4-1 ERADICATION OF A DISEASE: How We Cured Symptomless Prostate Cancer
      “Certainly SPC was common. And now, in the new millennium, what is the frequency of this disease? Perhaps we haven’t progressed quite as far as with smallpox, but we are getting close. Symptomless prostate cancer is no longer a very rare disease.”
      What key discovery led to this remarkable reduction in frequency of SPC? The key was an inexpensive blood test called prostate specific antigen (PSA) which provided patients and their doctors with evidence of the presence of PC cells. An avalanche of studies in the past 15 years assured the end of peaceful co-existence between microscopic deposits of PC cells and their symptom-free hosts. “No longer do patients arrive for yearly checkups, enjoying their lives in blissful ignorance of their cancer. They now arrive monthly, flustered and anxious, some of them with graphs in hand. They no longer have symptomless PC, but symptomatic PC.”
      Practical point: Patients should be informed about the potential harms as well as the potential benefits of PCA testing before the test is performed.

4-2 GASTROESOPHAGEAL REFLUX, BARRETT ESOPHAGUS, AND ESOPHAGEAL CANCER
      Although strong evidence links GERD and adenocarcinoma, the risk in any given individual is low. Given the low incidence of cancer, and the lack of demonstrated efficacy of endoscopic screening, insufficient evidence exists to endorse routine endoscopy screening for patients with chronic symptoms.
      Practical point: Patients with chronic, severe symptoms of GERD may be given the results of this study, and then decide for themselves. Primary care clinicians should treat these patients with proton pump inhibitors. This will reduce the risk of erosion caused by the acid reflux.

4-3 LONG-TERM EFFECTIVENESS AND SAFETY OF PRAVASTATIN IN 9014 PATIENTS WITH CORONARY HEART DISEASE AND AVERAGE CHOLESTEROL CONCENTRATIONS: THE LIPID TRIAL FOLLOW-UP
      Long-term therapy (8 years) yields benefits in addition to 6 years treatment. Benefits of therapy continued to accumulate after years of therapy. Older patients, women, and patients with cholesterol <210 mg/dL benefit. Incidence of stroke is reduced.
      Practical point: Almost all patients with established coronary atherosclerotic heart disease should be treated with long-term statins.

4-4 TOO MUCH MEDICINE?
      Death, pain, and sickness are part of being human. All cultures have developed means to help people cope with all three. Indeed good health care can even be defined as being successful in coping with these realities.
      Modern medicine has launched an inhuman attempt to defeat death, pain, and sickness. It has sapped the will of the people to suffer reality. “People are conditioned to get things rather than to do them. They want to be taught, moved, treated, and guided rather than to learn, to heal, and to find their own way.”
      The more a society spends on health care, the more likely are its inhabitants to regard themselves as sick.
      The concept of what is and what is not a “disease” is extremely slippery. It is easy to create new diseases and new treatments. Many of life’s normal processes – birth, aging, sexuality, unhappiness, and death can be medicalized.
      Practical point: Primary care clinicians bear the responsibility of balancing medicalization with undertreatment. (Application of the “art” of medicine to the individual.)

4-5 UNDERSTANDING THE TREATMENT PREFERENCES OF SERIOUSLY ILL PEOPLE
      The desirability of an intervention depends heavily on its outcome. Elicitation of patients’ preferences should be based on outcomes rather than specific treatments
      Planning should take into account patients’ attitudes toward the burden of treatment, and the likelihood of adverse functional and cognitive outcomes. Discussions of advanced care planning should shift from whether patients would accept or reject specific treatments, to what they consider acceptable in terms of quality-of-life, the burdens of treatment, and the probability of successful outcome
      “Clearly, treatment outcomes are a strong determinant of patients’ preferences.”
      Practical point: We should try to give terminally patients the best advice about possible outcomes and then let them choose the course.

4-6 BETWEEN HOPE AND ACCEPTANCE: The Medicalization of Dying
      An active, rather than a passive approach to the care of dying people, is supplanting the fatalistic resignation of the doctor (“There is nothing more we can do”). We are challenged to find new and imaginative ways to continue caring up to the end of life.
      The challenge for palliative physicians is no different from that facing their counterparts elsewhere in medicine: how to reconcile high expectations of technical expertise with calls for a humanistic and ethical orientation.
      Practical point: Primary care clinicians should continue care and caring until the end of life.

