By P. Ramirez. Ottawa University. 2019.

Clinical characteristics of coronary heart disease in women: Emphasis on gender differences buy 5mg finasteride free shipping. Cardiovascular front and back of the index and long fingers buy finasteride online, as well as Research generic 1mg finasteride with amex, 53, 558567. The median nerve and the tendons that flex women may be due to the smaller size of the carpal tun- and extend the fingers pass through this small tunnel. Repetitive bend- ment of the diagnosing physician and are dependent ing and extending of the tendons in the hands and upon many considerations. Such postures of the hands the case of factors related to the workplace to evalu- and wrists often occur in job-related circumstances in ate the work environment, including the workstation which the worker might perform repeated movements and the tools themselves; the repetitive movements of the hands; hold the wrist in awkward postures, such involved in getting a task accomplished; and the as in a bent position; use forceful grips such as holding possibility of incorporating rest breaks or rotating to a tool too tightly because it is too big or heavy; or exert different jobs. What you need to checking, carpentry, and other jobs where there is a know about carpal tunnel syndrome: A physical therapists per- combination of highly repetitive, forceful work have spective. Today, due to advances in medical instru- Suggested Resources mentation and surgical technique, an extracapsular Mayo Clinic. Once the natural lens is removed, a new one must replace it to focus the eye and provide clear vision. This can be done in three ways: Cataract A cataract is a clouding of the eyes natural 1. This is the oldest method, and for quite can cause a little blur in vision to near total loss of vision. The glasses The rate at which a cataract will progress is highly vari- required after cataract surgery are thick; they give good able. A cataract is not a film over the eye that can be central vision but the side vision is compromised. A cataract is not visible in the mirror unless Objects are magnified by 25% which makes it difficult it is very dense. Generally, waiting to have a cataract removed poor choice and almost never done presently. Difficulty arises due symptoms which patients experience will help to decide to trouble inserting the lens, irritation caused by the whether to proceed with surgery. The lens ished vision interferes with daily living patterns and is placed in the eye in nearly every cataract operation removing the cataract is worth the rare risks involved. Excellent results have placed intraoc- The majority of cataracts are formed later in life as ular lenses well beyond the experimental stage. Some patients develop last 20 years, over 5 million intraocular implants have cataracts earlier than others. Cataracts can develop as a result of injury, chronic tions, the lens need not be replaced. It does not have eye disease, systemic diseases (such as diabetes), and to be removed to be cleaned at any time. Cataracts are not caused Intraocular lenses that we use are placed in one of by reading, watching too much television, sewing, or two locations. Vitamins place for the implanted lens as it is the position where and herbal remedies have not been proven to prevent the natural lens existed. In The only treatment now for cataracts is surgical some patients, this may be the only option if the mem- removal. Laser surgery at present is not Intraocular lenses may be inserted after a previous used to remove cataracts. There are several ways to surgery when the patient did not originally have any 143 Cervical Cancer implant inserted. Many surgeons feel that the placement is detected early, it can be reattached surgically with of a lens as a second procedure is somewhat less satis- usually little vision loss. Macular edema or swelling of factory and more hazardous than placing it at the time the macula (the center of the retina) may occur in of surgery, but many thousands of lens implants have 20% of cases. Glaucoma may In the old days, cataract surgery involved pro- occur after cataract surgery, but usually can be con- longed hospitalization and sand bags for immobiliza- trolled with drops. Many people remember their grandparents During surgery, the membrane that supports the undergoing this type of operation and are unnecessar- implant may be too weak and part of the cataract may ily alarmed about surgery. This has happened to nearly all techniques, cataract surgery has become safer and heal- cataract surgeons. The surgery is plication is usually to have a retinal surgeon remove the done on an outpatient basis. The operation is performed under a local anesthe- It should be emphasized that cataract surgery is sia, with monitoring of the patients heart rate and blood very safe in the majority of cases. Future developments will be performed with a block anesthesia injection around make the operation even safer and more rewarding for the eye or performed just with topical eyedrop anes- both the patient and the surgeon. Eyedrops are taken before and after the The American Academy of Ophthalmology: www. It may be impossible to predict who may develop an important worldwide health problem. A rare complication may be dislocation of the Death rates in the developing countries from this intraocular lens implant and it may need to be reposi- disease are similar to death rates from breast cancer and tioned. Infection is a very serious