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Abstract Background Norway is a high-income nation with universal tax-financed health care and among the highest per person health spending in the world. This study estimates Norwegian health expenditures by health condition, age, and sex, and compares it with disability-adjusted life-years (DALYs). Methods Government budgets, reimbursement databases, patient registries, and prescription databases were combined to estimate spending for 144 health conditions, 38 age and sex groups, and eight types of care (GPs; physiotherapists & chiropractors; specialized outpatient; day patient; inpatient; prescription drugs; home-based care; and nursing homes) totaling 174,157,766 encounters. Diagnoses were in accordance with the Global Burden of Disease study (GBD). The spending estimates were adjusted, by redistributing excess spending associated with each comorbidity. Disease-specific DALYs were gathered from GBD 2019. Results The top five aggregate causes of Norwegian health spending in 2019 were mental and substance use disorders (20.7%), neurological disorders (15.4%), cardiovascular diseases (10.1%), diabetes, kidney, and urinary diseases (9.0%), and neoplasms (7.2%). Spending increased sharply with age. Among 144 health conditions, dementias had the highest health spending, with 10.2% of total spending, and 78% of this spending was incurred at nursing homes. The second largest was falls estimated at 4.6% of total spending. Spending in those aged 15–49 was dominated by mental and substance use disorders, with 46.0% of total spending. Accounting for longevity, spending per female was greater than spending per male, particularly for musculoskeletal disorders, dementias, and falls. Spending correlated well with DALYs (Correlation r = 0.77, 95% CI 0.67–0.87), and the correlation of spending with non-fatal disease burden (r = 0.83, 0.76–0.90) was more pronounced than with mortality (r = 0.58, 0.43–0.72). Conclusions Health spending was high for long-term disabilities in older age groups. Research and development into more effective interventions for the disabling high-cost diseases is urgently needed.

Abstract Background Reliable statistics on the underlying cause of death are essential for monitoring the health in a population. When there is insufficient information to identify the true underlying cause of death, the death will be classified using less informative codes, garbage codes. If many deaths are assigned a garbage code, the information value of the cause-of-death statistics is reduced. The aim of this study was to analyse the use of garbage codes in the Norwegian Cause of Death Registry (NCoDR). Methods Data from NCoDR on all deaths among Norwegian residents in the years 1996–2019 were used to describe the occurrence of garbage codes. We used logistic regression analyses to identify determinants for the use of garbage codes. Possible explanatory factors were year of death, sex, age of death, place of death and whether an autopsy was performed. Results A total of 29.0% (290,469/1,000,128) of the deaths were coded with a garbage code; 14.1% (140,804/1,000,128) with a major and 15.0% (149,665/1,000,128) with a minor garbage code. The five most common major garbage codes overall were ICD-10 codes I50 (heart failure), R96 (sudden death), R54 (senility), X59 (exposure to unspecified factor), and A41 (other sepsis). The most prevalent minor garbage codes were I64 (unspecified stroke), J18 (unspecified pneumonia), C80 (malignant neoplasm with unknown primary site), E14 (unspecified diabetes mellitus), and I69 (sequelae of cerebrovascular disease). The most important determinants for the use of garbage codes were the age of the deceased (OR 17.4 for age ≥ 90 vs age

