11-1 HOMOCYSTEINE AND CARDIOVASCULAR DISEASE
      “A raised serum homocysteine concentration is a cause of cardiovascular disease.” Risk can be reduced by folic acid supplementation.

11-2 NUT AND PEANUT BUTTER CONSUMPTION AND RISK OF TYPE 2 DIABETES IN WOMEN
      Higher nut and peanut butter intake was related to a reduced risk of DM-2
      Regular nut consumption can be recommended as a replacement for consumption of refined grains and red or processed meats.

11-3 A CONTROLLED TRIAL OF A HUMAN PAPILLOMA VIRUS TYPE 16 VIRUS
      A HPV-16 vaccine given to young women reduced incidence of HPV-16 infection and cervical intraepithelial neoplasia. The vaccine may prevent cervical cancer.

11-4 TRANSIENT ISCHEMIC ATTACK – PROPOSAL FOR A NEW DEFINITION
      A TIA is a brief episode of neurological dysfunction caused by focal brain or retinal ischemia, with clinical symptoms typically lasting less than one hour, and without evidence of acute infarction.
      With the new definition, the difference between a TIA and a stroke becomes similar to the distinction between an episode of angina pectoris and a myocardial infarction. Angina is a symptom of ischemia, which is usually brief, but can be prolonged, without myocardial infarction. If there is evidence of myocardial damage, myocardial infarction is diagnosed.

11-5 TRANSIENT ISCHEMIC ATTACK: Review Article
      The high short-term risk of stroke after a TIA supports an approach involving rapid evaluation and initiation of treatment. Initial evaluation should include electrocardiography, imaging studies of the head, and Doppler ultrasonography of the carotids. Brain imaging may reveal a non-ischemic cause – eg, brain tumor or subdural hematoma.

11-6 OSTEOPOROSIS AND FRACTURES IN POSTMENOPAUSAL WOMEN USING ESTROGEN
      Estrogen replacement increases bone density and lowers probability of fractures. However, risk of osteoporosis and fractures is still high in older women even if they use estrogens for years after menopause.
      Other interventions are required to prevent osteoporosis.

11-7 EXERCISE TO REDUCE CARDIOVASCULAR RISK – HOW MUCH IS ENOUGH?
      Exercise is associated with a graded response in a number of different lipoprotein variables. The ensemble of changes is likely to be beneficial. The study documented an effect of exercise on lipoproteins with only minimal changes in body weight and provides a ray of hope for those who find it easier to exercise than lose weight.

11-8 USE OF POSTMENOPAUSAL HORMONES, ALCOHOL, AND RISK FOR INVASIVE BREAST CANCER
      Women who use PMH and consume an average of over one alcoholic drink daily had a significantly increased risk of BC, independent of the risk of using PMH alone. “Women who are currently using PMH may wish to consider the added risks of regular alcohol consumption.”

11-9 EFFECTS OF COGNITIVE TRAINING INTERVENTIONS WITH OLDER ADULTS
      Cognitive training interventions improved targeted cognitive abilities. Effects were of a magnitude equivalent to prevention of the usual amount of decline expected over 7- to 14-year intervals.

11-10 HORMONE REPLACEMENT THERAPY AND INCIDENCE OF ALZHEIMER DISEASE IN OLDER WOMEN.
      Prior HRT use was associated with reduced risk of AD. There was no apparent benefit with current use unless such use exceeded 10 years.

11-11 TREATING ACUTE GOUTY ARTHRITIS WITH SELECTIVE COX 2 INHIBITORS
      Work just as well as other NSAIDs, but no better. Is the added cost worthwhile?

11-12 DEXAMETHASONE IN ADULTS WITH BACTERIAL MENINGITIS
      In adults with acute bacterial meningitis, dexamethasone given before initiation of antibiotic therapy improved outcomes and reduced rate of death. Dexamethasone should be given before the first dose of antibiotic.

11-13 PARATHYROID HORMONE FOR TREATMENT OF OSTEOPOROSIS
      PTH increases BMD in the spine in a dose-dependent manner. But fracture reduction data are not robust, especially at non-vertebral sites. PTH may have detrimental effects on the radius BMD.
      It protects against vertebral fractures, regardless of time since menopause. Approximately the same degree of fracture reduction resulted from PTH as from the bisphosphonate, alendronate (Fosamax), and the selective estrogen receptor modulator raloxifene (Evista)

11-14 THE MULTICENTER ANEURYSM SCREENING STUDY (MASS) INTO THE EFFECT OF ABDOMINAL ANEURYSM SCREENING OF MORTALITY IN MEN.
      Substantial reductions in AAA-related mortality could be achieved by the implementation of a population-screening program for older men. Screening and following surgery was not associated with any decrease in quality-of-life.

