5-1 EXECUTIVE SUMMARY OF THE THIRD REPORT OF THE NATIONAL CHOLESTEROL EDUCATION PROGRAM (NCEP) EXPERT PANEL ON DETECTION, EVALUATION, AND TREATMENT OF HIGH BLOOD CHOLESTEROL IN ADULTS (Adult Treatment Panel III)
      Practical point: All primary care clinicians should have a copy of these guidelines available for reference and distribution to patients with lipid problems. This will include millions.

5-2 PREVENTION OF TYPE 2 DIABETES MELLITUS BY CHANGES IN LIFESTYLE AMONG SUBJECTS WITH IMPAIRED GLUCOSE TOLERANCE
      Type 2 diabetes can be prevented by changes in the lifestyle of patients with impaired glucose tolerance
      Although the average amount of weight lost was not large, the difference between groups in incidence of diabetes was substantial. Even a relatively small loss of 5% of weight was important. The conservative target of more than 4 hours of exercise per week was associated with a significant reduction in risk. "The reasonably low dropout rate in our study indicates that subjects with impaired glucose tolerance are willing and able to participate in a demanding intervention program."
      Practical point: This is an important study. Glucose metabolism should be checked in older patients. Discovery of moderate abnormalities (impaired fasting glucose and impaired glucose tolerance) will provide an excellent opportunity to encourage patients to modify their lifestyles. RTJ

5-3 IS THE PLACEBO POWERLESS?
An Analysis of Clinical Trials Comparing Placebo with No Treatment
      This investigation concludes that placebo response represents a regression of symptoms to the mean and not a true therapeutic effect.
      Practical point: Primary care clinicians must decide whether to 1) accept the possibility that placebos do indeed have a beneficial effect some times, for some patients. or 2) to believe they have no beneficial effect whatsoever, and avoid their use. Most clinicians will still tilt toward 1).

5-4 ENDOGENOUS OPIOIDS, PLACEBO RESPONSE, AND PAIN
      It was suggested as early as 1978 that the analgesic response to placebo is mediated by endogenous opioids. Well designed studies have shown clearly that the placebo response to pain exists and that endogenous opioids have an important role in its mediation.
      Practical point: The placebo response is physiological and mediated by endogenous opioids – a system which can provide pain relief. It is wrong to assume, as many clinicians still do, that a placebo response represents imagined pain or malingering.

5-5 MEDICAL TREATMENT OF PERIPHERAL ARTERIAL DISEASE AND CLAUDICATION
      Peripheral atherosclerotic disease is an important manifestation of systemic atherosclerosis. It carries the same relative risk of death from cardiovascular disease as does a history of coronary heart disease or cerebrovascular disease.
      Practical point; Patients with PAD should be candidates for secondary prevention strategies, including aggressive risk factor modification and antiplatelet drug therapy. Most patients are undertreated. The FDA has approved cilostazol (Pletal) for treatment of claudication. It inhibits platelet aggregation, arterial thrombus formation, and vascular smooth-muscle proliferation, and causes vasodilation.

5-6 EFFECT OF CARVEDILOL ON OUTCOME AFTER MYOCARDIAL INFARCTION IN PATIENTS WITH LEFT VENTRICULAR DYSFUNCTION: THE CAPRICORN RANDOMISED TRIAL.
      In patients treated long-term after an acute MI complicated by left ventricular systolic dysfunction. carvedilol,a beta-blocker, started within days after the MI, was associated with reduction in all-cause and cardiovascular mortality, and recurrent non-fatal MI. Benefits were in addition to aspirin and ACE inhibitors.
      Practical point: Primary care clinicians will be following more patients taking beta-blockers. Starting low and going slow is a critical clinical application.

