Hemodynamic and morphologic evaluation of sequelae of primary upper extremity deep venous thromboses treated with anticoagulation

ObjectivesThis study was performed to describe venous function, residual morphologic abnormalities, and the occurrence of post-thrombotic syndrome in patients with conservatively treated primary upper-extremity deep venous thromboses (UEDVT).MethodThis was a retrospective follow-up study of 31 patients with previous primary UEDVT treated with anticoagulation only, identified by a search of medical records. The mean follow-up time was 5 years. The patients were evaluated by interview, clinical examination, computerized strain-gauge plethysmography, and color duplex ultrasound imaging. The grade of post-thrombotic syndrome was rated according to the Villalta score (0 to 3 on each of four subjective and five clinically assessed features).ResultsThe rate of venous emptying was significantly lower in the arms with DVTs than in the contralateral arms (P < .001). Eleven of the patients (35%) had a remaining outflow obstruction in the affected arm (venous emptying <68 mL/100 mL per min). Eighteen (58%) had a residual thrombus according to color duplex ultrasound scans, with four remaining occluded subclavian veins. None of the patients had deep or superficial venous reflux. There was no statistically significant relationship between plethysmographic and duplex findings. Most (77%) of the patients reported remaining symptoms in the affected arm, and there was a significant side difference in upper arm circumference (P < .001). Approximately one third had developed a moderate grade of post-thrombotic syndrome according to the Villalta score (total, 5 to 9). No significant relation was evident between the post-thrombotic syndrome score and duplex findings. Patients with post-thrombotic syndrome had a lower venous emptying value than those without (69 vs 84 mL/100 mL per min), but this difference was not statistically significant.ConclusionsPatients with conservatively treated previous primary UEDVT had significantly reduced venous outflow capacity and a residual thrombus was common. Swelling of the arm was the most common symptom, and one third had a moderate grade of post-thrombotic syndrome. However, there was no clear relation between hemodynamic and morphologic factors and the development of post-thrombotic syndrome in these 31 patients, examined at a mean of 5 years after an acute DVT episode

A follow-up study of the fate of small asymptomatic deep venous thromboses

<p>Abstract</p> <p>Background</p> <p>Postoperative asymptomatic deep venous thromboses (ADVT) can give rise to posttthrombotic syndrome (PTS), but there are still many unresolved issues in this context. For example, there is a lack of knowledge regarding the fate of small ADVT following minor orthopedic surgery. This follow-up study evaluates postthrombotic changes and clinical manifestations of PTS in a group of patients with asymptomatic calf vein DVT after surgery for Achilles tendon rupture.</p> <p>Methods</p> <p>Forty-six consecutive patients with distal ADVT were contacted and enrolled in a follow-up consisting of a single visit at the hospital at a mean time of 5 years postoperatively, including clinical examination and scoring, ultrasonography and venous plethysmography. All patients had participated in DVT-screening with colour duplex ultrasound (CDU) 3 and 6 weeks postoperatively and 80% of them were treated with anticoagulation.</p> <p>Results</p> <p>With CDU postthrombotic changes and deep venous reflux were detected at follow-up in more than 50% of the patients, more commonly in somewhat larger calf DVT:s initially affecting more than one vessel. However, only about 10% of the patients had significant venous reflux according to venous plethysmography. No patient had plethysmographic evidence of remaining outflow obstruction, but presence of postthrombotic changes shown with CDU negatively influenced venous outflow capacity measured with plethysmography. A clinical entity of PTS was rarely found and occurred only in two patients (4%) and then classified by Villalta scoring as of mild degree with few clinical signs of disease. Distal ADVT:s detected in the early postoperative period (3 weeks) showed DVT-progression in 75% of the limbs that were still immobilized and without anticoagulation.</p> <p>Conclusions</p> <p>Asymptomatic postoperative distal DVT:s following surgery for Achilles tendon rupture have a good prognosis and a favourable clinical outcome. In our material of 46 patients the general appearance of the clinical entity of PTS at 5 years follow-up was low (<5%). Morphological and functional abnormalities were mainly seen in those patients that initially had somewhat larger distal DVT:s involving more than one deep calf vein segment.</p