11-15 META-ANALYSIS OF EFFECTS AND SIDE-EFFECTS OF LOW DOSAGE TRICYCLIC ANTIDEPRESSANTS IN DEPRESSION
      Treatment of depression with low dose tricyclics is effective ion many patients. Adverse effects and withdrawals are lees frequent than with “standard” doses.

11-16 WALKING AND LEISURE-TIME ACTIVITY AND RISK OF HIP FRACTURE IN POSTMENOPAUSAL WOMEN
      More leisure-time activity was associated with a lower risk of hip fractures in postmenopausal women. Moderate levels of activity, including walking, were associated with substantially lower risk.

11-17 COMPARISON OF C-REACTIVE PROTEIN AND LOW-DENSITY LIPOPROTEIN CHOLESTEROL LEVELS IN PREDICTION OF FIRST CARDIOVASCULAR EVENT.
      CRP is a stronger predictor of cardiovascular risk than LDL-c. It adds to prognostic information to that conveyed by the Framingham risk score.

1. Meta-analysis of two studies of the above 3 diseases:

   A.	72 case-control studies in which persons with the mutation of the MTHFR gene (and its resultant increase in homocysteine) were compared with controls. MTHFR mutation studies included: A. Homozygous gene (TT) patients, and B. “normal” gene (CC) patients. Mean difference in serum concentration of homocysteine between TT and CC was 2.7 umol/L. (Higher in the TT group.)
   B.	20 prospective studies comparing homocysteine levels with risk of disease.

2. Main outcome = odds ratio of the 3 diseases associated with a 5 umol/L increase in serum homocysteine.

1. There were significant associations between increased homocysteine and the 3 diseases.
2. The odds ratio for a 5 umol/L increase in serum homocysteine:

   	Ischemic heart disease	Deep vein thrombosis	Stroke
   Genetic studies	1.4	1.6	1.7
   Prospective studies	1.3	No study	1.6

3. Evidence of risk reduction:
         A previous randomized trial (“Decreased Rate of Coronary restenosis after Lowering Plasma Homocysteine Levels” NEJM 2002; 345: 1593) reported lowering homocysteine with folic acid, B12, and B6 in patients with ischemic heart disease reduced risk of coronary restenosis.
         The maximum reduction in homocysteine achieved by 800 ug folic acid is about 3 umol/L.
4. In this study, a reduction by 3 umol/L of homocysteine was associated with a reduction in risk of:

   Ischemic heart disease	Deep vein thrombosis	Stroke
   16%	25%	24%

1. “On the basis that the association is causal and reversible, we estimate that folic acid could reduce the risk of ischemic heart disease by 16%, deep vein thrombosis by 25%, and stroke by 24%.”
2. The causal association is based on these observations:

   A.	The genetic studies showed a moderate increase in risk for a moderate increase in homocysteine. The genetic linkage to some unknown risk factor might be the explanation, although no such linkage is known.
   B.	The prospective studies showed an association between homocysteine and cardiovascular disease after allowance for confounding.
   C.	These two types of study are susceptible to different sources of error, but show quantitatively similar associations, a result that is unlikely to have occurred through different potential sources of confounding acting independently.
   D.	The homocystinurias1 cause high serum levels and high risks of premature cardiovascular disease.
   E.	Lowering homocysteine reduces risk.
   F.	“In the light of these five observations, we could not have concluded otherwise.”

1. Prospectively followed over 83 000 women (age 34 to 59 at baseline). None had history of diabetes, cardiovascular disease, or cancer.
2. Dietary questionnaire at baseline, and periodically thereafter, determined consumption of nuts and peanut butter. (How often, on average, do you consume nuts (average size 1 oz) or peanut butter (1 tablespoon)?
3. Main outcome = incident DM-2
4. Follow-up = 16 years.