5-7 EXPANDING INDICATIONS FOR BETA-BLOCKERS IN HEART FAILURE
      It is now clear that the interaction between the adrenergic nervous system and the failing heart is more complex than first realized. Chronic overexposure of the heart to norepinephrine causes hypertrophy, ischemia, and myocyte damage. The theory that the adrenergic system has a maladaptive role in chronic HF is supported by the salutary effects of beta-blockade on clinical outcomes demonstrated by large clinical trials.
      Practical point: Beta-blockers represent an advance in the treatment of HF. They appear to be effective in patients with a wide spectrum of systolic HF — mild to severe.
      These drugs must be administered cautiously and the dose escalated slowly in all patients with HF.

5-8 BENEFITS OF PRAVASTATIN ON CARDIOVASCULAR EVENTS AND MORTALITY IN OLDER PATIENTS WITH CORONARY HEART DISEASE ARE EQUAL TO OR EXCEED THOSE SEEN IN YOUNGER PATIENTS: The LIPID Trial
      Practical point: Older persons with established coronary disease and average or moderately elevated cholesterol levels may benefit from secondary prevention with pravastatin therapy. Co-morbidity, expected length of life, and personal preference are contraindications, not age.

5-9 PROSTATE-SPECIFIC-ANTIGEN TESTING FOR EARLY DETECTION OF PROSTATE CANCER
      PSA testing does detect PC at an early age in many cases. However, at present, data are not available from large, well-designed, randomized trials to determine whether early detection is beneficial, harmful, or has no effects. As a result, the optimal strategy remains unknown.
      A discussion about testing should include: the likelihood that PC will be diagnosed; the possibility of false positive and false negative tests; the anxiety associated with a positive test; and the uncertainty regarding whether screening reduces the risk of death from PC. Randomized trials have indicated that routinely providing such information reduces the proportion of men who elect to be tested, although many still elect to do so.
      Practical point: Primary care clinicians should not automatically order a PSA screen on their male patients over age 50. They should first make sure the patient has enough understanding of adverse effects of possible follow-up procedures and surgery (or radiation) in order to make an informed decision about screening.

5-10 CURRENT APPROACHES TO CERVICAL-CANCER SCREENING
      Although screening saves lives, there is no consensus about when screening should start, how long it should continue, the frequency of screening, or the optimal screening technique. Information needed to make informed decisions is, in many respects, incomplete. The article offers suggestions and guidelines.

5-11 AUTOMATED SPHYGMOMANOMETRY: AMBULATORY BLOOD PRESSURE MEASUREMENT
      Practical point: Due to the frequent occurrence of difficult-to-treat hypertension, all primary care practices should have some method of measuring ambulatory BP

5-12 WHAT TO DO WHEN BLOOD PRESSURE IS DIFFICULT TO CONTROL
      In the majority of patients treated for hypertension, target BP levels are not achieved. Practical point: Primary care clinicians should consult a check-list of the reasons for inadequate control.

5-13 ROUTINE HOME TREATMENT OF DEEP VEIN THROMBOSIS
      A study in this issue of BMJ adds to the growing evidence supporting the safety and feasibility of home treatment for acute DVT. The investigators concluded that most outpatients presenting with acute DVT can be treated at home. Admission to hospital is required mainly due to infrastructure problems, rather than for medical reasons.
      Practical point: Some primary care clinicians may be able to arrange home care. It requires adequate resources.

5-14 MENINGOCOCCAL DISEASE
      A review. Smoking and inhaling smoke may predispose to meningococcemia.
      Practical point: Primary care clinicians should be prepared to administer antibiotics empirically to sick patients suspected of meningococcemia. Delay increases mortality.

5-15 MANAGEMENT OF CHRONIC TENSION-TYPE HEADACHE WITH TRICYCLIC ANTIDEPRESSANT MEDICATION, STRESS MANAGEMENT THERAPY, AND THEIR COMBINATION
      Practical point: Antidepressant medication and stress management therapy were each modestly effective in treating chronic tension-type headache. Combined therapy may be more beneficial.