Bleeding from gastrointestinal angioectasias is not related to bleeding disorders - a case control study

n/aOriginal Publication:Charlotte M Hoog, Olle Brostrom, Tomas Lindahl, Andreas Hillarp, Gerd Larfars and Urban Sjoqvist, Bleeding from gastrointestinal angioectasias is not related to bleeding disorders - a case control study, 2010, BMC GASTROENTEROLOGY, (10), 113.http://dx.doi.org/10.1186/1471-230X-10-113Licensee: BioMed Centralhttp://www.biomedcentral.com

Human polymorphonuclear granulocytes in inflammation : studies with an emphasis on nitric oxide

The function of the polymorphonuclear neutrophil granulocyte (PMN) is of vital importance in inflammation. For the defense against infections PMNs are armored with different weapons such as chemotaxis, phagocytosis and production of cytotoxic substances. During the past decade, a new mediator and effector molecule, nitric oxide (NO), has been identified and, for PMNs production of NO, could constitute a way to further tailor the response according to the nature of the activating event. Nitric oxide release was studied by means of two highly sensitive and specific real-time methods, the oxyhemoglobin method and an electrochemical method. Human PMNs activated with the surface receptordependent agonist, N-formyl-methionyl-leucyl-phenylalanine (fMLP), the calcium ionophor, AMU and the direct stimulator of protein kinase C, phorbol myristate acetate (PMA), produced NO which was inhibited by a specific NOS inhibitor, NG-monomethyl-L-arginine (L-NMMA). The NO production induced by fMLP or A231987 was dependent on the presence of extracellular Ca2+ but this was not the case for PMA. The stimulatory effect of fMLP was almost completely inhibited by Bordetella pertussis toxin (PT). These results show a strong similarity with previously known pathways for other PMNs functions. Because arachidonate metabolites are potent mediators in inflammation, the effects of leukotriene B4 and the cysteinyl leukotrienes D4 and C4 were studied on the release of NO, in vitro, by PMNs. When activated with LTB4, LTD4 or LTC4, but not with other lipoxygenase products such as 5S-HETE, 5-oxo-ETE or 5S12S-diHETE, PMNs produced NO in a stimulus- and concentration-dependent manner. Cysteinyl leukotrienes and LTB4 antagonists inhibited the agonist-induced NO production by 70%, and treatment with PT, or chelation of cytosolic Ca2+ also efficiently inhibited this response. This effect differs from activation of the NADPH-oxidase for which only LTB4 is an activator. Both overproduction of O2- and/or NO radicals are important mediators of tissue injury in rheumatoid arthritis (RA). There were a high systemic NO production in patients with untreated RA and lower oxidative response in fMLP-stimulated PMNs, in vitro, compared to controls. When treated with a soluble tumor necrosis factor (TNF)-[alpha] receptor plasma nitrite and fMLP-induced PMN-derived O2- production both became similar to controls. In chronic granulomatous disease (CGD) treatment with gamma-interferon (IFN-[gamma]) is associated with reduced frequency of infections. In CGD patients an increased NO formation in fMLP-stimulated PMNs, in vitro, was detected after IFN-[gamma] administration with a maximal enhancement on day 3, concurrently with an increased bactericidal capacity. Thus, human PMNs possess the ability to produce NO after stimulation with various agonists. This could be an additional pathway for PMNs to exert or modulate functional responses in inflammation and infections

Ethical challenges associated with Alzheimer’s disease with a special focus on healthcare priority setting and screening

