Yale New Haven Health System

BACKGROUND: In the hierarchy of research designs, the results of randomized, controlled trials are considered to be evidence of the highest grade, whereas observational studies are viewed as having less validity because they reportedly overestimate treatment effects. We used published meta-analyses to identify randomized clinical trials and observational studies that examined the same clinical topics. We then compared the results of the original reports according to the type of research design. METHODS: A search of the Medline data base for articles published in five major medical journals from 1991 to 1995 identified meta-analyses of randomized, controlled trials and meta-analyses of either cohort or case-control studies that assessed the same intervention. For each of five topics, summary estimates and 95 percent confidence intervals were calculated on the basis of data from the individual randomized, controlled trials and the individual observational studies. RESULTS: For the five clinical topics and 99 reports evaluated, the average results of the observational studies were remarkably similar to those of the randomized, controlled trials. For example, analysis of 13 randomized, controlled trials of the effectiveness of bacille Calmette-Guérin vaccine in preventing active tuberculosis yielded a relative risk of 0.49 (95 percent confidence interval, 0.34 to 0.70) among vaccinated patients, as compared with an odds ratio of 0.50 (95 percent confidence interval, 0.39 to 0.65) from 10 case-control studies. In addition, the range of the point estimates for the effect of vaccination was wider for the randomized, controlled trials (0.20 to 1.56) than for the observational studies (0.17 to 0.84). CONCLUSIONS: The results of well-designed observational studies (with either a cohort or a case-control design) do not systematically overestimate the magnitude of the effects of treatment as compared with those in randomized, controlled trials on the same topic.

BACKGROUND: Since in hospitalized older patients delirium is associated with poor outcomes, we evaluated the effectiveness of a multicomponent strategy for the prevention of delirium. METHODS: We studied 852 patients 70 years of age or older who had been admitted to the general-medicine service at a teaching hospital. Patients from one intervention unit and two usual-care units were enrolled by means of a prospective matching strategy. The intervention consisted of standardized protocols for the management of six risk factors for delirium: cognitive impairment, sleep deprivation, immobility, visual impairment, hearing impairment, and dehydration. Delirium, the primary outcome, was assessed daily until discharge. RESULTS: Delirium developed in 9.9 percent of the intervention group as compared with 15.0 percent of the usual-care group, (matched odds ratio, 0.60; 95 percent confidence interval, 0.39 to 0.92). The total number of days with delirium (105 vs. 161, P=0.02) and the total number of episodes (62 vs. 90, P=0.03) were significantly lower in the intervention group. However, the severity of delirium and recurrence rates were not significantly different. The overall rate of adherence to the intervention was 87 percent, and the total number of targeted risk factors per patient was significantly reduced. Intervention was associated with significant improvement in the degree of cognitive impairment among patients with cognitive impairment at admission and a reduction in the rate of use of sleep medications among all patients. Among the other risk factors per patient there were trends toward improvement in immobility, visual impairment, and hearing impairment. CONCLUSIONS: The risk-factor intervention strategy that we studied resulted in significant reductions in the number and duration of episodes of delirium in hospitalized older patients. The intervention had no significant effect on the severity of delirium or on recurrence rates; this finding suggests that primary prevention of delirium is probably the most effective treatment strategy.