5-16 RANDOMISED CROSSOVER TRIAL OF TRANSDERMAL FENTANYL AND SUSTAINED RELEASE ORAL MORPHINE FOR TREATING NON-CANCER PAIN
      Patients with chronic non-cancer pain preferred transdermal fentanyl over oral sustained release morphine. Fentanyl provided better pain relief with less constipation, and an enhanced quality of life.
      Practical point: Primary care clinicians must be able to provide adequate pain relief to patients with chronic pain, especially terminal patients. Fentanyl may be a good choice.

5-17 OPIOIDS IN CHRONIC NON-MALIGNANT PAIN
      "The use of opioids in chronic non-malignant pain is profoundly messy. A simple start is to say that if somebody has severe pain which responds to opioids, and for which there is no other effective remedy, then why should they not receive opioids?" Two judgements are then implicit: 1) that opioids are effective, and 2) that other remedies are not.
      "There is no evidence base on which we can rely other than common sense, our own experience, and that of others."
      Practical point: A trial of opioids beckons only when the many other conventional pain treatments have been tried. It should not be withheld for fear of addiction in sick patients with chronic pain.

5- 18 ORAL MUCOLYTIC DRUGS
      Practical Point: A trial of oral mucolytics may be worthwhile in patients with severe COPD.

5-19 EFFECT OF PARATHYROID HORMONE (1-34) ON FRACTURES AND BONE MINERAL DENSITY IN POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS
      Practical point: Primary care clinicians should be aware of this possibly beneficial advance. Look for general release and further information.

5-20 MICROBUBBLE CONTRAST AGENTS: A New Era in Ultrasound
      Until recently, contrast agents had little place in ultrasonography. This has changed with the introduction of microbubbles— small (typically 3 um in diameter, gas filled bubbles that are usually given intravenously). Injecting a gas into the circulation may seem potentially hazardous, but extensive clinical experience has shown that the tiny volume of air or gas given (under 200 uL) is not dangerous.
      Microbubbles work by resonating in an ultrasound beam, rapidly contracting and expanding in response to the pressure changes of the sound wave. They vibrate strongly at the high frequencies used for diagnostic ultrasound. This makes them several thousand times more reflective than normal body tissues.
      Powerful applications are emerging.

5-21 RACIAL PROFILING IN MEDICAL RESEARCH
      This editorialist maintains that attributing differences in a biological endpoint to race is not only imprecise, but also of no proven value in treating an individual patient.
      Race is a social construct, not a scientific classification.
      Sadly, the idea of race remains ingrained in clinical medicine. On ward rounds, it is routine to refer to a patient as “black”, “white”, or “Hispanic”. Yet these vague epithets lack medical relevance.
      Practical point: The editorialist has a valid moral point, but not a practical clinical application. Race still plays an important role in determining pretest probabilities.

Screening:

All adults over age 20 should have a lipid profile done every 5 years.
A complete lipid profile should be used at least as the initial test

The goals:

LDL-cholesterol -- optimal under 100 mg/dL
Total cholesterol -- optimal under 200
HDL-cholesterol --- optimal over 40
Triglycerides --- optimal under 150
(Elevated LDL-cholesterol remains the primary goal of therapy. HDL-c is also a target.)

1. Use Framingham projections of the 10-year absolute risk of coronary heart disease (CHD) to identify patients for more intensive treatment.
2. Clinical atherosclerotic disease: symptomatic carotid artery disease, peripheral artery disease, abdominal aortic aneurysm.
3. Patients with diabetes (without CHD) are raised to the same risk category as patients with established CHD. Most have multiple risk factors.
4. Identify patients with multiple metabolic risk factors (metabolic syndrome) as candidates for intensified therapeutic lifestyle.
5. Consider the metabolic syndrome as a constellation of risk factors:

   Abdominal obesity: (waist circumference: men-- > 40 in; women >35 in 1
   Elevated triglyceride: > 150 mg/dL
   Low HDL-cholesterol: < 40 for men; < 50 for women
   Raised BP: > 130/85
   Fasting glucose: > 110 mg/dL
   

6. Consider other major risk factors as increasing risk and requiring attention:

   Cigarette smoking
   Hypertension (> 140/90)
   Family history of premature CHD
   Age : men > 45; women > 55
   

1. Complete lipoprotein profile as initial test. (Ie, fasting)
2. Encourage use of plant stanols and sterols and soluble fiber to enhance lowering of LDL-cholesterol
3. Recommends treatment beyond LDL lowering for patients with triglycerides >200 (When treating high triglycerides, the primary objective is still to reach the LDL-c goal. Exercise and weight loss are essential components of triglyceride-lowering therapy.)