4-7 NONALCOHOLIC FATTY LIVER DISEASE
      “NAFLD is the most common cause of abnormal liver-test results among adults in the USA. ” Obesity, type 2 diabetes, and hyperlipidemia frequently coexist. NAFLD is histologically indistinguishable from liver damage due to alcohol abuse. A net retention of lipids within hepatocytes, mostly triglycerides, is a prerequisite for NAFLD.
      Insulin resistance is the most reproducible factor. Insulin resistance and hyperinsulinism leads to fat accumulation in hepatocytes.
      Although symptoms of liver disease rarely develop in patients with steatotic livers they may be vulnerable to further injury when challenged by additional insults.
      Practical point: Another good reason to prevent and treat obesity, diabetes, and dyslipidemia.

4-8 TREATING HELICOBACTER PYLORI INFECTION IN PRIMARY CARE PATIENTS WITH UNINVESTIGATED DYSPEPSIA
      “Testing (with C-urea breath test) and treating” to eradicate H pylori in patients with uninvestigated dyspepsia provided long-term relief of symptoms and reduced health costs.
      Practical point: Patients in the USA with H pylori infection (with or without dyspepsia) should be treated.

4-9 SINGLE FLEXIBLE SIGMOIDOSCOPY SCREENING TO PREVENT COLORECTAL CANCER
      This flex-sig screening regimen was acceptable, feasible, and safe. The prevalence of neoplasia detected was high.
      Practical point: Some patients who refuse colonoscopy may accept this less stressful procedure, even if they know it is incomplete screening.

4-10 MALE CIRCUMCISION, PENILE HUMAN PAPILLOMA VIRUS INFECTION, AND CERVICAL CANCER IN FEMALE PARTNERS.
      Male circumcision was associated with a reduced risk of penile HPV.
      In the case of men with a history of multiple sexual partners, a reduced risk of cervical cancer was evident in their current female partner.
      Practical point: A reasonable indication for circumcision.

4-11 BLOOD LEVELS OF LONG CHAIN N-3 FATTY ACIDS AND THE RISK OF SUDDEN DEATH.
      These prospective data suggest that long chain n-3FA found in fish may reduce the risk of sudden death from cardiac causes, even in men without a history of cardiovascular disease. More than 50% of all sudden deaths from cardiac causes occur in people with no history of cardiac disease. Practical point: Fish are an important part of the healthy diet.

4-12 ERYTHROMYCIN-RESISTANT GROUP A STREPTOCOCCI IN SCHOOLCHILDREN IN PITTSBURGH
      A longitudinal study of schoolchildren detected the emergence of erythromycin resistance in pharyngeal isolates of group A streptococci. The clonal outbreak also affected the wider community.
      Practical point: “We recommend that macrolide antibiotics not be used for the routine treatment of pharyngitis due to group A streptococci until more epidemiological information is available.

4-13 THROMBOLYTIC THERAPY VS PRIMARY PERCUTANEOUS CORONARY INTERVENTION FOR MYOCARDIAL INFARCTION IN PATIENTS PRESENTING TO HOSPITALS WITHOUT ON-SITE CARDIAC SURGERY.
      After an extensive development program, primary PCI can be performed safely, promptly, and effectively in the community hospitals without an elective PCI or cardiac surgery program.
      Compared with thrombolysis, the availability of primary PCI resulted in a reduction in deaths, recurrent MI, and stroke.
      In this study, the absolute reduction in mortality in patients with acute ST-elevation MI was 5.5% with primary PCI vs 7.6% for thrombolysis. (NNT to prevent one death = 43). Intracranial hemorrhage was essentially eliminated.
      Practical point: “Primary PCI is considered a superior strategy both for efficacy and safety.” It should be made more available in the community.

4-14 SMOKING AND ALANINE AMINOTRANSFERASE LEVELS IN HEPATITIS C VIRUS INFECTION
      Alcohol and cigarette consumption were independently associated with elevated ALT levels among persons with HCV infection, but not among those infected with hepatitis B. “Smoking, like alcohol, is an independent promoting factor for hepatic necroinflammation.”
      The liver is a target organ for the chemicals in tobacco and alcohol. Abstinence from both would probably slow the progression of hepatitis.
      Practical point: Patients with HCV infection are strongly advised not to smoke as well as to abstain from alcohol.

1. Medline search of GERD, BE, and ACE.

1. What is the prevalence of GERD? What degree of reflux is pathologic?
         Cohort studies demonstrate that symptoms of GERD occur monthly in almost 50% of US adults.
         Because most individuals usually experience several episodes of undetected acid reflux daily, and because many others experience symptomatic reflux only rarely, defining what degree of reflux constitutes disease is uncertain. If only those who sustain tissue damage are considered to have GERD, the 30% to 70% of individuals who have painful, treatable reflux symptoms but non-erosive disease would be excluded. If all who experience occasional symptoms are labeled as having GERD, the problem may be overmedicalization, defining a symptom as a disease.
   
