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Tender red papules or nodules resembling 100 oil immersion field) to 6 (>1000 bacilli per field) buy zetia paypal. Two kinds of lepromin are smear examination commonly used: Sites of bacteriological examination are usually from the 1 order zetia with mastercard. Smears should be made by “slit and scrape” method and stained by Ziehl­Neelsen Specific serological tests can detect subclinical infection buy zetia once a day. Leprae antigen by immune­ Histopathology fluorescent technique and is useful in identifying healthy In some cases of indeterminate lesions it becomes necessary contacts of patients who are at risk of developing disease purchase zetia 10 mg line. Leprosy patients should be treated with patience, Serological testing is not useful for diagnosis as it does perseverance and understanding. Besides the medical not detect most paucibacillary cases and it remains positive treatment, the patients and their parents need moral even after treatment of multibacillary patients. Parents should be explained Molecular biological approaches hygienic measures, proper diet and importance of taking treatment completely and regularly. Based on the It is now a well known fact that, simultaneous administration gene sequences of M. Leprae, several probes have been of several different antibacterial agents may prevent the designed in recent years. These have been reported to be highly clofazimine is acceptable for children and, therefore, no sensitive and specific. When compared to histopathological like chloroquine (given orally), antimonials, e. In: In order to accelerate the elimination of leprosy as Kliegman, Behrman, Jenson, Stanton (Eds). Philadelphia: Elsevier Saunders; a public health problem in India the following activities 2008. As of 1st August 2010, more than 214 countries to 7 days after novel H1N1 infection. If illness persists and overseas territories or communities have reported beyond 7 days, person remains infective till resolution of laboratory confirmed cases of pandemic influenza H1N1 symptoms. This is of course the tip of the iceberg as is affected healthy young people more often than the elderly evident from a seroepidemiology study done from Pune, people. In India, 33% of cases were reported in 5–19 India during the peak transmission showed that the peak years of age group and 40% in 20–39 years of age group; seroprevalence was 7. Pregnancy, asthma, other lung diseases, diabetes, morbid obesity, autoimmune disorders and Antigenic shift leading to point mutations in the H and or N associated immunosuppressive therapies, neurological antigens of the circulating influenza viruses occurs regularly disorders and cardiovascular disease are some of the risk which results in outbreaks or epidemics in the community factors for increased morbidity and mortality associated from time to time. The novel H1N1 2009 strain responsible for current fever, malaise, sore throat, and headache; and recover pandemic is a re-assortant virus with gene segments from spontaneously. Up to 40% can develop gastrointestinal viruses of swine (European, North American and Asian; symptoms like diarrhea and vomiting. However this novel virus is not infective in positive for novel H1N1 virus, 2–10% of these patients swine and is actually a misnomer. Novel H1N1 2009 virus is needed hospitalization, and 30% of hospitalized patients antigenically different from the earlier human H1N1 viruses. Mortality due to pandemic H1N1 2009 It was believed that this virus has no cross protection from has been estimated to be less than 0. However we now but it is difficult to estimate as many cases are mild or sub- know that the novel H1N1 2009 virus infection is milder in clinical giving an incorrect denominator. Mean time from onset like respiratory distress, breathlessness, excessive vomiting, of disease to death is 10 days (2–22 days). Thirty percent persistent high fever, somnolence, inability to take or retain of patients with fatal pandemic influenza had secondary adequate fluids, convulsion or cyanosis, etc. They are also counseled complications following influenza infection because of to take rest and measures of infection control at home underlying medical conditions that includes those who as discussed later to prevent spread of infection to their have chronic pulmonary (including asthma), cardiovascular contacts and in community. Pending the report, they the influenza season; those aged 6 months to 18 years and are given oseltamivir. The specimen should resistant to M2 ion channel inhibitors (amantadine and be collected by experienced clinician or microbiologist. Antiviral therapy should be started as early swab should be placed in transport medium containing as possible, preferably within 48 hours of onset of illness tube and stored and transported at 4°C within 24 hours of to be maximally effective. Its sensitivity even if it is delayed at any stage of active disease when and specificity in a symptomatic patient is nearly 100%. Serological testing is not It is especially recommended in individuals