1. Documented over 3600 new cases of DM-2
2. After adjustment for multiple other risk factors, nut consumption was inversely associated with risk of DM-2.
   Relative risks:
   

   Almost never	< once / wk	1-4 times/wk	5 or more times /wk (5% of cohort)
   1.0	0.92	0.84	0.73

   (By my calculation from their tables, comparing consumers of nuts with non-consumers, 800 women would have to consume nuts daily for one year to benefit one person; and 1400 would have to consume peanut butter daily to benefit one. These probabilities could be meaningful on a population basis. RTJ)
3. Consumption of peanut butter was also inversely associated with risk of DM-2. Relative risk = 0.79 in those consuming peanut butter 5 times per week compared with those rarely consuming peanut butter.
4. Further adjustment for intakes of fat, cereal fiber, and other dietary factors did not appreciably change results.
5. Of interest – women who consumed more nuts:

   Generally weighed less.
   Were less likely to smoke, and more likely to exercise
   Consumed more polyunsaturated fat, dietary fiber, alcohol, and multivitamin supplements.
   Consumed a lower glycemic load and less trans fat.
   Consumed less meat and refined grain.
   (Nevertheless, the authors believed they had resolved any confounding effects. )

1. Consumption of nuts and peanut butter was inversely associated with risk of DM-2, independent of known risk factors for DM-2.
2. Recent studies suggest that specific types of fat, rather than total fat as percentage of energy play an important role in development of DM-2. (Eg, high saturated fat diet is associated with decreased insulin sensitivity compared with high monounsaturated fat diet.) Women in the highest quintile of vegetable fat had a 40% lower risk of DM-2 compared with those in the lowest quintile. Higher intake of oils, consisting mostly of polyunsaturated fat, was associated with lower fasting glucose.
3. Nuts are rich in fiber and magnesium and have a relatively low glycemic index. Some studies reported a decrease in demand for insulin.
4. There have been concerns that nut consumption may result in weight gain. In this cohort there was no association between weight gain and nut consumption.
5. Other studies have reported a beneficial effect of nuts on blood lipids and a reduced risk of coronary heart disease.
6. “It is advisable to recommend regular nut consumption as a replacement for refined grain products or red or processed meats, which would avoid increasing caloric intake.”

1. Double-blind study entered over 2300 young women (age 16 – 23). Women with evidence of HPV-16 infection at enrollment were excluded.
2. Randomized to:
   1) HPV-16 virus-like particle vaccine 3 doses at 0 month, month 2, and month 6 or
   2) Placebo vaccine.
3. Tested genital samples for HPV DNA at enrollment, one month after the third vaccination, and every 6 months thereafter.
4. Obtained biopsy tissue to evaluate for cervical intraepithelial neoplasia and HPV-16 DNA by polymerase chain reaction.
5. Primary end point = persistent HPV-16 infection, defined as the detection of HPV-16 DNA in samples obtained at two or more visits.

1. Over 1500 women were followed for a median of 17 months after completing the vaccination regimen.
2. 99.7% of women receiving the vaccine seroconverted. Mean titer of HPV-16 antibodies: 1510 mMU/mL among those receiving vaccine vs less than 6 mMU/mL in the placebo group.
   (For reference, the mean titer of HPV-16 antibodies in patients with HPV-16 infection at baseline was 26 mMU/L.)
3. Incidence of persistent HPV-16 infection:
   Placebo group -- 4 per 100 women-years at risk
   Vaccine group – 0 per 100 woman-years at risk.
4. All 41 cases of HPV-16 infection occurred in the placebo group (31 were persistent). Vaccine efficacy = 100%
5. Nine women contracted HPV-16 related cervical intraepithelial neoplasia, all in the placebo group.
6. An additional 44 cases of cervical intraepithelial neoplasia that were not associated with HPV-16 infection were detected, equally distributed between groups.
7. Adverse events were similar in the 2 groups, the most frequent was pain at the injection site.

1. The data provide evidence of a highly efficacious prophylactic vaccine against HPV-16 infection.
2. All 41 cases of new HPV-16 infection and all 9 cases of cervical intraepithelial neoplasia occurred in the placebo group.
3. Only 6 cases in which tests were positive at a single visit occurred among vaccine recipients; vs 26 cases were expected on the basis of the observed rate in the placebo group, “Assuming that all women with a single positive had a new infection, the data support the possibility that sterilizing immunity developed in some women.”
4. There was no evidence that the vaccine provided post-infection protection against either persistent infection or lesions.
5. Some women who received the vaccine were infected with other types of HPV. Cross-protection is either minimal or absent.
6. The primary reason to vaccinate is to prevent cervical cancer. Persistent HPV-16 infection is a reasonable surrogate end point, since approximately 50% of cervical cancers are associated with HPV-16 infection. ( HPV-16 is a potent carcinogen.) A broad spectrum vaccine of HPV types would be more advantageous. Multivalent vaccines are being tested.