I skrivande stund pågår det intensiv forskning för att få fram ett sjukdomsmodifierande läkemedel mot Alzheimers sjukdom (AD). Vid introduktion av sådana läkemedel kommer en rad etiskt svåra frågor kring screening och prioriteringar av vårdens resurser, att aktualiseras. Föreliggande rapport behandlar dessa frågor. Trots att de nya läkemedlens effekt sannolikt har en påverkan på närstående till personer med AD så är det vår bedömning att den svenska etiska plattformen inte lämnar något utrymme för sådan hänsyn. Det finns också skäl att vara särskilt uppmärksam på utsträckningen i vilken de surrogatmått som används i de kliniska studierna faktiskt är av klinisk relevans. När det gäller att väga samman patientnytta som tillfaller olika individer är det vår bedömning att plattformen inte tillåter aggregering av patientnytta på ett sådant sätt. Det innebär att det faktum att personer med AD utgör en stor patientgrupp utgör i sig inte ett skäl för högre prioritet då effekten skall bedömas med avseende på hur den tillfaller varje enskild individ. I ett scenario där budgetpåverkan blir så stor att man behöver prioritera inom gruppen så tycks det saknas för prioriteringar relevanta kriterier. Manifest AD är ett tillstånd med mycket stor svårighetsgrad. Men eftersom de nya läkemedlen siktar in sig på den prekliniska eller fasen i vilken patienter har en lindrig kognitiv störning så bör svårighetsgraden av tillståndet viktas ned med avseende på sannolikheten att faktiskt insjukna i AD. Tillståndets svårighetsgrad blir därmed olika för läkemedel som siktar på den prekliniska fasen, de som siktar på fasen med lindrig kognitiv störning och de som siktar på kliniska stadier av AD. Eftersom personer med AD kan ha sämre förutsättningar än andra patientgrupper att kommunicera sina behov bör de beaktas särskilt. Det innebär dock inte någon högre prioritet utan en markering att personer med AD har samma rätt till hälso- och sjukvård som andra grupper med liknande behov. Populationsscreening för AD är förknippat med flera problem. Det finns generella problem med screening ur exempelvis autonomisynpunkt. Men det finns också problem som relaterar till att nuvarande metoder för riskstratifiering är så opålitliga vilket i sin tur resulterar i falska negativa (med risk för underbehandling) och falska positiva (med risk för överbehandling). Screening i fasen då patienten har en lindrig kognitiv störning har (förutom de problem som kommer med populationsscreening) problem med ojämlikhet och godtycke. När den kliniska fasen inträder har poängen med screening gått förlorad: ju senare identifikation, desto mindre potentiella behandlingsfördelar jämfört med vanlig diagnostik som den går till idag. Det är vår sammantagna bedömning att de nya läkemedlen måste generera stora hälsovinster för personer som riskerar att insjukna i AD för att berättigas allmän finansiering och för att rättfärdiga de etiska kostnader som kommer med de nuvarande diagnostiska metoderna.Intensive research is carried out by several pharmaceutical companies in order to develop a disease modifying drug for Alzheimer’s disease (AD). The development of drug candidates which reduce Aß and tau in the brain seems particularly promising. These drugs and the characteristics of AD raise a number of ethical challenges. In this report we analyze these challenges in relation to priority setting and the diagnostic measures associated with these drugs. The former analysis draws primarily on the Swedish ethical platform for health care priority setting, whereas the latter draws on the guidelines for screening developed by the National Board of Health and Welfare. Although the effect of the new drugs is likely to have an impact on relatives of people with AD, it is our interpretation that the Swedish ethical platform leaves no room for such considerations. In relation to the effect of the drugs there is also reason to pay special attention to the extent to which the surrogate measures used in the clinical studies are of clinical relevance. When it comes to aggregating benefits across individuals, it is our interpretation that the platform does not allow aggregation of patient benefits in such a way. This means that the fact that people with AD constitute a large group of patients does not in itself constitute a reason for giving this group a higher priority. The ethical platform rather seems to prescribe that the effect must be assessed with regard to how it accrues to each individual. In a scenario where the budgetary impact becomes so great that decision makers need to prioritize within the group, it seems that there are no relevant criteria for these priorities. AD is a condition with a very high degree of severity. However, as the new drugs are targeting the preclinical or Mild Cognitive Impairment (MCI) phase, the severity of the condition should be decreased with respect to the likelihood of actually developing AD. The severity of the condition thus becomes different for drugs that aim at the preclinical phase, those that aim at the MCI phase and those that aim at clinical stages of AD. Solidarity considerations in the platform prescribes that people with AD may be less able than other patient groups to communicate their needs, they should therefore be given special consideration. However, this does not mean a higher priority but to stress that people with AD have the same right to health care as other groups with similar needs. Population screening for AD is associated with several problems. There are general problems with screening from, for example, an autonomy point of view. But there are also problems related to the fact that current methods of risk stratification are so unreliable, which in turn results in false negatives (with risk of undertreatment) and false positives (with risk of overtreatment). Screening in the MCI phase has (in addition to the problems that come with population screening) problems with inequality and arbitrariness. When the clinical phase begins, there is no longer any point with screening: the later the identification, the less potential treatment benefits compared to standard diagnostics. It is our overall assessment that the new drugs must generate large health benefits for people at risk of developing AD in order to be eligible for general funding and to justify the ethical costs that come with current diagnostic methods