complication, use of screening tests such as the Pap smear has both which can significantly reduce vision after surgery. To reduced the number of women getting the disease and help prevent this, eyelashes are draped and the face improved the chances of surviving the disease. Hemorrhage or entry, we will review the risk factors for cervical cancer bleeding is a complication that can range from mild to and its precursor, cervical dysplasia, the screening very serious. The worst bleed is called an expulsive methods available, and the basics about the symptoms hemorrhage and can leave the eye without vision. If a patient is very nearsighted or myopic, there is a greater Many women are not aware of the fact that cervi- risk of developing a retinal detachment. This test has been shown to be able to identify as: early age at first intercourse, multiple sexual part- women who do not need to proceed with colposcopy ners, or having a partner with multiple sexual partners. Problems in the cer- Cervical dysplasia causes no symptoms in most vical cells leading to cervical cancer can take years to women. In women with undetected or untreated cervi- occur, or in many women will never occur at all. Symptoms of more virus can enter the cells of the zone of the cervix called advanced disease include pelvic or back pain or the transition zone. Although the Pap test is designed to look for dysplasia, it can also be read as All cancers are assigned a stage which is a repre- abnormal due to other changes such as inflammation sentation of how advanced it is when it is diagnosed. The stage helps to determine both the treatment options For that reason, when a Pap smear is abnormal, an and the prognosis. In cervical cancer, Stage I disease examination of the cervix with a microscope called a refers to cancer that has not progressed beyond the colposcope and actual biopsies of the cervix are done. In some cases of advanced dis- In some cases, a woman may undergo radical ease, surgery will be used to obtain more information hysterectomy designed to be the definitive treatment, prior to making a treatment plan. This may include but then may require radiation after surgery due to find- cystoscopy (looking in the bladder with a telescope), ings at the time of surgery, such as cancer spread to the proctoscopy (looking in the rectum with a telescope), lymph nodes. Surgical options, the side effects which is a cone-shaped removal of the outer cervix. These who undergo treatment for this disease are able to are highly effective treatments and result in cure rates recover complete function and do not suffer from last- over 95%.

Early lesions display quite unspecifc changes with dilatation of the papillary capillaries discount 5mg finasteride with amex, oedema and a mononuclear infltrate purchase finasteride amex, from which fewer cells exocytose into the lower epi- dermis (Braun-Falco and Christophers buy finasteride 5 mg fast delivery, 1974). Only then, epidermal changes develop with parakeratosis (incomplete cornifcation) and disappearance of the granular layer. At this stage the phenomenon of the squirting papillae occurs, with release of neutrophilic gran- ulocytes (Pinkus and Mehregan, 1966) from the dermal capillaries. The fully developed lesions are characterized by acanthosis (thickening of the epider- mis), elongated rete ridges with ofen club-shaped dermal papillae and thinning of the su- prapapillary layers of the epidermis (Fig. Only the intra-epidermal pustules or microab- scesses, however, represent fully pathognomonic features of psoriasis. Tey become pre- dominant in pustular psoriasis, with spongiform macropustules in a degenerated epider- mis (Shelley and Kirschbaum, 1961). Histopathology with acanthosis, parakeratosis, loss of granular cell layer 9 Gene expression analysis Large scale gene expression analysis of afected and unafected psoriatic skin as well as skin from healthy individuals demonstrated that more than 1300 genes are diferentially ex- pressed in psoriatic infammation. Tey refect the diferent compartments involved in the pathogenic cas- cade (Bowcock et al. Interestingly, gene expression revealed no diference between type 1 and type 2 psoriasis patients. Environmental factors Troat infections with group A -haemolytic streptococci are the most frequent trigger of psoriasis onset, but may also induce relapses. Reports on the incidence of streptococ- cal throat infection preceding frst psoriasis onset range from 56 to 97% (Norrlind, 1954; Tervaert and Esseveld, 1970). Tese factors somehow seem to act on the genetic predisposition to turn the latent state into the full psoriatic phenotype. Immune mechanisms in the pathogenesis of psoriasis Several fully reversible features shape the clinical appearance of psoriasis. Tey include a strong increase in keratinocyte proliferation and epidermal turnover, accumulation of neu- trophilic granulocytes, infammatory changes with elongation of the papillary capillaries, and a mononuclear infltrate with activated T cells. Intensive analysis of these compartments, however, did not reveal clues to ex- plain the pathogenesis of psoriasis. T cell activation in psoriasis Recent progress in the understanding of psoriasis vulgaris has suggested that activation of the specifc cellular immune system, particularly T cells, in the skin is an essential step in disease manifestation, and that it is responsible for all the diferent lesional psoriatic changes including the increased keratinocyte