Aspirin reduces the long-term risk of cardiovascular events after a TIA (as well as stroke). The risk of brain hemorrhage is probably less in patients with TIA, so the net benefit is likely to be greater. Start immediately.

Anticoagulation Warfarin has not been evaluated in patients with atrial fibrillation who have a TIA. In view of the benefit in stroke prevention, patients with TIA are also likely to benefit. In patients without AF, anticoagulation is no better than aspirin. What about heparin? Given the high risk of stroke after a TIA, in patients with AF and a relatively low risk of brain hemorrhage, heparin is probably justified until warfarin has produced effective anticoagulation.

Carotid endarterectomy is beneficial in patients with internal carotid stenosis of 70% to 99% who have had a TIA attributed to the stenosis. It is marginally beneficial in those with stenosis 50% to 69%. Benefits are highly dependent on surgical experience. Optimum timing of surgery is unknown. However, interventions need to be rapid to be effective. When infarction is absent, urgent surgery is probably indicated for patients who can undergo surgery with a low risk of complications.

Treatment of risk factors is likely to reduce risk of stroke after a TIA:

Statin drugs (even in patients with ”normal” lipids).
Treatment of hypertension. One recent study suggested the ACE inhibitor losartan (Cozaar) might be more beneficial in reducing risk of stroke than the beta-blocker, atenolol BP should not be lowered if the cause of TIA is likely to be due to narrowing of an artery.
Lifestyle changes – smoking cessation, exercise, weight control, moderate alcohol consumption

1. Followed over 8500 women over age 65 (mean = 70) from community settings in the USA.
2. Determined type of estrogen use and incidence of fractures.
3. Main outcomes = hip, vertebral, and other fractures. Follow-up over 10 years.

1. At baseline, 40% of continuous estrogen users (n = 373 used estrogen over a mean of 24 years until baseline) were osteopenic; 13% osteoporotic according to WHO criteria.
2. Women who currently used estrogen lost less bone than past users or never-users.
3. During 10 years of observation, the probability of non-vertebral fractures was 19% for continuous users, similar to current partial users 22%), and lower than never-users 31%). These comparisons were similar for hip and vertebral fractures.
4. Probability of an incident fracture over 4 years was 2.5% in continuous users, and 4% in never-users.

1. A substantial number of women who used estrogen continuously were osteoporotic or osteopenic. Most (80%) lost bone density.
2. Results are consistent with previous findings that women who use estrogen have a lower risk of fractures than never- or past-users, particularly if initiated early after the menopause. But, about 1 in 5 of these women experienced a fracture within 10 years. “A substantial health burden persists among women using estrogen.”
3. Other causes of fracture that are not estrogen-dependent such as falls, become more frequent with age, and may become more important than the estrogen effect.
4. Estrogen users should be considered in screening and treatment guidelines. The National Osteoporosis Foundation recommendations include the need for bone density assessments in estrogen users.
5. Other preventive measures could be added: vitamin D and calcium; exercise; bisphosphonate; raloxifene; and now, parathyroid hormone.

1. Prospective cohort study (The Nurses’ Health Study) followed over 44 000 women. (Median age = 60)
2. Repeatedly determined self-reported data on PMH use and alcohol consumption from 1980 to 1990.
3. Calculated risk of developing BC according to use.

1. During over 550 000 person-years of follow-up, 1722 women developed BC over the 10 years.
2. Relative risks of BC compared with non-users:

   Current PMH use; no alcohol	1.3
   Current use of alcohol (1.5 to 2 drinks daily): no PMH	1.3
   Current use of both PMH (5 years or more) and alcohol	2.0

3. “A hypothetical woman whose lifetime risk of breast cancer is 4% could increase her risk to 8% with 5 or more years of current PMH use and consumption of more than one alcoholic drink daily.”

1. Average alcohol intake of less than 10 g did not significantly increase the risk.
2. Current users of PMH for 5 or more years who also consumed 1.5 to 2 drinks of alcoholic had almost twice the risk of BC compared with those who did not drink alcohol and did not use PMH.
3. A hypothetical woman with a lifetime risk of BC of 4% in the absence of alcohol or PMH use would increase her risk to 6% with current PMH use for at least 5 years, and to 8% with current use of PMH for more than 5 years, and current consumption of more than one drink per day.
4. Women who used both would theoretically increase risk from 4% to 8% compared with those who used neither.
5. The effects of PMH use is most closely tied to current use. Risk decreases to baseline with past use. For alcohol the same seems to hold true.