2. What is Barrett esophagus?
         BE is associated with increased risk of adenocarcinoma.
         BE is a metaplastic change from the normal squamous epithelium to a specialized intestinal-type columnar lining – ie, containing goblet cells. The first step is destruction of the squamous epithelium by acid. Whether BE is a necessary precursor in all cases of ACE is not known. The relative contributions of acid, pepsin, and duodenal refluxates are unclear. There are no prospective cohort studies of reflux patients to assess cancer risk.
         Individuals with erosive esophagitis and BE have, on average, more severe reflux symptoms. The degree of overlap of symptoms of those with severe tissue injury and non-erosive disease may make it difficult to identify individuals with the potential to develop complications. Even short segments of BE can evolve into CE. Length is not a risk factor.
         Five percent to 15% of those with long term reflux symptoms will have BE of some length. But even patients with only mild symptoms can develop BE. The number of individuals in the US with BE may be higher than 3 million.
         BE progresses through degrees of dysplasia before development of ACE.. The most predictive factor in progression of BE to ACE is the degree of dysplasia. The risk of ACE in those with high-grade dysplasia exceeds 25%. Some authorities have recommended resection of the esophagus for those with high grade dysplasia.. Others, citing the low incidence of incurable metastatic disease among those developing cancer suggest patients be observed closely with frequent endoscopy, reserving resection only for those who develop ACE. The optimum treatment is still undecided.
         It is clear that proton pump inhibitors do not avert progression nor cause regression.1 The reason for proton pump inhibitors in treating BE is only to relieve reflux symptoms. 1 It is unclear if surgical anti-reflux procedures diminish the likelihood of developing ACE. Endoscopic ablation treatment results are also not clear. At present these therapies are considered experimental.
   
3. What is the association between GERD and adenocarcinoma of the esophagus?
         Three large case-control studies demonstrated a positive association between reflux symptoms and risk of adenocarcinoma of the esophagus. The more prolonged and severe the symptoms the greater the risk. However, because of the low incidence of adenocarcinoma and the ubiquity of reflux symptoms, the risk of cancer in any given individual is low.
         Despite the increase in incidence of adenocarcinoma over the past 40 years, the absolute numbers of persons with the condition in the US remains low. About half of the 13 000 cancers of the esophagus seen annually in the USA are adenocarcinoma. White men have the highest risk.
         Subjects with esophageal adenocarcinoma are almost 8 times more likely to report at least weekly symptoms of reflux or regurgitation. A dose response relation exists. For long term (20 years) and severe symptoms the adjusted odds ratio of developing ACE is 43. However, since the cancer is rare even among those with frequent severe symptoms, the absolute risk in patients with GERD is low. The annual cancer incidence has been calculated to be 6500 cases for every 10 million reflux patients.
         Another problem using reflux symptoms as a marker is that many patients developing ACE never experience severe chronic reflux symptoms. The annual incidence of ACE in those who report severe GERD symptoms is less than 1 in 1000. About 40% of those who develop ACE do not have frequent symptoms. The use of reflux symptoms to stratify risk is associated with multiple epidemiological problems.
   
4. Does endoscopy for those with GERD avert death from ACE?
         No randomized trials are available to demonstrate either decreased cancer incidence or increased life expectancy in individuals who undergo screening endoscopy.
         Alarm symptoms are associated with development of ACE (dysphagia, odynophagia, anemia, weight loss, hemetemesis).
         These call for endoscopic diagnosis, or barium swallow.
         It is less clear if patients with classic reflux without alarm symptoms should undergo further testing. The American College of Gastroenterology guidelines recommend patients over age 50 with long-standing GERD have screening endoscopy to assess for the presence of BE, and presumably for ACE at a more curable stage. Despite the ACG recommendations, there are no prospective data demonstrating that periodic endoscopic surveillance prolongs life expectancy or decreases cancer mortality.
         The commentator considers these recommendations too aggressive. The incidence of ACE is low; overall risk is small. Major complications of endoscopy are approximately 1 in 1000. Mass screening of the 10 million GERD patients over age 50 would be expected to yield about 10 000 major complications to detect a cancer with an annual incidence of about 6500. The costs would be prohibitive.
         We should not ignore the potential psychosocial effects of giving patients a diagnosis of BE. “Many patients with BE are terrified that they are doomed to develop esophageal cancer.” In our zeal to prevent an uncommon cancer, we physicians should not recommend unproved and potentially harmful therapies.
         Even if BE is identified, it is not clear whether the patient will derive any benefit from this knowledge. “This message must be transmitted to patients choosing to undergo surveillance.” Even if screening endoscopy were limited to individuals considered at high risk, more than 500 yearly endoscopies would be necessary to find one ACE.
         It is not clear whether the benefits of screening endoscopy outweigh its monetary and quality-of-life costs.
   