Treatment:

Lifestyle changes:

Diet:

25% to 35% of calories as fat
Saturated fat < 7% of calories Polyunsaturated fat < 10% of calories
Monounsaturated fat < 20% Cholesterol < 200 mg
Increase soluble fiber intake up to 25 g daily
Add plant sterols and stanols 2 g/d

Weight management
Increase physical activity

Drug therapy:

Consider lipid-modifying drugs (mainly statins)

Risk category LDL level to consider drug therapy
0 to 1 risk factor 160
2 or more risk factors
10 year risk 10-20% 130
10 year risk < 10% 160
10-year risk > 20% 130
(The higher the risk, the lower the goal for LDL-c)

Aspirin for established CHD

1. Followed over 500 middle-aged (mean age 55), overweight persons (mean BMI = 31). All had impaired glucose tolerance -- plasma glucose 140 to 200 2 hours after 75 g glucose challenge).1
   Mean fasting glucose = 110; mean 2-h glucose = 159.
2. Randomized to: 1) individualized counseling aimed at reducing weight, reducing intake of total fat and saturated fat, increasing intake of fiber, and increasing fitness, or 2) control group.
3. Performed an OGTT annually. The diagnosis of diabetes was confirmed by a second test.
4. Mean duration of follow-up = 3.2 years.

1. Mean weight loss between baseline and end of 1 year = 4.2 kg in the treatment group and 0.8 kg in the control group. Mean fasting glucose in the intervention group at 1 year declined by a mean of 4 mg/dL; 2-hour post glucose challenge declined by a mean of 15 mg/dL.
2. Cumulative incidence of diabetes after 4 years = 11% vs 23%.
3. The reduction in the incidence of diabetes was directly associated with changes in lifestyle.
4. At 4 years, 10% of treatment group had developed diabetes vs 21% % of controls. (Absolute difference = 11% ; NNT for 4 years with lifestyle changes to prevent development of one case of diabetes = 9)

1. Type 2 diabetes can be prevented by changes in lifestyle of individuals at high risk for diabetes.
2. The preventive effect of the intervention was most pronounced among subjects who made comprehensive changes in lifestyle.
3. Although the average amount of weight lost was not large, the difference between groups in incidence of diabetes was substantial. Even a relatively small loss of 5% of weight was important.
4. The conservative target of more than 4 hours of exercise per week was associated with a significant reduction in risk.
5. "The reasonably low dropout rate in our study indicates that subjects with impaired glucose tolerance are willing and able to participate in a demanding intervention program."

1. A systematic review identified 114 clinical trials in which patients were randomized to either 1) placebo or 2) no treatment. Considered 40 different clinical conditions - eg, hypertension, asthma, anemia, hyperglycemia, hypercholesterolemia, alcohol abuse, smoking, obesity, common cold, pain, and others.

   A.	32 trials (over 3700 patients) had binary outcomes ie, reported relative risks of outcomes – placebo vs no treatment
   B.	82 trials (over 4700 patients). reported continuous outcomes (ie, effect of placebos vs no treatment on a sliding scale -- eg, 0 to 100).

2. A placebo could be pharmacologic (eg, a tablet typically lactose); physical (eg, a manipulation -sham transcutaneous electrical nerve stimulation, machine turned on or off); or psychological (eg, a conversation , non-directional).