1. Randomized, controlled trial entered a diverse sample of over 2800 volunteers age 65 to 94 (mean = 74) recruited from senior housing, community centers, and hospitals/clinics in 6 metropolitan areas. None had substantial cognitive or functional decline at baseline.
2. Randomized to one of four groups:

   1)	Memory training (Mneumonic strategies and exercises for remembering).
   2)	Inductive reasoning -- ability to solve problems that follow a serial pattern. (Understanding the pattern in every day activity and abstract reasoning tasks.).
   3)	Speed of processing (Visual search skills and ability to identify and locate visual information quickly).
   4)	No contact group.

   [See text for details]
3. Each intervention group received a 10-session intervention by certified trainers.
4. For the 3 treatment groups, 4-session booster training was offered to 60% of subjects 11 months later.
5. Main outcome = cognitive function and cognitively demanding every-day functioning. (Eg, food preparation, driving, medication use, financial management).
6. Follow-up = 2 years.

1. Each intervention improved the targeted cognitive ability as compared with baseline. 26% of the memory group, 74% of the reasoning group, and 26% of the memory group demonstrated cognitive improvement immediately after the intervention.
2. Booster training enhanced gains in speed and reasoning. The benefits were maintained at a 2-year follow-up.
3. However, no training effects on everyday functioning were detected at 2 years.

1. The study “demonstrated that cognitive interventions helped normal elderly individuals to perform better on multiple measures of the specific cognitive ability for which they were trained”.
2. It did not, however, demonstrate the generalization of such interventions in everyday performance in the initial 2 years. (Most of the subjects were functioning at high levels at baseline, leaving little room for improvement. In addition, the control group had little functional decline over 2 years.)
3. Age-related decline occurs later for everyday functioning. Declines in basic abilities such as reasoning and memory typically occur earlier in life. Because of minimal functional decline across all groups, longer follow-up is likely required to observe training effects on everyday function.
4. These interventions may have the potential to reverse age-related decline.

1. Prospective study of incident dementia entered over 1300 men and over 1800 women (mean age = 73) residing in a single county in Utah. (This is a generally healthy and long-lived population.)
2. First assessed in 1995-1997 by the Mini-Mental State examination. Followed up in 1998-2000. (Mean = 3 years)
3. Obtained history of current and former HRT use (the majority estrogen-alone), as well as calcium and vitamin D supplementation.
4. Determined association between HRT use and AD.
5. Main outcome = diagnosis of incident AD.

1. Thirty five men (2.6%) and 88 women (4.7%) developed AD between the time of the first interview and a 3-year follow-up.
2. The annual hazard for AD appeared similar for men and women before age 80. It diverged rapidly afterward with an excess risk found in women. (Adjusted hazard ratio women over 80 vs men over age 80 = 2.)
3. Among women completing the study, those who used HRT at any time had a reduced risk of AD (26 of 1066 – 2.4%) compared with non-users (58 of 800 – 7.3%). Adjusted hazard ratios were 0.4 for HRT users compared with non-users, and 0.77 compared with men. (Ie, HRT use reversed the female/male risk ratio.)
4. Risk varied with duration of HRT use. Women’s sex-specific increase in risk of AD (vs men) disappeared entirely with more than 10 years of use.
5. Almost all the HRT-related reduction in incidence reflected former use of HRT. There was no effect with current use unless duration of treatment exceeded 10 years.
6. No similar effect was seen with calcium and multivitamin use. (The authors considered this use an indicator or a healthy life-style. They therefore concluded the effect of HRT was not biased by a healthy lifestyle.)

1. The study provides new evidence to suggest a protective effect of HRT. The adjusted risk of incident AD among women who used HRT during their lifetime was reduced to more than half that among non-users.
2. Considerably stronger effects were observed with longer usage. Compared with never-users, women who had used HRT for more than 10 years experienced a 2.5-fold lower incidence compared with the risk observed in men.
3. “Taken to their logical conclusion, our findings suggest that if women were to use long-term HRT, their excess risk of AD over that of men in late old age might disappear.”
4. There is an apparent limited time window during which sustained HRT exposure seems to reduce risk of AD. In contrast with earlier use, HRT exposure within 10 years of AD onset yielded little, if any, apparent benefit. This in accord with prior findings of reduced cognitive decline in elderly women who initiated HRT at menopause, but not in those with more recent exposures. This and all prior observational studies are consonant with no benefit of HRT begun near the onset of dementia. (This finding is similar to those reported by use of NSAIDs in reducing risk of AD.) This suggests that HRT, to be protective, may be useful only if taken in the latent pathogenic stages of AD. There is also no evidence of benefit from HRT in patients with established AD.
5. The study attempted to control for “healthy user” biases. However, the investigators state that all observational studies are subject to unsuspected confounding, and do not suggest that these results are generalizable to other populations.
6. “Benefits of HRT, if any, may take years to appear, and a considerable latency period may intervene between treatment and perceptible effects.”