   

1. The original 6-year study followed over 9000 patients with previous MI or unstable angina randomized to pravastatin or placebo. All had a baseline cholesterol of 150 to 270 mg/dL (4.0 to 7.0 mmol/L).
2. After completion of the original study, over 7500 of these patients were continued on open label pravastatin. Those originally receiving pravastatin were continued; the control patients were started on pravastatin:

   A	3766 originally received pravastatin 6 years then open label pravastatin for an additional 2 years.
   B	3914 received placebo controls 6 years then open label pravastatin 2 years.

1. After start of the second phase (both groups on pravastatin) mean total cholesterol and LDL-cholesterol were identical in the 2 groups for the ensuing 2 years. [174 and 102 mg/dL; 4.52; 2.65 mmol/L ]
2. Outcomes second 2 years:

   	1) Pravastatin-pravastatin	2) Control-pravastatin	Absolute difference	NNT
   Death (all causes)	5.6%	6.8%	1.2%	83
   Coronary deaths	2.8%	3.6%	0.8%	125
   CHD death or non-fatal MI	4.5%	5.2%	0.7%	143

   (Ie, continuing pravastatin for 2 years after 6 years provided additional benefit. The first 2 years of pravastatin after 6 years of placebo was not as beneficial.)
3. Outcomes total 8 years

   Death (all causes)	15.9%	19.7%	3.8%	26
   CHD mortality	8.8%	11.3%	2.5%	40
   Myocardial infarction	9.6%	12.7%	3.1%	33
   Stroke	5.0%	6.0%	1.0%	100

4. There was strong evidence of treatment benefits in subgroups in the pravastatin-pravastatin group:

   Women	15%	18%	3%	33
   Patients over age 70	15%	28%	5%	20
   Total cholesterol under 210	15%	18%	3%	33

5. Pravastatin had no significant adverse effects.

1. The absolute benefits of treatment and the strength of the evidence for effectiveness were greater for the 8-year follow-up than over the 6-year follow-up. [Ie, the difference between group 1) and group 2) in total mortality, CHD death, and stroke continued to diverge, favoring the pravastatin-pravastatin group.]
2. For every 1000 patients treated with pravastatin for 6 years, death and MI were prevented in 47. With treatment extended for 8 years, these events were prevented in 58 of 1000. With this extended follow-up, the benefits of the first 6 years of cholesterol-lowering treatment continued to accumulate at least for an additional 2 years. (Ie, the benefits in the pravastatin-pravastatin group over the additional 2 years could be attributed only to the first 6 years of treatment. )
3. The findings support the thesis that full treatment effects of statin therapy are delayed. (Ie, in the control-pravastatin group, 2 years of statin therapy did not confer as much benefit as 2 years of additional pravastatin therapy after 6 years of pravastatin therapy.
4. The long term benefits of statin drugs could be underestimated if trials extend only for 5 years.
5. There is evidence that statins reduce risks within 6 months, but not immediately This may be mediated by plaque stabilization, improved endothelial function and vascular reactivity, and reduced thrombotic tendency.
   Now there is evidence that reduction in risk continues to expand after 6 years.
6. The results also strengthen the evidence that long-term statins reduce risk of stroke.
7. Almost all patients with established coronary atherosclerotic heart disease should be treated with long-term statins.

1. Long-term therapy (8 years) yields additional benefits in risk reduction. Benefits of therapy continued to accumulate after years of therapy.
2. Older patients, women, and patients with cholesterol <210 mg/dL benefit. benefit.
3. Incidence of stroke is reduced.

1. Questionnaire asked 226 patients about treatment preferences. All were over age 60 (mean age = 73) and had a limited life expectancy due to cancer, heart failure or chronic obstructive pulmonary disease.
2. Asked whether they would want to receive a given treatment 1) when the outcome was known with certainty and 2) when different likelihoods of an adverse outcome were possible.
3. The outcome without treatment was specified as death from the underlying disease.