BACKGROUND: Childhood obesity, epidemic in the United States, has been accompanied by an increase in the prevalence of type 2 diabetes among children and adolescents. We determined the prevalence of impaired glucose tolerance in a multiethnic cohort of 167 obese children and adolescents. METHODS: All subjects underwent a two-hour oral glucose-tolerance test (1.75 g [DOSAGE ERROR CORRECTED] of glucose per kilogram of body weight), and glucose, insulin, and C-peptide levels were measured. Fasting levels of proinsulin were obtained, and the ratio of proinsulin to insulin was calculated. Insulin resistance was estimated by homeostatic model assessment, and beta-cell function was estimated by calculating the ratio between the changes in the insulin level and the glucose level during the first 30 minutes after the ingestion of glucose. RESULTS: Impaired glucose tolerance was detected in 25 percent of the 55 obese children (4 to 10 years of age) and 21 percent of the 112 obese adolescents (11 to 18 years of age); silent type 2 diabetes was identified in 4 percent of the obese adolescents. Insulin and C-peptide levels were markedly elevated after the glucose-tolerance test in subjects with impaired glucose tolerance but not in adolescents with diabetes, who had a reduced ratio of the 30-minute change in the insulin level to the 30-minute change in the glucose level. After the body-mass index had been controlled for, insulin resistance was greater in the affected cohort and was the best predictor of impaired glucose tolerance. CONCLUSIONS: Impaired glucose tolerance is highly prevalent among children and adolescents with severe obesity, irrespective of ethnic group. Impaired oral glucose tolerance was associated with insulin resistance while beta-cell function was still relatively preserved. Overt type 2 diabetes was linked to beta-cell failure.

Interview with Dr. Harlan Krumholz on a condition of generalized risk after patients are discharged from the hospital. (17:28)Download Patients who were recently hospitalized experience a period of generalized risk for myriad adverse health events. Their condition may be characterized as a post-hospital syndrome, an acquired condition of vulnerability not necessarily linked to the original illness.

Widespread acceptance of COVID-19 vaccines is crucial for achieving sufficient immunization coverage to end the global pandemic, yet few studies have investigated COVID-19 vaccination attitudes in lower-income countries, where large-scale vaccination is just beginning. We analyze COVID-19 vaccine acceptance across 15 survey samples covering 10 low- and middle-income countries (LMICs) in Asia, Africa and South America, Russia (an upper-middle-income country) and the United States, including a total of 44,260 individuals. We find considerably higher willingness to take a COVID-19 vaccine in our LMIC samples (mean 80.3%; median 78%; range 30.1 percentage points) compared with the United States (mean 64.6%) and Russia (mean 30.4%). Vaccine acceptance in LMICs is primarily explained by an interest in personal protection against COVID-19, while concern about side effects is the most common reason for hesitancy. Health workers are the most trusted sources of guidance about COVID-19 vaccines. Evidence from this sample of LMICs suggests that prioritizing vaccine distribution to the Global South should yield high returns in advancing global immunization coverage. Vaccination campaigns should focus on translating the high levels of stated acceptance into actual uptake. Messages highlighting vaccine efficacy and safety, delivered by healthcare workers, could be effective for addressing any remaining hesitancy in the analyzed LMICs.

In this letter, the investigators report that saliva specimens and nasopharyngeal swab specimens had similar sensitivity in the detection of SARS-CoV-2 RNA in both symptomatic and asymptomatic persons.

BACKGROUND: Female athletes are at significantly greater risk of anterior cruciate ligament (ACL) injury than male athletes in the same high-risk sports. Decreased trunk (core) neuromuscular control may compromise dynamic knee stability. HYPOTHESES: (1) Increased trunk displacement after sudden force release would be associated with increased knee injury risk; (2) coronal (lateral), not sagittal, plane displacement would be the strongest predictor of knee ligament injury; (3) logistic regression of factors related to core stability would accurately predict knee, ligament, and ACL injury risk; and (4) the predictive value of these models would differ between genders. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: In this study, 277 collegiate athletes (140 female and 137 male) were prospectively tested for trunk displacement after a sudden force release. Analysis of variance and multivariate logistic regression identified predictors of risk in athletes who sustained knee injury. RESULTS: Twenty-five athletes (11 female and 14 male) sustained knee injuries over a 3-year period. Trunk displacement was greater in athletes with knee, ligament, and ACL injuries than in uninjured athletes (P < .05). Lateral displacement was the strongest predictor of ligament injury (P = .009). A logistic regression model, consisting of trunk displacements, proprioception, and history of low back pain, predicted knee ligament injury with 91% sensitivity and 68% specificity (P = .001). This model predicted knee, ligament, and ACL injury risk in female athletes with 84%, 89%, and 91% accuracy, but only history of low back pain was a significant predictor of knee ligament injury risk in male athletes. CONCLUSIONS: Factors related to core stability predicted risk of athletic knee, ligament, and ACL injuries with high sensitivity and moderate specificity in female, but not male, athletes.