Intra-articular corticosteroids (methyl prednisolone 5 – 24 mg per joint)
Oral corticosteroids (prednisone 20 mg/d tapered over 4 to 10 days)
Parenteral corticosteroid (intramuscular triamcinolone 60 mg/d, repeated in 1 -4 days)
ACTH 40 – 80 units (intramuscular every 6 – 24 hours)

1. Prospective, randomized, double-blind study entered over 300 patients (mean age 45) with acute bacterial meningitis.
2. Organisms included: Streptococcus pneumoniae (35%) ; Neisseria meningitides (33%); other bacteria (10%); and negative culture (22%).
3. Randomized to:
   1) Dexamethasone 10 mg up to 20 minutes before first dose of antibiotic and every 6 hours thereafter for 4 days, or 2) Placebo.
4. Primary outcome = score on the Glasgow Outcome Scale at 8 weeks.
   Glasgow Outcome scale score:

   Death	1
   Vegetative state	2
   Unable to be independent	3
   Living independently, but unable to return to work	4
   Mild or no disability able to return to work	5

1. Dexamethasone was associated with a reduction in risk: (Relative risk -- dexamethasone vs placebo):
   Unfavorable outcomes (1,2,3 and 4 on the scale)

   Strep pneumoniae	0.5 (Statistically significant)
   N. meningitidis	0.75
   Other bacteria	2.8
   Negative culture	0.4

   
   Death

   Strep pneumoniae	0.5 (Statistically significant)
   N. meningitidis	0.75
   Other bacteria	2.8
   Negative culture	0.4

2. Focal neurological abnormalities and hearing loss were less frequent in the dexamethasone group, but not at a statistically significant level.
3. Among those with pneumococcal meningitis, unfavorable outcomes were 26% in the dexamethasone group vs 52% in the placebo group.

1. Early treatment with dexamethasone improved outcomes in some adults with acute bacterial meningitis, reducing rate of death and unfavorable outcomes.
2. The benefit was most evident in patients with pneumococcal meningitis. A beneficial effect in those with meningococcal meningitis could not be ruled out.
3. The investigators recommend dexamethasone treatment for all patients with acute bacterial meningitis.
4. The delay in initiation antibiotic therapy in this cohort was a matter of concern. In the setting of suspected acute bacterial meningitis, antibiotic therapy should be started empirically immediately. Don’t wait for a CT scan or lumbar puncture before starting treatment when meningitis is suspected.
5. Dexamethasone has been shown to be beneficial in children only if given before the first dose of antibiotic.
6. Monotherapy with amoxicillin was the initial treatment. Resistance of the pneumococcus and meningococcus to amoxicillin is very low.

1. Systematic review found 20 randomized trials involving PTH and postmenopausal osteoporosis. Trials were heterogeneous. Treatment duration and the dose of PTH varied. PTH was usually given subcutaneously daily. Almost all trials used human PHT (1-34). Most subjects also took supplemental calcium/vitamin D.

1. In the range of 50 to 100 ug/d, effects were dose-related. Increases in BMD of the lumbar spine ranged from 4% to 9%. Some increase in BMD also occurred in the total hip, femoral neck, and femoral trochanter. Effects were evident within 9 to 12 months.
2. PTH decreased the incidence of radiographically detected spinal fractures. It also reduces the corollary – pain.
3. One trial comparing PTH alone vs PTH + estrogen reported combination therapy was superior in increasing BMD of the spine and total hip.
4. Trials suggested detrimental effects on BMD of the radius. Some studies, however, reported that PTH recipients were less likely to experience non-vertebral fractures as compared with the placebo group, but results were conflicting.
5. Benefit was also demonstrated in patients with glucocorticoid-induced osteoporosis.
6. Some patients found compliance with the injections difficult. Withdrawals were more frequent in the PTH groups.
7. No serious adverse effects were reported. Mild hypercalcemia was occasionally reported. It was dose-dependent, but remaining within the normal range. Levels decreased with lowering of calcium intake.
8. An increase in cancer was not reported.