Abstract Background Disparities in health by adult income are well documented, but we know less about the childhood origins of health inequalities, and it remains unclear how the shape of the gradient varies across health conditions. This study examined the association between parental income in childhood and several measures of morbidity in adulthood. Methods We used administrative data on seven complete Norwegian birth cohorts born in 1967–1973 (N = 429,886) to estimate the association between parental income from birth to age 18, obtained from tax records available from 1967, linked with administrative registries on health. Health measures, observed between ages 39 and 43, were taken from registry data on consultations at primary health care services based on diagnostic codes from the International Classification of Primary Care (ICPC-2) and hospitalizations and outpatient specialist consultations registered in the National Patient Registry (ICD-10). Results Low parental income during childhood was associated with a higher risk of being diagnosed with several chronic and pain-related disorders, as well as hospitalization, but not overall primary health care use. Absolute differences were largest for disorders related to musculoskeletal pain, injuries, and depression (7–9 percentage point difference). There were also differences for chronic disorders such as hypertension (8%, CI 7.9–8.5 versus 4%, CI 4.1–4.7) and diabetes (3.2%, CI 3.0–3.4 versus 1.4%, CI 1.2–1.6). There was no difference in consultations related to respiratory disorders (20.9%, CI 20.4–21.5 versus 19.7%, CI 19.2–20.3). Childhood characteristics (parental education, low birth weight, and parental marital status) and own adult characteristics (education and income) explained a large share of the association. Conclusions Children growing up at the bottom of the parental income distribution, compared to children in the top of the income distribution, had a two- to threefold increase in somatic and psychological disorders measured in adulthood. This shows that health inequalities by socioeconomic family background persist in a Scandinavian welfare-state context with universal access to health care.

Summary: Background: Given the projected trends in population ageing and population growth, the number of people with dementia is expected to increase. In addition, strong evidence has emerged supporting the importance of potentially modifiable risk factors for dementia. Characterising the distribution and magnitude of anticipated growth is crucial for public health planning and resource prioritisation. This study aimed to improve on previous forecasts of dementia prevalence by producing country-level estimates and incorporating information on selected risk factors. Methods: We forecasted the prevalence of dementia attributable to the three dementia risk factors included in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 (high body-mass index, high fasting plasma glucose, and smoking) from 2019 to 2050, using relative risks and forecasted risk factor prevalence to predict GBD risk-attributable prevalence in 2050 globally and by world region and country. Using linear regression models with education included as an additional predictor, we then forecasted the prevalence of dementia not attributable to GBD risks. To assess the relative contribution of future trends in GBD risk factors, education, population growth, and population ageing, we did a decomposition analysis. Findings: We estimated that the number of people with dementia would increase from 57·4 (95% uncertainty interval 50·4–65·1) million cases globally in 2019 to 152·8 (130·8–175·9) million cases in 2050. Despite large increases in the projected number of people living with dementia, age-standardised both-sex prevalence remained stable between 2019 and 2050 (global percentage change of 0·1% [–7·5 to 10·8]). We estimated that there were more women with dementia than men with dementia globally in 2019 (female-to-male ratio of 1·69 [1·64–1·73]), and we expect this pattern to continue to 2050 (female-to-male ratio of 1·67 [1·52–1·85]). There was geographical heterogeneity in the projected increases across countries and regions, with the smallest percentage changes in the number of projected dementia cases in high-income Asia Pacific (53% [41–67]) and western Europe (74% [58–90]), and the largest in north Africa and the Middle East (367% [329–403]) and eastern sub-Saharan Africa (357% [323–395]). Projected increases in cases could largely be attributed to population growth and population ageing, although their relative importance varied by world region, with population growth contributing most to the increases in sub-Saharan Africa and population ageing contributing most to the increases in east Asia. Interpretation: Growth in the number of individuals living with dementia underscores the need for public health planning efforts and policy to address the needs of this group. Country-level estimates can be used to inform national planning efforts and decisions. Multifaceted approaches, including scaling up interventions to address modifiable risk factors and investing in research on biological mechanisms, will be key in addressing the expected increases in the number of individuals affected by dementia. Funding: Bill & Melinda Gates Foundation and Gates Ventures.