at high risk of recommended as it can only tell whether the strain is type A complications like children less than 5 years of age, patients or type B and cannot differentiate between pandemic H1N1 with progressive respiratory disease including pneumonia and other type A seasonal influenza strains. Oseltamivir is the recommended treatment for to monitor drug sensitivity to oseltamivir and genetic drift lower respiratory tract complications. Surgical mask is not but the contribution of oseltamivir to these events is as effective and tends to clog within 2–4 hours making it unknown. Only N95 masks are highly Inhaled zanamivir has been temporally associated effective in preventing spread of virus, but are expensive, with bronchospasm and patients with pre-existing airway not easily available and are best used in hospital set up. Avoidance of mass gathering also will prevent supportive measures spread of virus. Closure of schools though practiced during Adequate hydration, proper nutrition, use of moist peak transmission, is not found to be effective and is oxygen, early detection of respiratory failure and timely impractical. General awareness about how the virus spreads management with moist oxygen and ventilatory support and messages regarding hand hygiene and cough etiquette are some of the important general supportive measures. Antibiotics are not used routinely and are reserved for cases with suspected secondary bacterial infection. Pneumococcus At the Healthcare Facility and Staphylococcus are important organisms involved in Healthcare personnel are at great risk of spread of virus secondary infection in pandemic influenza in children. Infection is uncontrolled mist of respiratory tract secretions of the control measures are of utmost importance in preventing patient generated like with open nebulization, suctioning spread of disease to close contacts. Use of protective gears like N95 mask (Ideal) or surgical disposable mask, head cap, and Prevention gowns; and strict hand hygiene before and after touching the patient are strongly recommended for those handling Novel H1N1 infection can be prevented by general measures patients of H1N1 influenza, which includes healthcare as well as specific vaccination. Such patients also have to be isolated in a reserved area with separate entrance and exit General Infection control measures where no or minimum human visitors are allowed. There are several 24–40 kg: 60 mg orally twice a day for 5 days manufacturers of these vaccines. Most of the manufacturers >40 kg: 75 mg orally twice a day for 5 days use chicken eggs for producing these vaccines. For infants: Vaccine Compositions <3 months: 12 mg orally twice a day for 5 days Before the current novel H1N1 pandemic, seasonal H1N1, 3–5 months: 20 mg orally twice a day for 5 days H3N2 and type B influenza viruses were co-circulating since 6–11 months: 25 mg orally twice a day for 5 days 1977. Accordingly influenza vaccine was a trivalent vaccine (Available as 75 mg per tablet and syrup containing 12 mg per ml) containing circulating seasonal H1N1, H3N2 and type B strains. Manufacturing flu vaccines is literally a race against (Duration of treatment can be extended up to 10 days in a severe case) the time. Every year the circulating virus drifts and hence Zanamivir: Zanamivir is indicated for treatment of influenza in adults and the vaccine strains change accordingly. The recommended dose for treatment of adults and laboratory collects samples isolated from patients with children from the age of 5 years is two inhalations (2 x 5 mg) twice daily influenza like illness from various sentinel sites in different 311 for 5 days. Rarely, such influenza vaccine (by August) and provides the seed vaccine virus to vaccines can cause allergic reactions such as hives, rapid the manufactures. The manufacturers then prepare vaccine swelling of deeper skin layers and tissues, asthma or a for commercial and public health use and come out with severe multisystem allergic reaction due to hypersensitivity vaccine in next 6 months so as to be used before next flu to certain vaccine components. Live vaccines are given season (by September for Northern vaccine and by March for via a nasal spray, and can commonly cause runny nose, Sothern vaccine). Wheezing and vomiting episodes have been of each of three types (total 45 µg) for more than 3 years of described in children receiving live influenza vaccines. Immunogenicity In the year 2009 novel H1N1 strain replaced the With experience of using seasonal flu vaccines in past, it circulating seasonal H1N1, H3N2 and B strains. Monovalent novel H1N1 vaccines have shown that became endemic and other strains circulating before the more than 90% of children achieve seroprotection rates pandemic started co-circulating with the pandemic strain with one or two doses. Two doses are better in children and hence in 2010, like in past, trivalent flu vaccines (live less than 3–9 years of age. H1N1 strain (A/California/7/2009 (H1N1)-like], seasonal Adjuvanted vaccines are better immunogenic and hence H3N2 strain [H3N2 (A/Perth/16/2009 (H3N2)-like], and type need lesser antigen doses than non-adjuvanted vaccines. Schedule Efficacy/Effectiveness Influenza vaccine is to be given annually as the vaccine Randomized placebo controlled vaccine efficacy trials using changes every year as discussed before. Hence recommended at 4 weeks interval in the first year for case controlled studies have looked at the effectiveness of children less than 9 years of age. In Canada, the effectiveness Inactivated flu vaccine can be used only for children was found to be 100% (79. Children from 6 months to 3 years of age receive year olds, 22% (−153 to 76) in 25–49 year olds and 41% (−71 0.

