and October 10, 2012, in which 369 men older than 45 years with an AUA symptom score of 8 to 24 were randomly assigned to placebo or dose escalation of saw palmetto, which consisted of 320 mg for the first 24 weeks, 640 mg for the next 24 weeks and 960 mg for the last 24 weeks of this 72-week trial. Serum prostate specific antigen levels were obtained at baseline and at weeks 24, 48 and 72, and were compared between treatment groups using the pooled t test and Fisher's exact test. RESULTS: Serum prostate specific antigen was similar at baseline for the placebo (mean ± SD 1.93 ± 1.59 ng/ml) and saw palmetto groups (2.20 ± 1.95, p = 0.16). Changes in prostate specific antigen during the study were similar, with a mean change in the placebo group of 0.16 ± 1.08 ng/ml and 0.23 ± 0.83 ng/ml in the saw palmetto group (p = 0.50). In addition, no differential effect on serum prostate specific antigen was observed between treatment arms when the groups were stratified by baseline prostate specific antigen. CONCLUSIONS: Saw palmetto extract does not affect serum prostate specific antigen more than placebo, even at relatively high doses.

Reconciling primary care and specialist perspectives on prostate cancer screening.

When specialists propose screening guidelines for primary care clinicians to implement, differences in perspectives between the 2 groups can create conflicts. Two recent specialty organization guidelines illustrate this issue. The American Urological Association guideline panel and National Comprehensive Cancer Network recommend that average-risk men first be counseled about the risks and benefits of prostate-specific antigen screening for prostate cancer at age 40 rather than at the previously recommended age of 50 years. There is no direct evidence, however, that this recommendation has any impact on prostate cancer-specific mortality. To avoid distracting primary care clinicians from providing services with proven benefit and value for patients, professional organizations should follow appropriate standards for developing guidelines. Primary care societies and health care systems should also be encouraged to evaluate the evidence and decide whether implementing the recommendations are feasible and appropriate.