1. Binary outcomes: Compared with no treatment, placebo had no effect on binary outcomes, regardless of whether outcomes were subjective or objective.
2. Continuous outcomes: Placebo had a beneficial effect, but the effect decreased with sample size, possibly indicating bias of the smaller trials. The pooled mean difference was significant for the trials with subjective outcomes, but not for those with objective outcomes. In 27 trials involving treatment of pain, placebo had a beneficial effect -- a reduction in intensity of pain by 6 mm on a 100 mm visual analogue scale.

1. "Placebo" is difficult to define. Generally, they are control treatments with similar appearance to the study treatment, but without any specific activity.
2. The investigators admit several types of bias may have affected their findings. Blinding was not possible. Patients in the no-treatment groups would know they were not treated; those in the placebo groups would think they had received treatment.

There are 2 important clinical implications:

1) The placebo response is physiological and mediated by endogenous opioids, a system which can provide pain relief. It is wrong to assume, as many clinicians still do, that a placebo response represents imagined pain or malingering.
2) There should be more investigations into the role of placebo, not as a confounding factor interfering with study design, but as a method of enhancing the efficacy of, and reducing the variable response to analgesics and other methods of pain control.

However, there is no place for use of placebo alone in the management of pain.

1. Multicenter, randomized, placebo-controlled trial entered over 1900 patients with acute MI. All had an ejection fraction less than 40% (mean = 33%) , with or without clinical heart failure.
2. Randomized 3 to 21 days after acute MI to: 1) carvedilol beginning at 6.25 mg twice daily and gradually increased as tolerated to a maximum of 25 mg twice daily, or 2) placebo.
3. Treatment of the index MI included nitrates, intravenous beta-blockers, heparin, diuretics, and thrombolysis or primary angioplasty. Almost all patients were taking ACE inhibitors and aspirin at randomization. These patients were being treated with the best evidence-based practice.
4. Follow-up = average of 1.3 years.

1. During the trial, about 20% of the patients withdrew permanently, and about 15% died.
2. All cause mortality was lower in the carvedilol group (12% vs 15%)
   [Absolute reduction = 3%; NNT(benefit one patient over 1.3 years) = 33].
3. Combined all-cause mortality and recurrent non-fatal MI = 14% vs 20%.
   [Absolute reduction 6%; NNT (benefit one patient over 1.3 years) = 17]

1. Carvedilol was started within days of an acute MI in patients with reduced cardiac output.
2. "The results of this study show substantial benefit from carvedilol with respect to major coronary events."
3. These patients were at particularly high risk. The acute phase of MI is an intrinsically unstable period, especially in patients with left ventricular dysfunction. About one third required intravenous diuretics during the acute event.
4. Based on previous studies, the investigators calculated the benefit at one year was in addition to any benefits from ACE inhibitors given alone.

1. Multicenter study randomized over 3500 patients age 65-75. All had a history of previous myocardial infarction (MI) or unstable angina.
2. Baseline total cholesterol levels ranged from 155 mg/dL to 271 mg/dL.
3. Randomized both older and younger patients to: 1) pravastatin 40 mg daily, or 2) placebo.
4. Follow-up = 6 years.

1. As expected, older patients were at greater risk than younger patients for death, recurrent MI, unstable angina, and stroke.
2. In the older age group (65+), mortality was reduced by 21%; death from CHD reduced by 24%; MI by 26%; and stroke by 12% in the pravastatin group as compared with the placebo group
3. For every 1000 older patients treated over 6 years, pravastatin prevented 45 deaths, 33 MIs, 32 unstable angina events, 34 coronary revascularization procedures, and 13 strokes.
4. Pravastatin was well tolerated ó no significant difference in reported adverse effects compared with placebo.