In the first trimester there may be an increased Preterm delivery Shoulder dystocia risk of miscarriage cheap zetia 10 mg with mastercard. Thereafter buy zetia 10mg otc, although there is no evi- Increase in birthweight dence of fetal harm with drinking one to two standard Stillbirth units of alcohol once or twice per week best order for zetia, there is no clear Risks to offspring of maternal obesity scientific evidence to support a quantified limit for drink- Neonatal hypoglycaemia ing in pregnancy generic 10 mg zetia mastercard. The dangers to the fetus of drinking Obesity as children and adults alcohol in pregnancy occur with greater consumption, so Diabetes that women who binge drink (more than five standard Hypertension drinks or 7. They should be informed of the adverse preg- perinatal death and developmental delay [1,13]. Alcohol misuse can result in maternal defer pregnancy until they have lost weight. Bariatric surgery results in weight loss either by reduc- ing gastric capacity (e. Roux‐en‐Y gastric bypass, biliopancreatic diversion) and Women should be advised to enter pregnancy with a 2 this weight loss results in improved fertility [15]. However, women should be advised not to get pregnant whilst they are losing weight following surgery. Maternal They are at risk of osteoporosis and nutritional deficien- and fetal outcomes improve following bariatric surgery, cies. They have an increased chance of fetal intrauterine with reduced rates of gestational diabetes, pre‐eclampsia, growth restriction and low birthweight babies. They may require referral to a comes, although few studies have compared pregnancy 42 Normal Pregnancy outcomes after different types of surgery. Unfortunately, this inaccurate belief is held by the Antihistamines public and many health professionals including doctors. Beta‐agonists Inhaled and oral steroids Many women will discontinue vital medications as soon Hormones (insulin, thyroxine) as they realize they are pregnant and risk a flare of their Laxatives disease, which will cause harm to them and their babies. A list of known teratogens and drugs safety data and can continue to be taken in pregnancy. Even if a drug is known to have a risk of teratogenicity, the consequences of discontinuing it may be worse than the effects of taking it, justifying continuation of therapy Summary box 4. If a drug with a better safety profile is ● Most commonly used medications have good safety available, it should be used instead. Delaying childbirth is associated with worsening repro- ● Second and third trimester: can cause growth restric- ductive outcomes, with more infertility, miscarriage and tion, affect neuropsychological behaviour (e. The fertility rate is taken from 10 different stage in pregnancy may have no effect on the fetus, for populations that did not use contraception between the example a teratogen will bear the risk of congenital mal- seventeenth and twentieth centuries. This provides the formation with first‐trimester use, but may be safe to use best approximation of the ability of women to conceive. Maternal Fertility rate per 1000 Spontaneous Maternal Risk of chromosomal Risk of Down’s age (years) married women miscarriages (%) age (years) abnormality syndrome 20–24 470 11 15–24 1 in 500 1 in 1500 25–29 440 12 25–29 1 in 385 1 in 1100 30–34 400 15 35 1 in 178 1 in 350 35–39 330 25 40 1 in 63 1 in 100 40–44 190 51 45 1 in 18 1 in 25 ≥45 40 93 woman in her twenties. However, it is important to remember that the absolute risk of stillbirth is still small. Maternal age the Royal College of Obstetricians and Gynaecologists states that women who start a family in their twenties or Pregnancy‐related disease 20–29 years >40 years complete it by age 35 years face significantly reduced risks. If they do delay pregnancy to their forties for whatever reason, they In current times, the fertility rate in older women is should be supported. Delaying childbirth is associated with worsening repro- the risk of pre‐existing hypertension, obesity, diabe- ductive outcomes, with more infertility, miscarriage, tes, ischaemic heart disease and cancer all increase with chromosomal abnormalities and medical comorbidity age and are twofold to fivefold greater in women over the and an increase in maternal and fetal morbidity and age of 40 compared with women in their twenties [17]. These risks need to be put into context, as the absolute incidences of these diseases are