1. The burden of treatment (ie, the length of hospital stay, extent of testing, and invasiveness of interventions), and the likelihood of adverse outcomes all influenced treatment preferences.
2. The number who said they would choose treatment declined as the likelihood of adverse outcome increased. Fewer participants would choose treatment when the likely outcome was functional or cognitive impairment.
3. For a low burden treatment with restoration of current health, almost all said they would choose the treatment (rather than not receive it and die). Eleven percent of the participants would not choose the treatment if it had a high burden even if non-treatment led to death.
4. If the outcome was survival with severe functional impairment, 75% would choose not to receive treatment. If the outcome was cognitive impairment, 89% would refuse treatment. (Note: fear of loss of cognition was greater. RTJ )

1. The burden of treatment and the likelihood of outcomes all influenced treatment preferences. “Clearly, treatment outcomes are a strong determinant of patients’ preferences.”
2. Almost all would choose low-burden treatments if the alternative was death. But, for low-burden treatments with an outcome of cognitive impairment, almost 90% would not want therapy.
3. The proportion of participants who wished to receive therapy changed, but to a lesser degree, when the burden differed but the outcome was the same. More than 10% rejected or were undecided about high burden therapy vs only 2% who would reject low-burden therapy.
4. Many patients would not wish to receive aggressive therapy if they knew they were dying. But, uncertainty about the prognosis coupled with a “deeply held desire not to be dead” makes patients willing to undergo therapy even when they are seriously ill but not close to death. The study forced participants to choose between a particular treatment and certain death. In reality, the choice may not be so simple. If preferences are to be honored, they first must be understood. Understanding depends on assessment of how patients view the burden of treatment in relation to outcomes.
5. The predominant clinical approach now focuses on preferences with regard to specific interventions. In the absence of probability of different outcomes, this may be misleading. (Eg, the proportion of persons who say they would want to undergo cardiopulmonary resuscitation is much lower after they have been told the low probability of survival. Uninformed estimates of survival after resuscitation have been mistakenly high.)
6. Identification and correction of misconceptions are especially important. Many patients would not want to receive therapy if there was a 50% chance of severe impairment. “The possibility of functional and cognitive impairment has a particularly important role in patients’ preferences.”

1. A shift in the literature on the care of dying people, from anecdote to systemic observation and research. This suggested ways in which terminal care could be promoted.
2. A view of dying began to emerge that sought to foster concepts of dignity and meaning along with a new openness about terminal sedation.
3. An active, rather than a passive approach to the care of dying people was promoted in which fatalistic resignation of the doctor (“There is nothing more we can do”) was supplanted by a determination to find new and imaginative ways to continue caring up to the end of life.
4. A growing recognition of the interdependency of mental and physical distress created the potential for a more embodied notion of suffering. This constituted a profound challenge to the body-mind dualism on which so much medical practice of the period was predicated. The notion of “total pain” emerged.

1. An impetus to move palliative care further upstream in the disease progression, seeking integration with curative medicine and rehabilitation therapies and shifting the focus beyond terminal care.
2. A growing interest in extending the benefits of palliative care to those diseases other than cancer to make “palliative care for all” a reality. This new specialty is delicately balanced, trying to blend technical interventions with a humanistic orientation to dying patients.

Pain-free death
Open acknowledgement of the imminence of death
Death at home, surrounded by family and friends
An “aware” death – in which personal conflicts and unfinished business are resolved
Death as personal growth
Death according to personal preference and in a manner that resonates with the person’s individuality.

1. Randomized, placebo-controlled trial entered 294 patients with dyspepsia. All had a positive H pylori 13C-urea breath test.
2. Defined dyspepsia as a symptom complex of epigastric pain or discomfort thought to originate in the upper gi tract. It included any of the following additional symptoms: heartburn, acid regurgitation, excessive belching, increased abdominal bloating, nausea, feelings of slow or abnormal digestion, early satiety. (Ie, symptoms frequently encountered in uninvestigated patients seen in primary care.)
3. Patients with only heartburn, regurgitation, or both were considered to have gastro-esophageal reflux disease and were not included.
4. Randomized to treatment for 7 days with: 1) omeprazole (Prilosec), metronidazole (Flagyl) and clarithromycin (Biaxin), or 2) omeprazole + placebos.
5. Otherwise treated as usual by their primary care clinicians.
6. Treatment success defined as no symptoms or minimal symptoms of dyspepsia at the end of one year.

1. Eradication treatment cured the infection in 80%
2. At one year, eradication treatment was significantly more effective than placebo in relieving symptoms. Absolute reduction = 14% (50% success rate vs 36% for placebo. NNT = 7.)
3. Test and treat strategy reduced annual costs, primarily through decreased visits to physicians and use of fewer drugs.
4. Quality-of life showed greater improvement in the eradicated group.