Quality-measurement and payment-for-performance programs encourage physicians to deliver care that is consistent with practice guidelines. In the treatment of patients with multiple medical problems, adherence to disease-specific guidelines often requires the use of 10 or more medications, yet the marginal benefits and adverse effects of the 8th, 9th, or 10th medication in such patients are not known. The authors emphasize the importance of considering patients' quality of life, preferences, and values when prescribing medications for those with multiple chronic illnesses.

BACKGROUND: Observational studies have suggested that estrogen-replacement therapy may reduce a woman's risk of stroke and death. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of estrogen therapy (1 mg of estradiol-17beta per day) in 664 postmenopausal women (mean age, 71 years) who had recently had an ischemic stroke or transient ischemic attack. Women were recruited from 21 hospitals in the United States and were followed for the occurrence of stroke or death. RESULTS: During a mean follow-up period of 2.8 years, there were 99 strokes or deaths among the women in the estradiol group, and 93 among those in the placebo group (relative risk in the estradiol group, 1.1; 95 percent confidence interval, 0.8 to 1.4). Estrogen therapy did not reduce the risk of death alone (relative risk, 1.2; 95 percent confidence interval, 0.8 to 1.8) or the risk of nonfatal stroke (relative risk, 1.0; 95 percent confidence interval, 0.7 to 1.4). The women who were randomly assigned to receive estrogen therapy had a higher risk of fatal stroke (relative risk, 2.9; 95 percent confidence interval, 0.9 to 9.0), and their nonfatal strokes were associated with slightly worse neurologic and functional deficits. CONCLUSIONS: Estradiol does not reduce mortality orthe recurrence of stroke in postmenopausal women with cerebrovascular disease. This therapy should not be prescribed for the secondary prevention of cerebrovascular disease.

IMPORTANCE: Opioid-dependent patients often use the emergency department (ED) for medical care. OBJECTIVE: To test the efficacy of 3 interventions for opioid dependence: (1) screening and referral to treatment (referral); (2) screening, brief intervention, and facilitated referral to community-based treatment services (brief intervention); and (3) screening, brief intervention, ED-initiated treatment with buprenorphine/naloxone, and referral to primary care for 10-week follow-up (buprenorphine). DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial involving 329 opioid-dependent patients who were treated at an urban teaching hospital ED from April 7, 2009, through June 25, 2013. INTERVENTIONS: After screening, 104 patients were randomized to the referral group, 111 to the brief intervention group, and 114 to the buprenorphine treatment group. MAIN OUTCOMES AND MEASURES: Enrollment in and receiving addiction treatment 30 days after randomization was the primary outcome. Self-reported days of illicit opioid use, urine testing for illicit opioids, human immunodeficiency virus (HIV) risk, and use of addiction treatment services were the secondary outcomes. RESULTS: Seventy-eight percent of patients in the buprenorphine group (89 of 114 [95% CI, 70%-85%]) vs 37% in the referral group (38 of 102 [95% CI, 28%-47%]) and 45% in the brief intervention group (50 of 111 [95% CI, 36%-54%]) were engaged in addiction treatment on the 30th day after randomization (P < .001). The buprenorphine group reduced the number of days of illicit opioid use per week from 5.4 days (95% CI, 5.1-5.7) to 0.9 days (95% CI, 0.5-1.3) vs a reduction from 5.4 days (95% CI, 5.1-5.7) to 2.3 days (95% CI, 1.7-3.0) in the referral group and from 5.6 days (95% CI, 5.3-5.9) to 2.4 days (95% CI, 1.8-3.0) in the brief intervention group (P < .001 for both time and intervention effects; P = .02 for the interaction effect). The rates of urine samples that tested negative for opioids did not differ statistically across groups, with 53.8% (95% CI, 42%-65%) in the referral group, 42.9% (95% CI, 31%-55%) in the brief intervention group, and 57.6% (95% CI, 47%-68%) in the buprenorphine group (P = .17). There were no statistically significant differences in HIV risk across groups (P = .66). Eleven percent of patients in the buprenorphine group (95% CI, 6%-19%) used inpatient addiction treatment services, whereas 37% in the referral group (95% CI, 27%-48%) and 35% in the brief intervention group (95% CI, 25%-37%) used inpatient addiction treatment services (P < .001). CONCLUSIONS AND RELEVANCE: Among opioid-dependent patients, ED-initiated buprenorphine treatment vs brief intervention and referral significantly increased engagement in addiction treatment, reduced self-reported illicit opioid use, and decreased use of inpatient addiction treatment services but did not significantly decrease the rates of urine samples that tested positive for opioids or of HIV risk. These findings require replication in other centers before widespread adoption. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00913770.