proliferation (Fig. The T cells accused for mediating psoriasis constitute a dense infammatory infltrate in the papillary dermis and, to a much lesser degree, in the epidermis. Tey mediate binding of T cells to the endothelium of the postcapillary venules and thus promote extravasation and migration into the dermal extracellular matrix. Functional analysis of T cells isolated and cloned from these infltrates revealed that a substantial proportion was capable of stimulating the proliferation of keratinocyte by the secretion of mediators (Prinz et al. Whether a particular hyperresponsiveness of psoriatic keratinocytes to growth promoting signals from T cells is involved in this efect is still a matter of investigation. Studies on cytokine secretion fur- thermore suggested, that the lesional T cells represent a particular regulatory T cell sub- set. Tey produce a particular cytokine pattern that by its biological activities should be able to mediate the features of psoriasis (Vollmer et al. Tese cytokines mediate epidermal hyperplasia, acantho- sis, hyperparakeratosis and orthohyperkeratosis (Nestle et al. This combination may result in a failure to constrain the activation and proliferation of patho- genic T cells, contributing to the ongoing infammation seen in psoriasis. Hence strate- gies that correct Treg function or increase the Treg: pathogenic T cell ratio may be poten- tial treatments for psoriasis. The same clonally expanded T cell populations were associated with the le- sional psoriatic immune response over prolonged periods of time and in relapsing disease (Chang et al. Tese results emphasize that the pso- riatic immune response involves a restricted subset of clonally expanded T cells. It is ap- parently induced against antigens, which are continuously present within the psoriatic skin lesions, and it shows no signs of epitope spreading. Potential autoantigens were identifed by molecular mimicry with an- tigens from Streptococcus pyogenes, which is the main infectious trigger of psoriasis. Identical T-cell clones in psoriatic skin lesions and tonsils of patients with streptococcal-driven psoriasis as well as the improvement of psoriasis fol- lowing tonsillectomy in these patients support that T cells may represent a cellular link be- 332 Arnd Jacobi and Jrg Christoph Prinz tween streptococcal infection and psoriatic immune activation (Diluvio et al. The classical psoriatic skin lesion is a well-defned sharply demarcated plaque of salmon pink colour covered with a variable amount of silvery scales (erythemato-squamous plaques). Scratching of the scaling reveals a 9 glossy, red, dry membrane that upon further removal develops small bleeding points from the elongated papillary capillaries (Auspitz sign). The extend may vary from a few small lesions to extensive confuent plaques that cover large areas of the body. Acute guttate psoriasis shows small pinpoint lesions with ofen only little scaling that are tightly scattered over trunk and limbs, less frequently also on face and scalp. It develops as acute, exanthematic form particularly afer streptococcal throat infections in frst onset psoriasis, but also in acute psoriasis relapses. Modification by site The scalp is ofen involved with infammation and scaling that extends approximately 1 cm onto the forehead. Taenia amiantacea can be considered as the most severe form of shell- like, frmly adherent scales. Although hair loss is not a prevailing sign of scalp psoriasis, a difuse reversible infammatory efuvium may develop. Fingernails and toenails may be afected in two diferent ways: psoriasis of nailbed and hyponychium leads to subungual hyperkeratosis, onycholysis, and yellow discoloration (oil drop). Small indentations (pitting), grooves and ridges of the nail result from psoriatic in- volvement of the nail matrix. Psoriasis of palms and soles is characterized by scaling, hyperkeratotic erythemata or in- tra-epidermal yellow, later on brown pustules. Different clinical manifestations of psoriasis Clinical variants Accumulation of neutrophilic granulocytes in small intra-epidermal microabscesses is a pathognomonic feature of psoriatic skin lesions. If this aspect becomes more pronounced macroscopic visible sterile pustules develop on the skin, leading to pustular psoriasis. Two main forms are distinguished: psoriasis of early onset may develop into pustular psoria- sis under certain circumstances such as withdrawal of internal steroids or external irrita- 334 Arnd Jacobi and Jrg Christoph Prinz tion or high eruption pressure (psoriasis cum pustulatione, generalized pustular psoriasis von Zumbusch). In erythrodermic psoriasis psoriatic infammation has become generalized with highly infammatory, exfoliative erythema and profuse scaling of the whole skin. Together with generalized pustular psoriasis it represents the most severe form of psoriasis and may be- come live-threatening. Psoriatic arthritis is defned as the association of psoriasis with peripheral or spinal ar- thropathy and negative serological tests for rheumatoid arthritis. The incidence of arthritis in psoriasis patients ranges from ~ 5 to 40%, depending on the diagnostic criteria included. In 65% of psoriatic arthritis patients psoriatic skin lesions preceded arthritis, in 16% joint and skin afection appeared simultaneously, and in 19% skin lesions developed afer arthri- tis onset. The classifcation of Wright and Moll distinguishes fve subgroups of psoriatic arthritis (Moll and Wright, 1973).