low. Maternal death in women Couples who have had a previous child with a chromo- over 40 years of age, though rare, is triple that of women somal abnormality, an inherited disease such as cystic in their early twenties [3]. Women should ling so that they can be informed of the risks of recur- be informed of these risks and advised that prenatal rence and whether prenatal diagnosis is available for diagnosis, both screening and definitive testing, is avail- detection of the disorder. Older mothers have poorer uterine contractility and a higher incidence of assisted vaginal deliveries and cae- Advice regarding access sarean sections compared with younger mothers. The to maternity care babies of older mothers are more likely to be of low birthweight and the stillbirth rate at all gestations is the importance of accessing maternity care early should higher. At 41 weeks’ gestation, the risk of a stillbirth in be emphasized to women of childbearing age contem- women aged 35–39 years is nearly double that of a plating pregnancy. They should aim to book for antenatal 44 Normal Pregnancy care as soon as possible, particularly if they have a lupus erythematosus. Women who conceive when pre‐existing medical disorder, but certainly by 10 weeks’ their disease is actively flaring are more likely to fur- gestation to allow the relevant screening tests to be ther clinically deteriorate in pregnancy, have a growth performed. Pre‐pregnancy control of diabetes directly influences ● Pulmonary arterial hypertension (mortality approxi- miscarriage and congenital malformation rates. All other blood glucose‐lowering medica- ● Marfan syndrome with aortic dilatation >4 cm. HbA1c over 10% and adequate contraception should be ● Severe renal failure (creatinine >250 mmol/L). Women should take a higher dose of folic acid the most effective contraceptive should be used in around conception as diabetes is associated with an these circumstances. Pre‐existing retinopathy can progress rapidly in pregnancy and should be treated tancy is limited, discussion on the appropriateness of having a baby (by pregnancy, surrogacy or adoption) as before pregnancy [7]. Urine should be tested for microal- well as issues of childcare in the event of maternal mor- buminuria. Women should be warned that diabetic tality or severe morbidity should be discussed. They should be reassured that they will be looked after in a multidisciplinary team if this is their Pre‐eclampsia choice. Women with a low dietary intake of calcium given cal- cium supplements at a dose of at least 1g before and Summary box 4. Women who have had pre‐eclampsia If pregnancy is not recommended due to severe maternal in a previous pregnancy have a 10% chance of recur- or fetal risks: rence. The recurrence is higher if the onset was early ● use the most effective contraceptive; (<34weeks’ gestation), and in this group administration ● discuss surrogacy and adoption if maternal life expec- of low‐dose aspirin from early pregnancy is associated tancy is not severely limited. Women should be advised to start aspirin as soon as their pregnancy test is positive. They should not take it Specific medical diseases before conception as this may increase their risk of lute- inized unruptured follicle syndrome, which can lead to In general, pregnancy outcome is better if women female subfertility. Pre-conception Counselling 45 Hypertension associated with them that pregnancy is not recom- mended (e. A deci- Women with pre‐existing hypertension should have had sion should be reached whether pregnancy should be secondary causes excluded and an assessment made of contemplated, delayed or avoided, with adequate contra- end‐organ damage in those with long‐standing hyper- ceptive advice [24]. Their current drug treatment and blood pres- the long‐term prognosis following pregnancy is sure control needs to be reviewed, with replacement of important. They should be diomyopathy) and others can deteriorate with age, informed of the increased risk of pre‐eclampsia and how increasing the risk to future pregnancies. Referral should this can be reduced by taking low‐dose aspirin once be made to a geneticist where there is a family history of pregnant. Renal impairment Women with renal disease should be advised to conceive when their degree of renal impairment is mild Summary box 4. A pregnancy in these circum- Pre‐existing medical disease stances not only increases the risk of pre‐eclampsia, ● Fully assess, and optimize medical and surgical treat- fetal growth restriction and preterm delivery, but also ment before conception. However, maternal and fetal outcomes ● Conceive when disease quiescent or well controlled. Previous pregnancy‐related disease ● Discuss recurrence risks and strategies for prevention Cardiac disease of recurrence. Women with cardiac disease should have a risk assess- ment, with full history, examination and investigations as appropriate (e. The Previous poor obstetric history effects of the cardiac disease on pregnancy and the effects of the pregnancy on the cardiac disease should be Women who have had a