BACKGROUND: Functional decline in physically frail, elderly persons is associated with substantial morbidity. It is uncertain whether such functional decline can be prevented. METHODS: We randomly assigned 188 persons 75 years of age or older who were physically frail and living at home to undergo a six-month, home-based intervention program that included physical therapy and that focused primarily on improving underlying impairments in physical abilities, including balance, muscle strength, ability to transfer from one position to another, and mobility, or to undergo an educational program (as a control). The primary outcome was the change between base line and 3, 7, and 12 months in the score on a disability scale based on eight activities of daily living: walking, bathing, upper- and lower-body dressing, transferring from a chair, using the toilet, eating, and grooming. Scores on the scale ranged from 0 to 16, with higher scores indicating more severe disability. RESULTS: Participants in the intervention group had less functional decline over time, according to their disability scores, than participants in the control group. The disability scores in the intervention and control groups were 2.3 and 2.8, respectively, at base line; 2.0 and 3.6 at 7 months (P=0.008 for the comparison between the groups in the change from base line); and 2.7 and 4.2 at 12 months (P=0.02). The benefit of the intervention was observed among participants with moderate frailty but not those with severe frailty. The frequency of admission to a nursing home did not differ significantly between the intervention group and the control group (14 percent and 19 percent, respectively; P=0.37). CONCLUSIONS: A home-based program targeting underlying impairments in physical abilities can reduce the progression of functional decline among physically frail, elderly persons who live at home.

BACKGROUND: The prevalence, efficacy, and risk for addiction for persons receiving opioids for chronic back pain are unclear. PURPOSE: To determine the prevalence of opioid treatment, whether opioid medications are effective, and the prevalence of substance use disorders among patients receiving opioid medications for chronic back pain. DATA SOURCES: English-language studies from MEDLINE (1966-March 2005), EMBASE (1966-March 2005), Cochrane Central Register of Controlled Clinical Trials (to 4th quarter 2004), PsychInfo (1966-March 2005), and retrieved references. STUDY SELECTION: Articles that studied an adult, nonobstetric sample; used oral, topical, or transdermal opioids; and focused on treatment for chronic back pain. DATA EXTRACTION: Two investigators independently extracted data and determined study quality. DATA SYNTHESIS: Opioid prescribing varied by treatment setting (range, 3% to 66%). Meta-analysis of the 4 studies assessing the efficacy of opioids compared with placebo or a nonopioid control did not show reduced pain with opioids (g, -0.199 composite standardized mean difference [95% CI, -0.49 to 0.11]; P = 0.136). Meta-analysis of the 5 studies directly comparing the efficacy of different opioids demonstrated a nonsignificant reduction in pain from baseline (g, -0.93 composite standardized mean difference [CI, -1.89 to -0.03]; P = 0.055). The prevalence of lifetime substance use disorders ranged from 36% to 56%, and the estimates of the prevalence of current substance use disorders were as high as 43%. Aberrant medication-taking behaviors ranged from 5% to 24%. LIMITATIONS: Retrieval and publication biases and poor study quality. No trial evaluating the efficacy of opioids was longer than 16 weeks. CONCLUSIONS: Opioids are commonly prescribed for chronic back pain and may be efficacious for short-term pain relief. Long-term efficacy (> or =16 weeks) is unclear. Substance use disorders are common in patients taking opioids for back pain, and aberrant medication-taking behaviors occur in up to 24% of cases.