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This was aprospective randomized open single-blind purchase finasteride 1 mg otc, parallel-group study with blinded endpoints discount finasteride amex. In Group 1 (n=26) Bs was uptitrated to 5mg pd and Ivabradine was added (5mg bid uptitrated to 7 order finasteride 5 mg on-line,5 mg or maximal tolerated dose). Due to withdrawal of informed consent after randomization by 4 Group 1 patients per protocol were assessed 22 patients. At baseline (M0) and 2 months (M2) patients were examined according to the trial protocol. The treadmill test was perfomed according to the Bruce symptom-limited protocol in the morning and in the fasting state at the trough of drugs activity (12h after last intake of ivabradine and 24h after last intake of Bs). Nonparametric criteria were used to measure the significance of the differences between mean values: the Wilcoxon criterion for dependent variables and Mann- Whitney criterion for independent variables. Correlation analysis was performed using Pearsons scale and Spearmans rank correlation test. Results Baseline characteristics of patients in Group 1 and 2 are presented in the Table 1. By M2 it improved in Group 1 (p<0,05, compared to M0), but didnt change in Group 2. The main reasons of treadmill test termination at M0 in groups 1 and 2 were fatigue and dyspnoe (64% and 58%, correspondingly), while ischemia was registered in 25% and 18% of patients (all p>0,05). The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Postmyocardial infarction remodeling and coronary reserve: effects of ivabradine and beta blockade therapy. Ivabradine improves coronary flow reserve in patients with stable coronary artery disease. Feedforward control of coronary blood flow via coronary beta-receptor stimulation. This advantage is achieved at the cost of accuracy due to simplified assumptions concerning vessel shape. Keywords: wall shear stress, coronary artery disease, Hagen-Poiseuille, computational fluid dynamics. But the Hagen-Poiseuille law grossly simplifies vascular geometry and flow in complex vascular beds by assuming non-tapering, non-bending (straight) and non-bifurcating vascular segments with cylindrical rigid walls and steady laminar flow of a Newtonian fluid. The assessment of vascular remodeling was based on the clinical judgment of experienced cardiologists. The three-dimensional complex coronary artery trees (see figure 1 A) were reconstructed from biplane angiograms by a validated algorithm developed in- house, which is described in detail elsewhere [6,7,8]. The Kolmogorov-Smirnov test was used to assess deviations from a normal distribution. Group differences were assessed by a t-test in normally distributed data and the Mann-Whitney U test otherwise. This is surprising in view of the many reductionist idealizations regarding geometry and flow underlying this approach as boundary conditions. These built-in components induce secondary flow and recirculation regions and generate a pressure loss that depends in a non-linear way on flow rate. The identical assumptions concerning inlet flow rate and flow division at bifurcations for both approaches should have no impact on the comparison. However, in practice, the use of the Hagen- Poiseille law is hampered by two-dimensional diameter assessment and incorrect estimates of flow division at bifurcations. Continuous cardiac pulsation is associated with local deformation of the coronary arteries. We did not consider these effects here, since they are thought to be negligible in measurements averaged over the heart cycle [10,14] and do not comply with the Hagen-Poiseille approach. The assumption of a rigid wall is acceptable for clinical studies of atherosclerosis [3,11,15]. The impact of non-Newtonian blood behavior on flow patterns was thoroughly investigated in prior studies [10,15] and should have no impact on the comparison. Non-dimensional modeling in flow simulation studies of coronary arteries including side-branches: a novel diagnostic tool in coronary artery disease. Conclusion: Calculation of wall shear stress in coronary arteries by numerical simulation is not sensitive to small changes in outlet boundary conditions. The relation of Qbranch1 to Qbranch2 is related to branch diameter (D) by a power law with exponents (E) which was experimentally determined for coronary arteries between 2. The three- dimensional complex coronary artery trees were reconstructed from biplane