previous traumatic delivery or assessed, particularly the risk of deterioration, the effect adverse pregnancy outcome may benefit from a discus- of treatment or intervention in pregnancy in the event of sion with an obstetrician prior to conception. Other plans for frequency of antenatal care, requirements for conditions may require planning for alteration of antico- fetal surveillance and delivery plans to be discussed, agulation in early pregnancy (e. In: Annual Report of the Chief Seventh Report on Confidential Enquiries into Maternal Medical Officer, 2014: the Health of the 51%: Women. The conceptionstatisticsenglandandwalesreferencetables Role of Bariatric Surgery in Improving Reproductive (accessed 1 June 2016). Cochrane Database Syst Rev 2016;(1): 23 National Institute for Health and Care Excellence. The Pregnancy pregnancy in an uncomplicated fashion and deliver Book [2] provides information on the developing fetus, a healthy infant requiring little medical or midwifery antenatal care and classes, rights and benefits as well as a intervention. Undoubtedly, good antenatal care has made a ticularly important to help women understand the significant contribution to this reduction.

The recipient does not undergo general anesthesia until the donor heart has been examined and found to be satisfactory buy generic zetia canada. We usually allow 1 hour from skin incision to the arrival of the donor heart for recipients who have not undergone a previous sternotomy order zetia master card. In patients with a prior sternotomy trusted 10mg zetia, this period is extended to 2 hours to allow adequate time to complete the dissection of the native heart buy zetia 10mg visa. Right Ventricular Wall Injury In patients with a prior sternotomy and biventricular failure with a distended right ventricle, the surgeon may expose the femoral artery and vein before opening the chest. If the right ventricle is injured during sternal opening, expeditious femoral cannulation and cardiopulmonary bypass can be achieved. Recipients with right heart failure usually have liver congestion and coagulopathy, which may lead to excessive blood loss. In redo surgeries, the native heart is dissected so that the superior vena cava, inferior vena cava, and the ascending aorta are accessible for cannulation and cross-clamping. Clot Embolization Patients with end-stage heart disease and global hypokinesis are at high risk of developing left ventricular thrombus. It is important to minimize the manipulation of the native heart before aortic cross-clamping in order to reduce the risk of clot dislodgment and possible embolization. Any graft injury or manipulation leading to spasm or distal embolization of debris may result in hemodynamic instability. Cardiopulmonary bypass is initiated once the donor heart is in the operating room and the patient is cooled to 28°C. The aortic cross-clamp is applied, and cardioplegia is administered into the aortic root until the native heart is arrested. The snares around the superior and inferior venae cavae are tightened and the native heart is excised. Superiorly, the incision is extended onto the roof of the left atrium, between the superior vena cava and aorta. The incision is extended superiorly to the dome of the left atrium to meet the superior extension of the right atrial incision. Inferiorly, the incision extends across the posterior left atrial wall parallel to the coronary sinus. The inferior aspect of the right atrial incision is extended onto the medial aspect of the inferior vena cava and posterior to the coronary sinus to meet the left atrial incision. With the apex of the heart elevated out of the pericardium, this incision is extended to the base of the left atrial appendage, completing the left atrial excision. A portion of the remaining wall of the right atrium is removed, leaving cuffs of superior and inferior venae cavae. The cuffs of recipient left atrium, inferior vena cava, superior vena cava, aorta, and main pulmonary artery are prepared for anastomosis to the donor heart. Optimal hemostasis of exposed muscle in the left atrial wall is accomplished with electrocautery before bringing the donor heart onto the operative field. The vent is inserted through a purse-string suture and connected to an active suction to remove the pulmonary venous return that can warm the donor heart. Warm Ischemia of Donor Heart If a vent is not used, the accumulation of venous return from the lungs can lead to warming of the donor heart which may negatively impact the function of the allograft. The donor heart is inspected again for a patent foramen ovale and valvular lesions by the implanting surgeon. If the donor heart has been harvested with attached branch pulmonary arteries, these are incised posteriorly to create a confluence, which is then trimmed to the appropriate length. The implantation of the donor heart is begun with the left atrial anastomosis, which is started at the level of the left atrial appendage. The use of a large noncutting circular needle allows adequate bites of both the donor and recipient left atrial