BACKGROUND: Phenylpropanolamine is commonly found in appetite suppressants and cough or cold remedies. Case reports have linked the use of products containing phenylpropanolamine to hemorrhagic stroke, often after the first use of these products. To study the association, we designed a case-control study. METHODS: Men and women 18 to 49 years of age were recruited from 43 U.S. hospitals. Eligibility criteria included the occurrence of a subarachnoid or intracerebral hemorrhage within 30 days before enrollment and the absence of a previously diagnosed brain lesion. Random-digit dialing identified two matched control subjects per patient. RESULTS: There were 702 patients and 1376 control subjects. For women, the adjusted odds ratio was 16.58 (95 percent confidence interval, 1.51 to 182.21; P=0.02) for the association between the use of appetite suppressants containing phenylpropanolamine and the risk of a hemorrhagic stroke and 3.13 (95 percent confidence interval, 0.86 to 11.46; P=0.08) for the association with the first use of a product containing phenylpropanolamine. All first uses of phenylpropanolamine involved cough or cold remedies. For men and women combined, the adjusted odds ratio was 1.49 (95 percent confidence interval, 0.84 to 2.64; P=0.17) for the association between the use of a product containing phenylpropanolamine and the risk of a hemorrhagic stroke, 1.23 (95 percent confidence interval, 0.68 to 2.24; P=0.49) for the association with the use of cough or cold remedies that contained phenylpropanolamine, and 15.92 (95 percent confidence interval, 1.38 to 184.13; P=0.03) for the association with the use of appetite suppressants that contained phenylpropanolamine. An analysis in men showed no increased risk of a hemorrhagic stroke in association with the use of cough or cold remedies containing phenylpropanolamine. No men reported the use of appetite suppressants. CONCLUSIONS: The results suggest that phenylpropanolamine in appetite suppressants, and possibly in cough and cold remedies, is an independent risk factor for hemorrhagic stroke in women.

Physicians, hospitals, and other health care facilities will assume the responsibility for aiding individuals injured by a terrorist act involving radioactive material. Scenarios have been developed for such acts that include a range of exposures resulting in few to many casualties. This consensus document was developed by the Strategic National Stockpile Radiation Working Group to provide a framework for physicians in internal medicine and the medical subspecialties to evaluate and manage large-scale radiation injuries. Individual radiation dose is assessed by determining the time to onset and severity of nausea and vomiting, decline in absolute lymphocyte count over several hours or days after exposure, and appearance of chromosome aberrations (including dicentrics and ring forms) in peripheral blood lymphocytes. Documentation of clinical signs and symptoms (affecting the hematopoietic, gastrointestinal, cerebrovascular, and cutaneous systems) over time is essential for triage of victims, selection of therapy, and assignment of prognosis. Recommendations based on radiation dose and physiologic response are made for treatment of the hematopoietic syndrome. Therapy includes treatment with hematopoietic cytokines; blood transfusion; and, in selected cases, stem-cell transplantation. Additional medical management based on the evolution of clinical signs and symptoms includes the use of antimicrobial agents (quinolones, antiviral therapy, and antifungal agents), antiemetic agents, and analgesic agents. Because of the strong psychological impact of a possible radiation exposure, psychosocial support will be required for those exposed, regardless of the dose, as well as for family and friends. Treatment of pregnant women must account for risk to the fetus. For terrorist or accidental events involving exposure to radioiodines, prophylaxis against malignant disease of the thyroid is also recommended, particularly for children and adolescents.