1. H pylori is known to cause peptic ulcers and is linked to gastric cancer. Its association with dyspepsia remains unclear.
2. Most studies have been done in patients with investigated dyspepsia. They show at best a small benefit, about 6%.
3. Symptoms do not reliably predict endoscopic findings or allow reliable diagnosis. Symptoms of heartburn and acid regurgitation are defined as synonymous with gastro-esophageal reflux disease (GERD). (Note, in the study patients with some of these symptoms were included if they were present in addition to other symptoms of dyspepsia.) Eradication treatment of patients with GERD who test positive for H pylori either does not affect clinical course, or may worsen it.
4. Most patients with dyspepsia have multiple overlapping symptoms.
5. “Our study showed consistent results in favour of eradication of H pylori for most outcome measures.” This is consistent with the hypothesis that H pylori is responsible for dyspepsia in some patients.
6. “Our results are robust and generalizable to primary care.” Nevertheless, at least half of treated patients will require further treatment for dyspepsia.

1. A questionnaire mailed to over 350 000 persons in the UK asked about their interest in attending for flex-sig screening. 55% responded positively.
2. Over 40 000 eligible individuals (age 55-64) underwent flex-sig.
3. Patients were prepared with a self-administered phosphate enema one hour before leaving home.
4. Flex-sig was undertaken with a 60 cm video-endoscope. Carbon dioxide was used to insufflate the bowel. The endoscope was advanced as far as could be achieved without causing undue pain or distress (usually to the junction of the sigmoid and the descending colon). Sedatives were rarely used. The examination was not expected to take longer than 5 minutes.
5. Small polyps were removed during screening. Colonoscopy was undertaken for those with high-risk: (three or more adenomas; size 1 cm or greater; villous, severely dysplastic, or malignant adenomas).

1. Among those receiving flex-sig: 5% were classified as high-risk and referred for colonoscopy. The remainder with no polyps or with only low-risk polyps (which were removed) were discharged.
2. Flex-sig completed to junction of sigmoid and descending colon depended on patients’ experience of pain -- 93% of those without pain were completed; 68% of the 3% of patients who had severe pain received a complete examination.
3.  

   Numbers with distal adenomas	Men (n = 20 000)	Women (n = 20 000)
   Any	16%	8%
   Three or more	1%	0.2%
   Tubulovillous or villous	3.2%	1.6%
   Severe dysplasia	1.1%	0.4%
   High risk lesions	6.4%	2.9%
   Cancer	0.5%	0.2%

4.  

   Numbers with adenomas or cancer in the proximal colon	Men ( n = 1396)	Women (n = 655)
   Any	23%	11%
   Three or more	5%	2%
   Tubulovillous or villous	4%	2.4%
   Severe dysplasia	1.4%	0.6%
   Advanced adenomas	6%	4%
   Cancers	0.6%	0.2%

   (This was my first encounter with a remarkable difference in prevalence between the sexes. The authors mention the difference, but gave no reason. RTJ )
5. 62% of cancers were Dukes’ stage A.
6. There was one perforation after flex-sig; 4 after colonoscopy. Twelve of the flex-sig group were hospitalized for bleeding
7. Almost all said they were glad they had the test.

1. Evidence already exists from case-control studies that a single sigmoidoscopy leads to reduction in risk of fatal distal CRC by about 60%.
2. The wider use of flex-sig in the USA and removal of adenomas has been suggested as an explanation for the reduction incidence of distal (but not proximal) CRC in the USA over the past 8 years.
3. Detection rate of large adenomas with flex-sig is about 4 times higher than detection with a single FOBT. (The sensitivity of FOBT increases on repeated testing.)
4. With increasing age, the prevalence of advanced proximal neoplasia increases. A strategy to prevent proximal CRC would be more cost-effective if focused on older people.
5. In the future, nurses or technicians might be able to undertake flex-sig examining.
6. The cost differential (flex-sig vs colonoscopy) would be tremendous. This is offset by the numbers of proximal cancers which would remain undiscovered.

1. Enrolled over 1900 couples in case-control studies of cervical carcinoma in situ and cervical cancer.
2. Women:
   Cases: 977 had invasive cervical cancer or cervical carcinoma in situ.
   Controls: 936 were matched controls recruited from the general population.
3. Determined male circumcision status by self-report in stable partners of the women (defined as reporting regular intercourse for at least 6 months).
4. Determined HPV status of the penis and cervix by polymerase-chain reaction. (Valid result obtained in 1139 men.)