walls to be taken. By incorporating 8 to 10 mm of donor and recipient tissue in this everting manner, hemostasis is better ensured. This is especially important for the left atrial suture line, which is difficult to expose after the transplant is completed. Before securing the suture line, a 12-French chest tube flushed with cold plasmalyte is placed under direct vision into the left ventricle and the suture is snared around the chest tube. The flow of plasmalyte is begun and adjusted to 300 to 500 mL per hour for optimal cooling of left ventricular cavity. Malalignment of the Venae Cavae the surgeon must be sensitive to the respective positions of the recipient and donor inferior and superior venae cavae while constructing the left atrial suture line. If the inferior and superior venae cavae are not lined up appropriately, these anastomoses may be compromised. In patients with preexisting pulmonary hypertension, this suture line may be reinforced with a strip of donor pericardium. It also may occur if the donor ascending aorta and pulmonary artery are not adequately dissected free of one another. In either case, a gradient is created across the pulmonary artery anastomosis, which results in right ventricular hypertension and dysfunction. While the patient is being rewarmed, the aortic anastomosis is performed using 5-0 Prolene continuous suture. After the completion of this anastomosis, the left ventricle is deaired before reperfusion of the heart begins. The chest tube that was used for cooling the inside of the left ventricle is removed, and the left atrial suture line is secured. Modified reperfusion solution is administered into the aortic root at a pressure of 40 mm Hg for 3 to 5 minutes. After this period, the modified reperfusion is switched to leukocyte-depleted blood until the aortic cross-clamp is removed (for a minimum total of 10 minutes). There is ample experimental data suggesting that modification of the initial reperfusate improves myocardial functional recovery after regional or global ischemia. The modification of the initial reperfusate involves leukofiltration, addition of substrates such as aspartate, glutamate, and glucose for metabolism, addition of magnesium to minimize calcium influx, supplementation with dextran to reduce cellular swelling, and addition of nitroglycerin to ensure homogeneous distribution of reperfusate. During this period of reperfusion, the inferior vena caval anastomosis followed by superior vena cava anastomosis is performed using 4-0 Prolene continuous sutures. These anastomoses are performed in such a way that endocardium is attached to endocardium in an everting manner. Narrowing of Caval Anastomosis Suturing of the cavae should be done carefully to avoid narrowing or purse-stinging of the anastomosis, which could complicate future endomyocardial biopsies. This allows for direct measurement of left ventricular filling pressures during the immediate postoperative period. A left atrial line is placed through the right superior pulmonary vein and secured in place with two pledgeted Prolene sutures. Transesophageal echocardiography is always used to assess both right ventricular and left ventricular function during the weaning process. Trapped Left Atrial Line After securing the left atrial line, it is important to pull on the catheter to ensure that it can be removed easily in the postoperative period. Training the Right Ventricle Preexisting pulmonary hypertension and the effects of cardiopulmonary bypass on pulmonary vascular resistance may give rise to perioperative right ventricular dysfunction, following heart transplantation. To minimize the risk of right ventricular dysfunction and to “train” the right ventricle of the donor heart, we use a segmental strategy in weaning cardiopulmonary bypass. This entails maintaining the systemic perfusion pressure while at the same time reducing the right ventricular afterload. If the donor right ventricular function remains stable with acceptable central venous pressure, the venting of the pulmonary artery is slowly decreased and the suction tubing is removed. This “segmental weaning protocol” has been associated with a low incidence of postoperative right ventricular dysfunction. Postoperative Hypoxemia Persistence of a patent foramen ovale postoperatively can lead to right-to-left shunting and hypoxemia, especially if the pulmonary vascular resistance is high. Sinoatrial Node Injury the sinoatrial node of the donor heart should not be manipulated during harvest or implantation to minimize the risk of sinoatrial node injury. Although they can occur in any chamber of the heart, most myxomas arise from the interatrial septum and are seen most commonly in the left atrium. Venous Cannulation through the Right Atrium the introduction of large cannulas into the superior and inferior venae cavae through the right atrium may dislodge tumor fragments as well as clutter the operative field during tumor resection. The aorta is clamped, and the heart is arrested with cold blood cardioplegia administered into the aortic root (see Chapter 3).