Health literacy as a discrete form of literacy is becoming increasingly important for social, economic and health development. The positive and multiplier effects of education and general literacy on population health, particularly women's health, are well known and researched. However, a closer analysis of the current HIV/AIDS epidemics, especially in Africa, indicates a complex interface between general literacy and health literacy. While general literacy is an important determinant of health, it is not sufficient to address the major health challenges facing developing and developed societies. As a contribution to the health literacy forum in Health Promotion International, this paper reviews concepts and definitions of literacy and health literacy, and raises conceptual, measurement and strategic challenges. It proposes to develop a set of indicators to quantify health literacy using the experience gained in national literacy surveys around the world. A health literacy index could become an important composite measure of the outcome of health promotion and prevention activities, could document the health competence and capabilities of the population of a given country, community or group and relate it to a set of health, social and economic outcomes.

OBJECTIVES: We sought to determine which ICD-9-CM codes in Medicare Part A data identify cardiovascular and stroke risk factors. DESIGN AND PARTICIPANTS: This was a cross-sectional study comparing ICD-9-CM data to structured medical record review from 23,657 Medicare beneficiaries aged 20 to 105 years who had atrial fibrillation. MEASUREMENTS: Quality improvement organizations used standardized abstraction instruments to determine the presence of 9 cardiovascular and stroke risk factors. Using the chart abstractions as the gold standard, we assessed the accuracy of ICD-9-CM codes to identify these risk factors. MAIN RESULTS: ICD-9-CM codes for all risk factors had high specificity (>0.95) and low sensitivity (< or =0.76). The positive predictive values were greater than 0.95 for 5 common, chronic risk factors-coronary artery disease, stroke/transient ischemic attack, heart failure, diabetes, and hypertension. The sixth common risk factor, valvular heart disease, had a positive predictive value of 0.93. For all 6 common risk factors, negative predictive values ranged from 0.52 to 0.91. The rare risk factors-arterial peripheral embolus, intracranial hemorrhage, and deep venous thrombosis-had high negative predictive value (> or =0.98) but moderate positive predictive values (range, 0.54-0.77) in this population. CONCLUSIONS: Using ICD-9-CM codes alone, heart failure, coronary artery disease, diabetes, hypertension, and stroke can be ruled in but not necessarily ruled out. Where feasible, review of additional data (eg, physician notes or imaging studies) should be used to confirm the diagnosis of valvular disease, arterial peripheral embolus, intracranial hemorrhage, and deep venous thrombosis.

OBJECTIVE: To examine physician-documented indications for cesarean delivery in order to investigate the specific factors contributing to the increasing cesarean delivery rate. METHODS: We analyzed rates of primary and repeat cesarean delivery, including indications for the procedure, among 32,443 live births at a major academic hospital between 2003 and 2009. Time trends for each indication were modeled to estimate the absolute and cumulative annualized relative risk of cesarean by indication over time and the relative contribution of each indication to the overall increase in primary cesarean delivery rate. RESULTS: The cesarean delivery rate increased from 26% to 36.5% between 2003 and 2009; 50.0% of the increase was attributable to an increase in primary cesarean delivery. Among the documented indications, nonreassuring fetal status, arrest of dilation, multiple gestation, preeclampsia, suspected macrosomia, and maternal request increased over time, whereas arrest of descent, malpresentation, maternal-fetal indications, and other obstetric indications (eg, cord prolapse, placenta previa) did not increase. The relative contributions of each indication to the total increase in primary cesarean rate were: nonreassuring fetal status (32%), labor arrest disorders (18%), multiple gestation (16%), suspected macrosomia (10%), preeclampsia (10%), maternal request (8%), maternal-fetal conditions (5%), and other obstetric conditions (1%). CONCLUSION: Primary cesarean births accounted for 50% of the increasing cesarean rate. Among primary cesarean deliveries, more subjective indications (nonreassuring fetal status and arrest of dilation) contributed larger proportions than more objective indications (malpresentation, maternal-fetal, and obstetric conditions).