angiograms by a validated algorithm developed in-house, which is described in detail elsewhere [6-8]. Left: and linear regression analysis of flow rates in vessel segments calculated with two different exponents of the power law (2. Values below color bar are surface averaged mean differences with standard deviations. Linear regression analysis of flow rates in vessel segments calculated with two different exponents of the power law (2. Discussion We found that calculation of wall shear stress in coronary arteries by numerical simulation is not sensitive to small changes in outlet boundary conditions. The exponent depends on outlet conditions and is related to expansion in cross-sectional area. In coronary vascular beds cross-sectional vessel area expands but is not uniform such that exponents increase from the large epicardial arteries to the capillary bed [4;10]. A limited variation of exponent may be assumed, however, in a local range of diameter size in a specific vascular bed of a given species. In human epicardial coronary arteries the exponent was experimentally determined between 2. The assumption of a rigid wall is a reasonable for clinical studies of atherosclerosis [14]. The impact of non-Newtonian blood behaviour on flow patterns was thoroughly investigated in prior studies [15]. Moreover, all those potential confounders should have a very limited impact on the comparison. Prediction of the localization of high-risk coronary atherosclerotic plaques on the basis of low endothelial shear stress: an intravascular ultrasound and histopathology natural history study. Assessment of Diffuse Coronary Artery by Quantitative Analysis of Coronary Morphology Based upon 3-D Reconstruction from Biplane Angiograms. Validation of an accurate method for three-dimensional reconstruction and quantitative assessment of volumes, lengths and diameters of coronary vascular branches and segments from biplane angiographic projections. In-vivo coronary flow profiling based on biplane angiograms: influence of geometric simplifications on the three-dimensional reconstruction and wall shear stress calculation.

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Suggested on-call action Acquisition None unless outbreak unrecognised in which case inform Public Health Author- The incubation period rages from 1 month to ities order cheap finasteride online. A person with warts is infectious for as Whooping cough 237 Epidemiology transplant discount finasteride 1 mg without prescription, breastmilk and transplacentally has been described order finasteride amex. Mostinfections are mild febrile illnesses, and about 1 in 150 infections is severe. Typically asep- tic meningitis or acute encephalitis associated Surveillance of virus in bird flocks and mos- with fever (characteristic if with acute flaccid quitoes can inform risk. Response to a cluster/control of an outbreak Laboratory conrmation Ensure public health advice about avoiding Virus-specific IgM can be detected in most mosquito bites. False positive results may be seen in those re- cently vaccinated against (or recently infected 3. Whooping cough (pertussis) is an acute bacte- rial respiratory infection caused by Bordetella Transmission pertussis (a related organism, Bordetella parap- ertussis, also causes a pertussis-like illness). Adults and vaccinated Start antibiotic treatment (erythromy- children have a milder illness that lasts 23 cin). Pertussis is being increasingly recog- Excludefromnurseryorschoolfor5days nised as a cause of chronic cough in adults. Laboratory conrmation Theclassicalmethodisculturefromapernasal Epidemiology swab, although the organism is difficult to grow,sosensitivityislow(althoughspecificity Pertussis is well controlled in countries with is high). Theseepidemicsaffectyoungchildren;infants under 6 months are particularly at risk. Transmission The incidence of pertussis varies widely across Europe and has changed over time in Man is the only reservoir. Epi- demics of pertussis also occurred in Sweden, Acquisition where pertussis vaccine was discontinued al- together for some years. Germany, the Nether- The incubation period is 710 days, but may lands and France have also experienced resur- occasionally be up to 3 weeks. Clinical features Prevention The initial illness starts with cough, cold and a fever. Over the next week, the cough grad- Immunisation is highly effective at prevent- ually becomes paroxysmal; there are bouts of ing illness, although its