1. Entered a population-based sample of men (over 68 000 -- age 65-74).
2. Randomized to:
   1) US to detect possible AAA (n = over 27 000)
   2) Control group
3. Determined maximum transverse diameter and maximum anterior-posterior diameters. Men with aortas less than 3 cm were not rescanned.
4. Men in whom AAA was over 3 cm in diameter were followed with repeat US for a mean of 4 years.
5. Surgery was considered if: 1) diameter was 5.5 cm or more, 2) expansion over 1 cm per year, or 3) symptoms occurred.
6. Obtained mortality data and assessed quality-of-life scores.
7. Primary outcome = mortality related to AAA.

1. In over 27 000 men screened, 1333 AAAs were detected. (5% of men age 65-74 had AAA):
2. Operations:
         Screened group = 354
         Controls = 146
3. AAA related deaths over 4 years:
         Screened group – 65 (absolute risk = 0.19%)
         Controls – 113 (absolute risk = 0.33%)
         Absolute benefit in reducing death = 0.14%. [NNT to benefit one patient = 714]
4. Thirty day mortality after elective surgery = 6%; after emergency surgery = 37%.
5. Quality-of-life assessments at all times and across all groups were within age-matched population norms. Those who underwent surgery rated their health equal to those who screened negative.

1. “Screening can significantly reduce mortality rates associated with abdominal aortic aneurysms.”
2. Because many aneurysms were detected in the screened group and required treatment in the first 1-2 years, the investigators anticipated that the mortality in the invited groups might exceed that of the control group over this period due to surgical mortality. However, this did not occur. The postoperative mortality was low
3. For men age 65-74, over 700 would need to be screened to prevent one death.
4. Screening was not associated with any adverse effects on the emotional state of men who had an AAA detected.
5. Few new AAAs will develop and proceed to rupture within an interval of less than 10 years. A national screening program could logically consist of a single screen at age 65.

1. Conducted a systematic review of randomized trials comparing low dosage of tricyclics with placebo, and with standard dose the same tricyclic for adults in treatment of the acute phase of depression. Low dose defined as 100 mg or less per day of amitriptyline (Elavil), clomipramine (Generic), or desipramine (Norpramin; generic ) and others. Standard dose defined as over 100 mg/d.
2. Main outcome = response in depression according to the author’s definition (usually defined as greater than 50% reduction in severity of depression).
3. Also determined relative risks of overall dropouts and dropouts due to side-effects.

1. Thirty five studies (over 2000 participants) compared low-dose TC with placebo:
         Low dose (usually 75 to 100 mg/d) was 1.7 times more effective than placebo in bringing about response at 4 weeks, and 1.5 times more effective at 6 to 8 weeks.
2. Six studies (551 participants) compared low-dose TC with standard dose:
         Standard doses failed to bring about more response, but produced more dropouts due to side-effects than low-dose. (Standard dose users were 55% more likely than low-dose users to drop out due to side-effects.)

1. Compared with placebo, low dose TC (75 to 100 mg/d) and possibly below this dose, brought about more reduction in depression at 4 to 8 weeks and beyond. However, there were more side effects and more dropouts. The number needed to treat to bring about response in depression was between 4 and 6 at 1-6 months of treatment. The NNT to harm or produce one dropout due of side-effects was about 24.
2. Standard dosage TC may or may not be able to bring about more reduction in depression than low-dosage, although they cause more dropouts due to side-effects than placebo. (NNT to harm = about 11.)
3. “These sensitivity analyses greatly strengthen the inference that in the treatment of depression, tricyclics at dosages lower than the usually recommended range, are more effective than placebo, but possibly a little bit less effective than standard dosage of tricyclics, although with fewer side effects.”

1. Nurse’s Health Study followed over 61 000 postmenopausal women for 12 years. None had diagnosis of cancer, stroke, heart disease, or osteoporosis at baseline.
2. Repeated questionnaires determined intensity and duration of leisure-time activity and time spent walking, sitting, and standing.
3. Determined rate of hip fracture resulting from low or moderate trauma.