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Bleeding from gastrointestinal angioectasias is not related to bleeding disorders -a case control study Hoog, Charlotte M.; Brostrom, Olle; Lindahl, Tomas L.; Hillarp, Andreas; Larfars, Gerd; Sjoqvist, Urban General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 07. Oct. 2016 R E S E A R C H A R T I C L E Open Access Bleeding from gastrointestinal angioectasias is not related to bleeding disorders -a case control study Abstract Background: Angioectasias in the gastrointestinal tract can be found in up to 3% of the population. They are typically asymptomatic but may sometimes result in severe bleeding. The reasons for why some patients bleed from their angioectasias are not fully understood but it has been reported that it may be explained by an acquired von Willebrand syndrome (AVWS). This condition has similar laboratory findings to congenital von Willebrand disease with selective loss of large von Willebrand multimers. The aim of this study was to find out if AVWS or any other bleeding disorder was more common in patients with bleeding from angioectasias than in a control group. Methods: We compared bleeding tests and coagulation parameters, including von Willebrand multimers, from a group of 23 patients with anemia caused by bleeding from angioectasias, with the results from a control group lacking angioectasias. Results: No significant differences between the two groups were found in coagulation parameters, bleeding time or von Willebrand multimer levels. Conclusion: These results do not support a need for routine bleeding tests in cases of bleeding from angioectasias and do not show an overall increased risk of AVWS among these patients

Ethical challenges associated with Alzheimer’s disease with a special focus on healthcare priority setting and screening