1. Men: penile HPV status:
   Circumcised            6%
   Uncircumcised          20%
   After adjustment for multiple potential confounders, circumcised men were less likely to have HPV. (Odds ratio = 0.37)
2. Women who were monogamous and whose circumcised male partners had 6 or more lifetime sexual partners had a lower risk of cervical cancer than monogamous women whose uncircumcised partners had 6 or more lifetime sexual partners (Odds ratio = 0.42).

1. In men, circumcision was associated with a reduced risk of penile HPV infection.
2. There was an inverse association between circumcision and risk of cervical cancers in women whose male partners engaged in sexual practices known to increase the risks of HPV infections (such as having multiple sexual partners).
3. Epidemiological evidence suggests that, in the absence of circumcision, there is an increased risk of phimosis, poor genital hygiene, genital warts, and HPV infection.
4. What mechanisms might removal of the foreskin protect against HPV? -- maintaining good penile hygiene, and less exposure to a non-keratinized mucosa. (The keratinized stratified squamous epithelium of the glans is less vulnerable to invasion by the virus than the non-keratinized mucosa of the foreskin.)
5. That male circumcision may reduce risk of cervical cancer is highly plausible. It reduces risk of penile HPV. Penile HPV infection is associated with a four-fold increase in risk of cervical cancer in the female partner. And cervical HPV is associated with a 77-fold increase in the risk of cervical cancer.

1. The Physician’s Health Study entered over 22 000 male physicians in a prospective case-control study.
2. None had history of MI, stroke, TIA, of cancer.
3. Determined FA composition on previously collected blood on:
   Cases – 94 men in whom sudden death occurred as the first manifestation of cardiovascular disease.
   Controls – 184 controls matched for age and smoking status.
4. Follow-up = 17 years.

1. Blood levels of long chain n-3FA were inversely related to risk of sudden death
2. Compared with men with blood levels of n-3FA in the lowest quartile, the relative risk of death of those in the 3rd and 4th quartiles was significantly lower. (Relative risk = 0.28 and 0.19)

1. “In this prospective case-control study of healthy male physicians without evidence of cardiovascular disease at enrollment, the base-line blood level of long chain n-3 fatty acids was inversely associated with the subsequent risk of sudden death after known confounders had been controlled for.”
2. The association was linear. As compared with men with the lowest quartile of n-3FA, those in the highest quartile had an 81 percent lower risk of sudden death.
3. The benefit may be in part to the anti-arrhythmic effects of n-3FA.
4. If the association is causal, increasing intake of n-3FA by eating more fish or by taking supplements is an intervention that could be applied with little risk.

1. Obtained surveillance throat cultures twice monthly -- October 2000 to May 2001-- in school children without infections, as well as from children with new respiratory illness.
2. Tested for erythromycin resistance.
3. Used the polymerase-chain-reaction to identify the resistance genes.

1. Obtained over 1700 throat cultures from 100 children.
2. Of these, 18% were positive for GAS.
3. Forty -eight % of the 18% were resistant to erythromycin. (Total of 9% of 1700)
4. Of 100 random cultures of children in the community, 38 were resistant to erythromycin.
5. None were resistant to clindamycin. (Cleocin)
6. The outbreak was due to a single mutated strain of GAS.

1. Beginning in the 1980s, the incidence of acute rheumatic fever increased, and serious invasive complications caused by GAS occurred while the incidence of pharyngitis due to group A remained stable. This emphasizes the need for correct diagnosis of streptococcal pharyngitis.
2. Prompt initiation of appropriate antibiotics will prevent suppurative and some non-suppurative complications of GAS. It will also reduce the pool of patients from which adults and other children acquire the infection.
3. The susceptibility of GAS to commonly prescribed antibiotics has been very stable in the USA. However, in many other countries, a high percentage of isolates are resistant to erythromycin and other macrolides. In Finland, the rates of erythromycin resistance prompted an intense effort to reduce use of macrolides. This resulted in a dramatic reduction in prevalence of resistance.
4. “We found an unexpectedly high incidence of erythromycin resistant group A streptococci among children in a single school; also a high prevalence in the community. The isolate spread very rapidly.”
5. The outbreak was due to a single clone of GAS.
6. The use of macrolide antibiotics in the USA has increased, accelerated by the wide use of short courses of azithromycin for treatment of pharyngitis, sinusitis, otitis media, and community-acquired pneumonia.
7. The children in the study were treated for GAS pharyngitis only if they had respiratory symptoms and a new positive culture for GAS. Children with resistant GAS were treated with amoxicillin, penicillin or clindamycin.
8. Children with streptococcal pharyngitis usually recover within several days, even in the absence of treatment. Only in the event of increased frequency of suppurative, invasive, or non-suppurative complications of erythromycin-resistant GAS might this trend toward resistance be detected.
9. “We recommend that macrolide antibiotics not be used for the routine treatment of pharyngitis due to group A streptococci until more epidemiological information is available, or unless susceptibility testing is first performed.”