role in limiting trans- coughing,whichareterminatedbythetypical mission is less clear. The cough often lasts been shown to reduce the incidence of sudden for 23 months. Whooping cough 239 There are two types of pertussis vaccine: 21daysofonsetofthefirstcase. Thedoseis125 killed whole-cell preparations and subunit mg, 6 hourly for children up to 2 years of age; acellular vaccines. Treatment should be The vaccines are given in combination with continued for 7 days. Response to a case Outbreaks in institutions can be controlled by a combination of case finding, antibiotic Isolate,withrespiratoryprecautions,inhos- treatment and case exclusion. Clinical: 14 days or more of cough plus one Arrange for laboratory confirmation. The mosquito vector does not occur in Europe, but thediseaseisapotentialrisktotravellerstoen- Prevention demic areas. Clinical features Vaccination requirements vary by country; information and addresses of vaccination cen- Cases are classified as inapparent, mild, mod- trescanbeobtainedfrompublichealthauthor- erately severe, and malignant. The pulse, rapid Eradication of urban yellow fever requires initially becomes slow for the fever. In mild widespreadmosquitocontrolandmassimmu- cases, the illness ends after 13 days. The fever then recurs, and albuminuria and epigastric Surveillance tenderness with haematemesis appear. Olig- uria or anuria may occur and petechiae and Yellow fever is a notifiable disease and should mucosal haemorrhages are common. Up to 10% of clinically diagnosed cases die, but overall mortality is actually lower, since Response to a case many infections are undiagnosed. Yersiniosis 241 Investigation of a cluster and be more common in rural areas and amongst control of an outbreak those exposed to pigs or their carcasses. Re- ported cases have fallen over the last decade Not usually relevant to Europe, but check that in England and Wales (from over 500 in 1990 cases have been to infected area in week before to under 40 since 2000), but this trend is not onset. Clinically compatible illness with fourfold rise in antibody titres or demonstration of virus, antigen or genome. Bloody diarrhoea occurs in approximately 2025% of affected chil- Non-plague yersiniosis has emerged in recent dren. Sequelae include reactive arthritis and years as an important cause of intestinal infec- erythema nodosum. Yersinia enterocolitica clude pharyngitis, appendicitis-like syndrome causes predominantly enterocolitis, whereas in older children and septicaemia in the Yersinia pseudotuberculosis mainly causes an infirm. Erythemanodosummayoccur, Exclude symptomatic cases in high-risk but enteritis and septicaemia are uncommon. Carriage of Yersinia species in studies of If you or reporting microbiologist/ asymptomatic individuals ranges from 0 to clinician know of other cases, consult out- 2. Laboratory conrmation Epidemiology Serological diagnosis is available for both species. Ifyersiniosis Scandinavia) and Canada, where it appears to is suspected on epidemiological grounds then be responsible for 24% of cases of diarrhoea. Peak incidence in bers of organisms may continue to be excreted Europeisinautumnandwinter. Theabilityoftheorganismtoreplicate which types 2, 3 and 4 are the most common, in refrigerators is likely to be relevant. The infectious dose is nousand,althoughthereare6serotypes,most likely to be high, perhaps 109 organisms. Genotyping may ondary infection appears to be rare, but it may be available in some countries. Humansusu- by improved slaughtering methods, improved ally acquire the infection orally via following: husbandry or irradiation of meat. Pork Avoidanceoflong-termrefrigerationofmeat is easily contaminated in the abattoir and if (maximum 4 days). Refrigeration offers little protection as the or- Pasteurisation of dairy products and sub- ganismcanmultiplyat4 C. Vegetables such as tofu or bean sprouts Exclusion of blood donors with recent his- become contaminated from growing in con- tory of diarrhoea or fever. The optimum temperature for ing, safe disposal of human and animal/pet growth is 2229 C. Respiratory trans- mission from cases with pharyngitis appears Cases of yersiniosis should be reported to unlikely. Other hazards 243 Response to a case Suggested case definition for outbreak Give hygiene advice to case (enteric precau- tions). Clinical: diarrhoea or combination of fever Exclude case and symptomatic contacts if and right lower abdominal pain with on- in risk group (Box 2.