Description: This guideline updates the 2008 American College of Physicians (ACP) recommendations on treatment of low bone density and osteoporosis to prevent fractures in men and women. This guideline is endorsed by the American Academy of Family Physicians. Methods: The ACP Clinical Guidelines Committee based these recommendations on a systematic review of randomized controlled trials; systematic reviews; large observational studies (for adverse events); and case reports (for rare events) that were published between 2 January 2005 and 3 June 2011. The review was updated to July 2016 by using a machine-learning method, and a limited update to October 2016 was done. Clinical outcomes evaluated were fractures and adverse events. This guideline focuses on the comparative benefits and risks of short- and long-term pharmacologic treatments for low bone density, including pharmaceutical prescriptions, calcium, vitamin D, and estrogen. Evidence was graded according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Target Audience and Patient Population: The target audience for this guideline includes all clinicians. The target patient population includes men and women with low bone density and osteoporosis. Recommendation 1: ACP recommends that clinicians offer pharmacologic treatment with alendronate, risedronate, zoledronic acid, or denosumab to reduce the risk for hip and vertebral fractures in women who have known osteoporosis. (Grade: strong recommendation; high-quality evidence). Recommendation 2: ACP recommends that clinicians treat osteoporotic women with pharmacologic therapy for 5 years. (Grade: weak recommendation; low-quality evidence). Recommendation 3: ACP recommends that clinicians offer pharmacologic treatment with bisphosphonates to reduce the risk for vertebral fracture in men who have clinically recognized osteoporosis. (Grade: weak recommendation; low-quality evidence). Recommendation 4: ACP recommends against bone density monitoring during the 5-year pharmacologic treatment period for osteoporosis in women. (Grade: weak recommendation; low-quality evidence). Recommendation 5: ACP recommends against using menopausal estrogen therapy or menopausal estrogen plus progestogen therapy or raloxifene for the treatment of osteoporosis in women. (Grade: strong recommendation; moderate-quality evidence). Recommendation 6: ACP recommends that clinicians should make the decision whether to treat osteopenic women 65 years of age or older who are at a high risk for fracture based on a discussion of patient preferences, fracture risk profile, and benefits, harms, and costs of medications. (Grade: weak recommendation; low-quality evidence).

OBJECTIVE: Prevalence studies indicate a 10-fold higher rate of Tourette syndrome (TS) among children compared with adults. The purpose of this investigation was to examine the course of tic severity during the first 2 decades of life. METHOD: A birth-year cohort of 42 TS patients followed at the Yale Child Study Center was recontacted an average of 7.3 years after their initial clinical evaluation. Data concerning the onset and course of tic severity until 18 years of age were available on 36 TS patients. A variety of statistical techniques were used to model aspects of the temporal patterning of tic severity. RESULTS: Mean (SD) tic onset at 5.6 (2. 3) years of age was followed by a progressive pattern of tic worsening. On average, the most severe period of tic severity occurred at 10.0 (2.4) years of age. In eight cases (22%), the frequency and forcefulness of the tics reached a severe level during the worst-ever period such that functioning in school was impossible or in serious jeopardy. In almost every case this period was followed by a steady decline in tic severity. By 18 years of age nearly half of the cohort was virtually tic-free. The onset of puberty was not associated with either the timing or severity of tics. CONCLUSIONS: A majority of TS patients displayed a consistent time course of tic severity. This consistency can be accurately modeled mathematically and may reflect normal neurobiological processes. Determination of the model parameters that describe each patient's course of tic severity may be of prognostic value and assist in the identification of factors that differentially influence the course of tic severity.

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.