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Alcohol consumption causes both physical and psychological harm and is a leading risk factor for noncommunicable diseases. Digital alcohol interventions have been found to support those looking for help by giving them tools for change. However, whether digital interventions can help tackle the long-term societal consequences of harmful alcohol consumption in a cost-effective manner has not been adequately evaluated. In this Viewpoint, we propose that studies of digital alcohol interventions rarely evaluate the consequences of wider dissemination of the intervention under study, and that when they do, they do not take advantage of modeling techniques that allow for appropriately studying consequences over a longer time horizon than the study period when the intervention is tested. We argue that to help decision -makers to prioritize resources for research and dissemination, it is important to model long-term costs and health outcomes. Further, this type of modeling gives important insights into the context in which interventions are studied and highlights where more research is required and where sufficient evidence is available. The viewpoint therefore invites the researcher not only to reflect on which interventions to study but also how to evaluate their long-term consequences., Funding Agencies|Swedish Research Council for Health, Working Life, and Welfare [2022-00193]

Background: Advanced fibrosis is associated with end-stage liver disease (ESLD) and mortality in NAFLD. As treatments specifically targeted at NAFLD are lacking, patient management focuses on surveillance for early detection of complications related to end-stage liver disease. Although current and emerging diagnostic tools for the detection of advanced fibrosis are crucial for surveillance, their added value is unclear. The aim of this study was to evaluate the costs and health outcomes of noninvasive tests in patient management strategies for diagnosing advanced fibrosis in NAFLD patients. Method: A decision analytical model was developed to evaluate 13 patient management strategies, including a no-testing strategy and 12 diagnostic algorithms with noninvasive tests (fibrosis 4-score, enhanced liver fibrosis, vibration controlled transient elastography), and liver biopsy. Model inputs were synthesized from the literature and Swedish registries. Lifetime health care costs, life years, quality-adjusted life years, clinical outcomes, and incremental cost-effectiveness ratios were calculated for a cohort of 55-year-old patients diagnosed with NAFLD. Result: The cost per quality-adjusted life year was above (sic)50 000 for all diagnostic algorithms compared to no-testing. The cost per quality-adjusted life year of the most promising diagnostic algorithm (fibrosis 4-score, enhanced liver fibrosis, vibration controlled transient elastography, and liver biopsy) was similar to(sic)181 000 compared with no testing. Sensitivity analysis indicated that if treatment slowed down disease progression, the value of testing increased. Conclusion: The result questions the overall value of comprehensive diagnostic testing in a broad NAFLD population in current routine clinical care. The role of noninvasive tests may change if evidence-based treatments to slow down disease progression emerge., Funding Agencies|Vinnova [2019-01189]; Region Ostergoetland ALF grants [RO~962520]

Background Effectiveness estimates from observational studies on ticagrelor use in routine clinical care are conflicting, with some contrary to the results of the pivotal randomized controlled trial of ticagrelor in acute coronary syndrome. The aim of this study was to estimate the effect of implementing and using ticagrelor in routine clinical care in patients with myocardial infarction using a natural experimental approach. Methods and Results This is a retrospective cohort study including patients hospitalized for myocardial infarction in Sweden between 2009 and 2015. The study exploited differences in the timing and speed of ticagrelor implementation between treatment centers as a source of random treatment assignment. The effect of implementing and using ticagrelor was estimated based on the admitting center's likelihood of treating patients with ticagrelor, measured as the proportion of patients treated in the 90 days before patient admission. The main outcome was 12‐month mortality. The study included 109 955 patients, of whom 30 773 were treated with ticagrelor. Being admitted to a treatment center with higher past ticagrelor use was associated with a reduction in 12‐month mortality (2.5 percentage points for 100% versus 0% past use [95% CI, 0.2–4.8]). The results are in line with the findings from the ticagrelor pivotal trial. Conclusions Using a natural experiment, this study finds that the implementation and use of ticagrelor in routine clinical care has reduced 12‐month mortality in patients admitted to the hospital with myocardial infarction in Sweden and supports the external validity of randomized evidence on ticagrelor effectiveness.

Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase-cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a 'folate trap'. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial 1-carbon metabolism enzyme, which is an attractive anticancer drug target as it is highly upregulated in cancer but is not expressed in healthy adult cells. Selective MTHFD2 inhibitors could therefore offer reduced side-effects during treatment, which are common with antifolate drugs that target other 1C-metabolism enzymes. This task is challenging however, as MTHFD2 shares high sequence identity with the constitutively expressed isozymes cytosolic MTHFD1 and mitochondrial MTHFD2L. In fact, one of the most potent MTHFD2 inhibitors reported to date, TH7299, is actually more active against MTHFD1 and MTHFD2L. While structures of MTHFD2 and MTHFD1 exist, no MTHFD2L structures are available. We determined the first structure of MTHFD2L and its complex with TH7299, which reveals the structural basis for its highly potent MTHFD2L inhibition. Detailed analysis of the MTHFD2L structure presented here clearly highlights the challenges associated with developing truly isoform-selective MTHFD2 inhibitors.

Background: Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated genetic disorder with high risk of premature atherosclerotic cardiovascular disease and death. Clinical decision support (CDS) systems have the potential to aid in the identification and management of patients with FH. Prior studies using computer-based systems to screen patients for FH have shown promising results, but there has been no randomized controlled trial conducted. The aim of the current cluster randomized study is to evaluate if a CDS can increase the identification of FH. Methods: We have developed a CDS integrated in the electronic health records that will be activated in patients with elevated cholesterol levels (total cholesterol > 8 mmol/L or low-density lipoprotein-cholesterol > 5.5 mmol/L, adjusted for age, ongoing lipid lowering therapy and presence of premature coronar y arter y disease) at increased risk for FH. When activated, the CDS will urge the physician to send an automatically generated referral to the local lipid clinic for further evaluation. To evaluate the effects of the CDS, all primary care clinics will be cluster randomized 1:1 to either CDS intervention or standard care in a Swedish region with almost 500,000 inhabitants. The primary endpoint will be the number of patients diagnosed with FH at 30 months. Resource use and long-term health consequences will be estimated to assess the cost-effectiveness of the intervention. Conclusion : Despite increasing awareness of FH, the condition remains underdiagnosed and undertreated. The present study will investigate whether a CDS can increase the number of patients being diagnosed with FH.

Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed beta,delta-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.

Tandvårds- och läkemedelsförmånsverket (TLV) genomför på uppdrag av regeringen ett arbete med att utveckla metoder för hälsoekonomiska utvärderingar av precisionsmedicin och betalningsmodeller för avancerade terapiläkemedel (ATMP). TLV redovisar i sin andra rapport inom ramen för uppdraget ett antal nya möjliga metoder som kan användas i en hälsoekonomisk utvärdering för att värdera huruvida de priser som företagen efterfrågar är rimliga i förhållande till läkemedlens nytta. Eftersom hälsoekonomiska utvärderingar alltid är behäftade med osäkerhet i skattningarna är frågan om hur osäkerhet skall analyseras och beskrivas central för precisionsmedicin och ATMP då dataunderlagen ofta är knapphändiga. I en slutsats från ett tidigare arbete om utmaningarna med att utvärdera kostnader och hälsoeffekter inom ramen för precisionsmedicin konstaterades det att osäkerheten i skattningarna av kostnadseffektivitet kommer att öka när patientpopulationerna som utvärderas blir allt mindre. Vidare framgick det i de tidigare arbetena att TLVs ansats för att beskriva och analysera osäkerhet inte alltid är helt tydlig. Som en del i TLVs regeringsuppdrag ingår det att beskriva och tydliggöra osäkerheter i skattningar av kostnadseffektivitet samt hur dessa osäkerhet kan påverka osäkerhet i prioriteringsbeslut och den här rapporten är en del i det arbetet. Rapporten är fristående från den rapport som TLV skrivit inom ramen för regeringsuppdraget men har som mål att ge en kompletterande beskrivning av de osäkerheter som oftast föreligger när hälsoekonomiska utvärderingar utgör en del av ett underlag för prioriteringsbeslut. Förhoppningen är att denna rapport tillsammans med TLVs rapport ska stimulera till fortsatt diskussion om potentiella lösningar för att hantera utmaningar inte bara med precisionsmedicin och ATMP utan även med beslutsfattande under osäkerhet generellt inom hälso- och sjukvården.