1. Entered 11 community hospitals where neither on-site surgery nor PPCI was available.
2. Completed a formal PPCI training program at all hospitals.
3. Randomized 451 acute ST elevation MI patients (mean age = 64) to receive: 1) PPCI, or 2) accelerated tissue plasminogen activator therapy.
4. Stents and glycoprotein IIb/IIIa receptor antagonists were widely available.
5. Main outcome = composite incidence of death, recurrent MI, and stroke at 6 months.

1. Outcomes at 6 months:

   	Thrombolysis (%)	PPCI(%)	Absolute difference	NNT
   Death	7.6	5.3	2.3	43
   Recurrent MI	10.9	4.7	5.2	19
   Stroke	3.8	1.8	2.0	50
   Composite	20.4	9.9	10.5	10

2. Median length of stay in the PPCI group was 4.5 days vs 6.0 days in the thrombolysis group.
3. No patient in the PPCI group was sent for emergency CABG surgery for a PPCI-related complication.
4. Sixty nine percent of the thrombolysis group was sent to a tertiary hospital for additional care vs 31% of the PPCI group.

1. Development of this method of care must include careful, detailed attention to standards, training, logistics, and quality and error management.
2. In other studies, PPCI was superior to thrombolytic therapy only at hospitals with higher procedure volumes.
3. Median door-to-thrombolysis was 46 minutes; median time for door-to-balloon time for PPCI was 105 minutes.
4. These results are applicable only to patients with acute ST elevation MI or left bundle branch block on presenting ECG.
5. “Our study adds to the evidence suggesting that there is no need for on-site cardiac surgery to back up primary PCI.” Abrupt closure or dissection requiring emergency surgery did not occur in the trial. Actually these complications (in acute ST-elevation MI) are extremely rare in primary PCI because the infarction-related artery is usually totally occluded from the outset.
6. Coronary perforation did not occur.
7. Access to PPCI capability can be increased by extending PPCI to hospitals without on-site cardiac surgery.
8. The results do not apply to patients with unstable angina or non-diagnostic EKGs, or to elective PCI.

1. Collected a cross-sectional sample of over 6000 inhabitants in a community with hyperendemic hepatitis B and C virus infections.
2. Assayed levels of ALT, hepatitis B surface antigen, and anti-hepatitis C virus antibody.
3. Determined relation between alcohol intake and cigarette smoking and elevated ALT (defined as over 40 IU/L ) among persons with different hepatitis virus infections.

1.  

   ALT level	Under 40 U/L	Over 40 U/L
   Seropositive for hepatitis B	639	80 (11%)
   Seropositive for hepatitis C	635	282 (31%)

2. Individuals with elevated ALT were more likely to be male, to drink alcohol, and to smoke.
3. Relation of elevated ALT with smoking and alcohol consumption in those positive for HCV: Smoking 1 pack or more daily + frequent drinking 71% Smoking 1 pack or more daily + rare drinking 50% No smoking; frequent drinking 44% No smoking; occasional drinking 42% Smoking less than 1 pack daily and rare drinking 32% No smoking; rare drinking 25%
4. Compared with abstainers, odds of elevated ALT was 7-times higher for HCV seropositive patients who smoked 1 or more packs of cigarettes daily and frequently drank alcohol.
5. No significant relation of alcohol and smoking with elevated ALT among those seropositive to hepatitis B surface antigen.

1. Consumption of alcohol and cigarettes was associated with elevated ALT levels in patients positive for antibody to hepatitis C, but not among those positive for hepatitis B surface antigen.
2. Seventy five percent of those with antibodies to HCV who did not smoke or drink had normal ALT levels. Cigarettes and alcohol had an additive effect on prevalence of elevated ALT.
3. The prevalence of elevated ALT in heavy smokers who did not drink alcohol was as great as those who drank frequently and did not smoke. “Smoking, like alcohol, is an independent promoting factor for hepatic necroinflammation.”
4. The liver is a target organ for the chemicals in tobacco and alcohol. Abstinence from both would probably slow the progression of hepatitis.
5. Smoking has been shown to influence all aspects of the immune system, including alterations in humoral and cellular immunity.