I skrivande stund pågår det intensiv forskning för att få fram ett sjukdomsmodifierande läkemedel mot Alzheimers sjukdom (AD). Vid introduktion av sådana läkemedel kommer en rad etiskt svåra frågor kring screening och prioriteringar av vårdens resurser, att aktualiseras. Föreliggande rapport behandlar dessa frågor. Trots att de nya läkemedlens effekt sannolikt har en påverkan på närstående till personer med AD så är det vår bedömning att den svenska etiska plattformen inte lämnar något utrymme för sådan hänsyn. Det finns också skäl att vara särskilt uppmärksam på utsträckningen i vilken de surrogatmått som används i de kliniska studierna faktiskt är av klinisk relevans. När det gäller att väga samman patientnytta som tillfaller olika individer är det vår bedömning att plattformen inte tillåter aggregering av patientnytta på ett sådant sätt. Det innebär att det faktum att personer med AD utgör en stor patientgrupp utgör i sig inte ett skäl för högre prioritet då effekten skall bedömas med avseende på hur den tillfaller varje enskild individ. I ett scenario där budgetpåverkan blir så stor att man behöver prioritera inom gruppen så tycks det saknas för prioriteringar relevanta kriterier. Manifest AD är ett tillstånd med mycket stor svårighetsgrad. Men eftersom de nya läkemedlen siktar in sig på den prekliniska eller fasen i vilken patienter har en lindrig kognitiv störning så bör svårighetsgraden av tillståndet viktas ned med avseende på sannolikheten att faktiskt insjukna i AD. Tillståndets svårighetsgrad blir därmed olika för läkemedel som siktar på den prekliniska fasen, de som siktar på fasen med lindrig kognitiv störning och de som siktar på kliniska stadier av AD. Eftersom personer med AD kan ha sämre förutsättningar än andra patientgrupper att kommunicera sina behov bör de beaktas särskilt. Det innebär dock inte någon högre prioritet utan en markering att personer med AD har samma rätt till hälso- och sjukvård som andra grupper med liknande behov. Populationsscreening för AD är förknippat med flera problem. Det finns generella problem med screening ur exempelvis autonomisynpunkt. Men det finns också problem som relaterar till att nuvarande metoder för riskstratifiering är så opålitliga vilket i sin tur resulterar i falska negativa (med risk för underbehandling) och falska positiva (med risk för överbehandling). Screening i fasen då patienten har en lindrig kognitiv störning har (förutom de problem som kommer med populationsscreening) problem med ojämlikhet och godtycke. När den kliniska fasen inträder har poängen med screening gått förlorad: ju senare identifikation, desto mindre potentiella behandlingsfördelar jämfört med vanlig diagnostik som den går till idag. Det är vår sammantagna bedömning att de nya läkemedlen måste generera stora hälsovinster för personer som riskerar att insjukna i AD för att berättigas allmän finansiering och för att rättfärdiga de etiska kostnader som kommer med de nuvarande diagnostiska metoderna.Intensive research is carried out by several pharmaceutical companies in order to develop a disease modifying drug for Alzheimer’s disease (AD). The development of drug candidates which reduce Aß and tau in the brain seems particularly promising. These drugs and the characteristics of AD raise a number of ethical challenges. In this report we analyze these challenges in relation to priority setting and the diagnostic measures associated with these drugs. The former analysis draws primarily on the Swedish ethical platform for health care priority setting, whereas the latter draws on the guidelines for screening developed by the National Board of Health and Welfare. Although the effect of the new drugs is likely to have an impact on relatives of people with AD, it is our interpretation that the Swedish ethical platform leaves no room for such considerations. In relation to the effect of the drugs there is also reason to pay special attention to the extent to which the surrogate measures used in the clinical studies are of clinical relevance. When it comes to aggregating benefits across individuals, it is our interpretation that the platform does not allow aggregation of patient benefits in such a way. This means that the fact that people with AD constitute a large group of patients does not in itself constitute a reason for giving this group a higher priority. The ethical platform rather seems to prescribe that the effect must be assessed with regard to how it accrues to each individual. In a scenario where the budgetary impact becomes so great that decision makers need to prioritize within the group, it seems that there are no relevant criteria for these priorities. AD is a condition with a very high degree of severity. However, as the new drugs are targeting the preclinical or Mild Cognitive Impairment (MCI) phase, the severity of the condition should be decreased with respect to the likelihood of actually developing AD. The severity of the condition thus becomes different for drugs that aim at the preclinical phase, those that aim at the MCI phase and those that aim at clinical stages of AD. Solidarity considerations in the platform prescribes that people with AD may be less able than other patient groups to communicate their needs, they should therefore be given special consideration. However, this does not mean a higher priority but to stress that people with AD have the same right to health care as other groups with similar needs. Population screening for AD is associated with several problems. There are general problems with screening from, for example, an autonomy point of view. But there are also problems related to the fact that current methods of risk stratification are so unreliable, which in turn results in false negatives (with risk of undertreatment) and false positives (with risk of overtreatment). Screening in the MCI phase has (in addition to the problems that come with population screening) problems with inequality and arbitrariness. When the clinical phase begins, there is no longer any point with screening: the later the identification, the less potential treatment benefits compared to standard diagnostics. It is our overall assessment that the new drugs must generate large health benefits for people at risk of developing AD in order to be eligible for general funding and to justify the ethical costs that come with current diagnostic methods

Ethical challenges associated with Alzheimer’s disease with a special focus on healthcare priority setting and screening