1. Identified 415 incident hip fractures. Median age at fracture was 67 years.
2. After controlling for age, bone mass index, use of postmenopausal hormones, smoking, and dietary intakes, risk of hip fracture was lowered by 6% for each increase in 3 metabolic equivalent-hours (MET-hours per week) of activity (equivalent to 1 h/ week of walking at an average pace).
3. Active women with at least 24 MET-hours/week had a 55% lower risk (RR = 0.45) compared with sedentary women with less than 3 MET-hours/week.
4. Even women at lower risk of hip fracture due to a higher body weight experienced a decrease in hip fracture with higher levels of activity.
5. Risk of hip fracture decreased linearly with increasing levels of activity among women who were not taking postmenopausal hormones, but not among women taking hormones.
6. Among women who did no other exercise, walking for at least 4 hours/week was associated with a 41% lower risk of hip fracture, compared with those with less than 1 hour/week.
7. More time spent standing was also independently associated with lower risk.

1. Total physical activity from exercise and leisure-time activity was associated with significantly lowered risk of hip fracture. A faster pace was also associated with a lower risk, perhaps because of a greater impact on bone.
2. Incidence of hip fracture decreased by 6% for each hour per week of walking an average pace.
3. Activity must be maintained to preserve the benefit.
4. In clinical studies, a combination of HRT plus exercise has been reported to increase bone mineral density more than exercise alone. In this study, active women not taking HRT had similar protection against hip fracture as that provided by HRT.
5. Activities that promote balance and flexibility are also important in reducing risk of falling. Weight bearing and resistance exercises can increase muscle size and strength, and lead to higher bone density.
6. Standing was also associated with a lower risk of hip fracture, independent of body-weight and time spent in leisure-time activities.. As a weight bearing activity, standing could confer benefits to balance and muscle that may translate into improved bone strength and protection against hip fracture.

1. At baseline, the Woman’s Health Study measured both CRP and LDL-c in a representative sample of over 27 000 apparently healthy women.
2. Followed for a mean of 8 years for occurrence of MI, ischemic stroke, coronary revascularization, or death from cardiovascular disease.
3. Evaluated whether CRP provided prognostic information on risk after adjustment for all components of the Framingham risk score.

1. The median CRP value was 1.52 mg/dL; median LDL-c was 124 mg/dL: Overall, 77% of all events occurred in women with LDL-c below 160 mg/dL. 46% occurred among those with LDL-c below 130 mg/dL.
2. CRP and LDL-c were minimally correlated. (Ie, rose independently of each other. They identify different high-risk groups.)
3. Baseline levels of both CRP and LDL-c had a strong linear relationship with the incidence of cardiovascular events. After adjustment for other risk factors, the risk of a first cardiovascular event rose according to increasing quintiles of CRP and LDL-c.

   Relative risks	1 (lowest level)	2	3	4	5 (highest level)
   CRP	1.00	1.4	1.6	2.0	2.3
   LDL-c	1.00	0.9	1.1	1.3	1.5

4. Similar effects were observed in separate analyses of each component of the composite end-point.
5. Screening with both biologic markers provided better prognostic information than screening with either alone. Relative risks of an event according to both CRP and LDL-c levels:

   Relative risk of event	Events per 1000 person-years
   1) Low-CRP and a low LDH-c, -- 1.0 (referent)	1.3
   2) Low CRP; high LDL-c -- 1.5	2.0
   3) High CRP; low LDL-c – 1.5	2.6
   4) High CRP; high LDL-c – 2.1	3.0

6. CRP remained a strong, independent predictor of risk, rising with each quintile.
7. Increasing CRP levels were associated with increased risk of events at LDL-levels below 130, 130 to 160, and above 160 mg/dL.
8. Independent effects were observed for CRP in analyses adjusted for all components of the Framingham risk score. (Ie, added to prognostic value of the score.)

1. CRP, a marker of systemic inflammation, is a stronger predictor of future cardiovascular events in women than LDL-c.
2. CRP was superior to LDL-c in predicting risk at all study end-points: MI, stroke, revascularization, and death.
3. CRP and LDL-c were minimally correlated in predicting events. The combined elevation of both CRP and LDL-c was superior as a method of risk detection.
4. Since a large proportion of a first cardiovascular event occurs in individuals with “normal” LDL-c levels, and below the threshold values for intervention and treatment according to the current guidelines, addition of CRP increases prognostic value.
5. Women with low-LDL-c but with high CRP were at higher absolute risk than those with a low CRP and a high LDL-c. Statin therapy may have clinical value for primary prevention among persons with low LDL-c and high CRP.
6. CRP is stable over long periods, has no diurnal variation, and can be measured inexpensively.