1. In this cohort of high-risk older patients who previously had an MI, pravastatin was associated with a reduction in risk of major coronary events. (Secondary prevention)
2. The absolute reduction in risk was greater among older patients than among the young because of the greater risk for outcome events in the elderly. Over 6 years, 45 deaths and 47 major coronary events were prevented per 1000 older individuals vs 22 and 32 per 1000 in the younger age group.
3. The investigators believe that benefits of cholesterol-lowering therapy are so strong that drug therapy should be considered in all patients over age 65 with established coronary disease. (Secondary prevention)

1. Beginning screening: Most guidelines suggest either at age 18, or when the woman becomes sexually active.
2. Ending screening: Most authorities do not specify any specific age. Women over age 65 who have undergone regular screening can discontinue if results have been consistently normal over the years.
3. Interval between screens: Interval can be extended to as long as 3 years if 2 or 3 consecutive tests have been normal. Annual examinations are recommended for high risk groups: first sexual intercourse younger than age 18; multiple partners or a consort with multiple partners; smoking; low socio-economic status; immunodeficiency. .
4. HPV testing: Newer methods of HPV detection have led to increasing interest in the role of testing for HPV. One of the most promising uses is to determine which women with low-grade cytologic abnormalities require colposcopic evaluation. HPV can help determine which women who have a single smear showing atypical squamous cells of undetermined significance (ASCUS) should undergo colposcopy. "At present, the role of HPV testing as an adjunct to, or substitute for, established and effective cytologic screening programs has not been evaluated adequately."
5. After hysterectomy: Women who have undergone total hysterectomy for reasons other than cervical neoplasia should no longer be screened.

1. Randomized, placebo-controlled trial entered over 200 patients with CTTH (mean age 37). Mean frequency of HA = 26 headache days per month. About 25% had comorbid migraine. Patients with more severe and frequent migraine were excluded.
2. Randomized to; 1) tricyclic antidepressants amitriptyline (Elavil) up to 100 mg daily of nortriptyline (Generic) up to 75 mg daily, 2) stress management therapy (SMT: relaxation, cognitive behavior, biofeedback), 3) the two therapies combined, or 4) placebo alone
3. Doses of the antidepressants were started low and gradually increased.
4. Psychologist- or counselor-administered SMT was given in 3 one-hour clinic visits.
5. Follow-up = 6 months.

1. Tricyclic drugs, and SMT each produced larger reductions in headache activity than placebo. They also reduced analgesic use and headache-related disability.
2. Antidepressants yielded more rapid improvements.
3. Combined therapy produced a 50% reduction in headache index scores; SMT (38%); placebo (29%).
4. At 6 months, mean headache index scores, days of at least moderate pain, analgesic medication use, and headache disability scores had all decreased in the 3 active treatment groups compared with placebo alone.
   (See figure 2 p 2212). There was no great difference between the 3 active groups.

1. Antidepressants alone, and stress management alone, and the combination were effective in reducing CTTH, analgesic medication consumption, and headache-related disability.
2. Response to placebo over 6 months was nil.
3. However, only 1/3 of patients in the antidepressant-only group recorded substantial (> 50%) reductions in headache activity.
4. Some benefit was recorded from SMT alone, but there was a lag of several months. Response was good in only 1/3 of patients.
5. Almost 2/3 of patients treated with combined therapy showed clinically significant (>50%) reductions in headache index scores. But, no significant advantage for combined therapy on other outcome variables.
6. Withdrawals varied between 17% and 31% in the active treatment groups; about 50% in the placebo group.

1. Randomized, multicenter, open-label, cross-over trial entered over 250 patients with chronic non-cancer pain. Mean age = 50. All had pain (mean duration = 9 years1) which required continuous treatment with potent opioids. 75% completed the trial.
2. Pain was classified as nocioceptive (stimulation of intact nocioceptors by noxious stimuli), neuropathic, (disease or trauma of the nervous system), or combined.
3. Randomized to: 1) oral sustained release oral morphine (MS Contin) 10, 30, 60, 100, or 200 mg, or 2) fentanyl patches (Durogesic) releasing 25, 50, 75, or 100 ug per hour. Then crossed over.