I skrivande stund pågår det intensiv forskning för att få fram ett sjukdomsmodifierande läkemedel mot Alzheimers sjukdom (AD). Vid introduktion av sådana läkemedel kommer en rad etiskt svåra frågor kring screening och prioriteringar av vårdens resurser, att aktualiseras. Föreliggande rapport behandlar dessa frågor. Trots att de nya läkemedlens effekt sannolikt har en påverkan på närstående till personer med AD så är det vår bedömning att den svenska etiska plattformen inte lämnar något utrymme för sådan hänsyn. Det finns också skäl att vara särskilt uppmärksam på utsträckningen i vilken de surrogatmått som används i de kliniska studierna faktiskt är av klinisk relevans. När det gäller att väga samman patientnytta som tillfaller olika individer är det vår bedömning att plattformen inte tillåter aggregering av patientnytta på ett sådant sätt. Det innebär att det faktum att personer med AD utgör en stor patientgrupp utgör i sig inte ett skäl för högre prioritet då effekten skall bedömas med avseende på hur den tillfaller varje enskild individ. I ett scenario där budgetpåverkan blir så stor att man behöver prioritera inom gruppen så tycks det saknas för prioriteringar relevanta kriterier. Manifest AD är ett tillstånd med mycket stor svårighetsgrad. Men eftersom de nya läkemedlen siktar in sig på den prekliniska eller fasen i vilken patienter har en lindrig kognitiv störning så bör svårighetsgraden av tillståndet viktas ned med avseende på sannolikheten att faktiskt insjukna i AD. Tillståndets svårighetsgrad blir därmed olika för läkemedel som siktar på den prekliniska fasen, de som siktar på fasen med lindrig kognitiv störning och de som siktar på kliniska stadier av AD. Eftersom personer med AD kan ha sämre förutsättningar än andra patientgrupper att kommunicera sina behov bör de beaktas särskilt. Det innebär dock inte någon högre prioritet utan en markering att personer med AD har samma rätt till hälso- och sjukvård som andra grupper med liknande behov. Populationsscreening för AD är förknippat med flera problem. Det finns generella problem med screening ur exempelvis autonomisynpunkt. Men det finns också problem som relaterar till att nuvarande metoder för riskstratifiering är så opålitliga vilket i sin tur resulterar i falska negativa (med risk för underbehandling) och falska positiva (med risk för överbehandling). Screening i fasen då patienten har en lindrig kognitiv störning har (förutom de problem som kommer med populationsscreening) problem med ojämlikhet och godtycke. När den kliniska fasen inträder har poängen med screening gått förlorad: ju senare identifikation, desto mindre potentiella behandlingsfördelar jämfört med vanlig diagnostik som den går till idag. Det är vår sammantagna bedömning att de nya läkemedlen måste generera stora hälsovinster för personer som riskerar att insjukna i AD för att berättigas allmän finansiering och för att rättfärdiga de etiska kostnader som kommer med de nuvarande diagnostiska metoderna.Intensive research is carried out by several pharmaceutical companies in order to develop a disease modifying drug for Alzheimer’s disease (AD). The development of drug candidates which reduce Aß and tau in the brain seems particularly promising. These drugs and the characteristics of AD raise a number of ethical challenges. In this report we analyze these challenges in relation to priority setting and the diagnostic measures associated with these drugs. The former analysis draws primarily on the Swedish ethical platform for health care priority setting, whereas the latter draws on the guidelines for screening developed by the National Board of Health and Welfare. Although the effect of the new drugs is likely to have an impact on relatives of people with AD, it is our interpretation that the Swedish ethical platform leaves no room for such considerations. In relation to the effect of the drugs there is also reason to pay special attention to the extent to which the surrogate measures used in the clinical studies are of clinical relevance. When it comes to aggregating benefits across individuals, it is our interpretation that the platform does not allow aggregation of patient benefits in such a way. This means that the fact that people with AD constitute a large group of patients does not in itself constitute a reason for giving this group a higher priority. The ethical platform rather seems to prescribe that the effect must be assessed with regard to how it accrues to each individual. In a scenario where the budgetary impact becomes so great that decision makers need to prioritize within the group, it seems that there are no relevant criteria for these priorities. AD is a condition with a very high degree of severity. However, as the new drugs are targeting the preclinical or Mild Cognitive Impairment (MCI) phase, the severity of the condition should be decreased with respect to the likelihood of actually developing AD. The severity of the condition thus becomes different for drugs that aim at the preclinical phase, those that aim at the MCI phase and those that aim at clinical stages of AD. Solidarity considerations in the platform prescribes that people with AD may be less able than other patient groups to communicate their needs, they should therefore be given special consideration. However, this does not mean a higher priority but to stress that people with AD have the same right to health care as other groups with similar needs. Population screening for AD is associated with several problems. There are general problems with screening from, for example, an autonomy point of view. But there are also problems related to the fact that current methods of risk stratification are so unreliable, which in turn results in false negatives (with risk of undertreatment) and false positives (with risk of overtreatment). Screening in the MCI phase has (in addition to the problems that come with population screening) problems with inequality and arbitrariness. When the clinical phase begins, there is no longer any point with screening: the later the identification, the less potential treatment benefits compared to standard diagnostics. It is our overall assessment that the new drugs must generate large health benefits for people at risk of developing AD in order to be eligible for general funding and to justify the ethical costs that come with current diagnostic methods