1. 65% of patients preferred fentanyl; 28% preferred morphine; 7% had no preference.
2. Better pain relief was the main reason for preferring fentanyl. More patients in the fentanyl group considered pain control to be "very good" or "good (35% vs 23%). Fentanyl was reported to be as effective in neuropathic pain as in nocioceptive pain.
3. In the investigator's opinion, global efficacy of fentanyl was good or very good in 58% of patients compared with 33% of morphine patients.
4. Patients receiving fentanyl had, on average, higher quality of life scores.
5. Incidence of adverse events was similar in both groups, but more patients receiving morphine experienced constipation; 41% experienced mild to moderate cutaneous problems associated with the fentanyl patch. Overall about one quarter of patients considered their pain control poor or very poor with either treatment.2

1. Potent opioids can provide satisfactory pain relief for the difficult clinical problem of chronic non-cancer pain. Both morphine and fentanyl provided effective pain relief. But, patients generally preferred treatment with transdermal fentanyl.
2. Similar results have been observed in other studies of patients with cancer pain.
3. Individual dose titration is vital and allows for the variability in patients' response to different opioids.
4. This study used a pragmatic, clinical practice approach which the authors thought justified in the light of recent problems applying quality designs to clinical trials. The "explanatory" (evidence based) approach requires a placebo for comparison, whereas the "pragmatic" approach generally compares a new treatment with the best older treatment in clinical use for the particular clinical circumstances. Pragmatic outcome measures such as quality of life and patients' preference may ultimately provide a more accurate evaluation of treatment effects than pain measures alone.

1. Systematic (Cochrane) review of randomized controlled trials in outpatients abstracted data from 23 trials. All compared at least 2 months of regular oral mucolytics with placebo.
2. The article did not list the different preparations used. An accompanying editorial remarked that acetylcysteine was one of the most frequently used.

1. Mucolytic treatment was associated with a mean reduction on 0.8 exacerbations per patient per year.
   Based on the annualized rate of exacerbations in the control subjects of 2.7 a year. This is a 29% reduction.
2. The number needed to treat for one subject to have no exacerbation in the study period = 6.
3. Days of illness and number of days that patients took antibiotics were reduced in the treated group.
4. No difference in lung function or in adverse effects.

1. Mucolytic drugs had a modest but significant benefit on exacerbation rates in patients with COPD and chronic bronchitis.
2. "Clinicians and patients will need to judge for themselves whether the reductions in exacerbation rate and days of illness seen with mucolytic drugs are large enough to warrant daily treatment for at least 3 to 6 months a year."
3. Cost is a factor. Short course antibiotics are much less expensive.
4. Benefit may be greater in those who have more severe COPD, and in those who have more frequent severe exacerbations and require hospitalization.

1. Randomly assigned over 1600 postmenopausal women (mean age 70). All had prior vertebral fractures (Ie, a secondary prevention study.)
2. Randomized to: 1) daily 40 ug of PH 1-34 given subcutaneously, or 2) placebo.
3. Mean follow-up = 21 months.

1.  

   	PH	Placebo
   New vertebral fractures	4%	14%
   New non-vertebral fractures	3%	6%

2. Change in bone mineral density: +13 more percentage points in the lumbar spine and +6 more percentage points in the femoral neck than placebo.
3. Adverse effects were minor (occasional nausea and headache).
4. Subcutaneous PH has the greatest effect during the first 4 to 6 hours. At this time mild hypercalcemia (defined as that exceeding 10.6 mg/dL ó most less than 11.2 mg/dL) occurred at least once in 28% of women. Mean 24-hour urinary calcium excretion increased slightly in the PH group, but did not exceed 300 mg/day.

1. Daily injections of 1-34 PH increased bone mineral density of the spine and reduced the risk of new vertebral fractures and non-vertebral fractures.
2. The clinical benefits of PH 1-34 reflect its ability to stimulate bone formation and thereby increase bone mass and strength.

It has become clear that human populations are not unambiguous, clearly demarcated, biological distinct groups. Throughout history whenever different groups have come into contact, they have interbred. The continued sharing of genetic materials has maintained humankind as a single species. Any attempt to establish lines of division among biological populations is both arbitrary and subjective.