Abstract Background For injury deaths, the underlying cause of death is defined as the circumstances leading to the injury. When this information is missing, the ICD-10 code X59 (Exposure to unspecified factor) is used. Lack of knowledge of factors causing injuries reduces the value of the cause of death statistics. The aim of this study was to identify predictors of X59-coded deaths in Norway, and to assess methods to identify the true underlying cause of injury deaths. Methods We used data from the Norwegian Cause of Death Registry from 2005 to 2014. We used logistic regression to identify determinants of X59-coded deaths. For redistribution of the X59 deaths, we used a multinomial logistic regression model based on the cases where injury circumstances were known. The data were divided into training and test sets. The model was developed on the training set and assessed on the test set before it was applied to the X59 deaths. The models used death certificate information on the nature of injury and demographic characteristics as predictor variables. Furthermore, we mailed a query to the certifying physicians of X59 deaths reported in the year 2015, where we asked for additional information on the circumstances leading to the fatal injury. Results There were 24,963 injury deaths reported to the Cause of Death Registry of Norway 2005–2014. Of these, 6440 (25.8%) lacked information on the circumstances leading to the death. The strongest predictor for a X59 death was the nature of injury (hip fracture), followed by lack of information on the scene of injury. Applying our redistribution algorithm, we estimated that 97% of the X59-coded deaths were accidental falls. The strongest covariate was the nature of injury, followed by place of death and age at death. In 2015, there were 591 X59-coded deaths. Queries were sent to the certifying doctors in 559 cases. Among the informative replies to the query, 88% of the deaths were reclassified to accidental falls. Conclusions A large proportion of injury deaths in Norway lack information on the circumstances leading to the fatal injury. Typically, these deaths represent accidental falls causing hip fracture in elderly individuals.

Summary: Background: The Nordic countries have commonalities in gender equality, economy, welfare, and health care, but differ in culture and lifestyle, which might create country-wise health differences. This study compared life expectancy, disease burden, and risk factors in the Nordic region. Methods: Life expectancy in years and age-standardised rates of overall, cause-specific, and risk factor-specific estimates of disability-adjusted life-years (DALYs) were analysed in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017. Data were extracted for Denmark, Finland, Iceland, Norway, and Sweden (ie, the Nordic countries), and Greenland, an autonomous area of Denmark. Estimates were compared with global, high-income region, and Nordic regional estimates, including Greenland. Findings: All Nordic countries exceeded the global life expectancy; in 2017, the highest life expectancy was in Iceland among females (85·9 years [95% uncertainty interval [UI] 85·5–86·4] vs 75·6 years [75·3–75·9] globally) and Sweden among males (80·8 years [80·2–81·4] vs 70·5 years [70·1–70·8] globally). Females (82·7 years [81·9–83·4]) and males (78·8 years [78·1–79·5]) in Denmark and males in Finland (78·6 years [77·8–79·2]) had lower life expectancy than in the other Nordic countries. The lowest life expectancy in the Nordic region was in Greenland (females 77·2 years [76·2–78·0], males 70·8 years [70·3–71·4]). Overall disease burden was lower in the Nordic countries than globally, with the lowest age-standardised DALY rates among Swedish males (18 555·7 DALYs [95% UI 15 968·6–21 426·8] per 100 000 population vs 35 834·3 DALYs [33 218·2–38 740·7] globally) and Icelandic females (16 074·1 DALYs [13 216·4–19 240·8] vs 29 934·6 DALYs [26 981·9–33 211·2] globally). Greenland had substantially higher DALY rates (26 666·6 DALYs [23 478·4–30 218·8] among females, 33 101·3 DALYs [30 182·3–36 218·6] among males) than the Nordic countries. Country variation was primarily due to differences in causes that largely contributed to DALYs through mortality, such as ischaemic heart disease. These causes dominated male disease burden, whereas non-fatal causes such as low back pain were important for female disease burden. Smoking and metabolic risk factors were high-ranking risk factors across all countries. DALYs attributable to alcohol use and smoking were particularly high among the Danes, as was alcohol use among Finnish males. Interpretation: Risk factor differences might drive differences in life expectancy and disease burden that merit attention also in high-income settings such as the Nordic countries. Special attention should be given to the high disease burden in Greenland. Funding: Bill & Melinda Gates Foundation. The work on this paper was supported by the Research Council of Norway through FRIPRO (project number 262030) and by the Norwegian Institute of Public Health.

Abstract Background Mental disorders often have onset early in life, contribute substantially to the global disease burden, and may interfere with young people’s ability to complete age-relevant tasks in important developmental periods. However, knowledge about prevalence and course of mental disorders in young adulthood is sparse. The aim of the current study was to estimate prevalence and stability of mental disorders from the twenties to the thirties/forties. Methods DSM-IV mental disorders were assessed with the Composite International Diagnostic Interview in two waves (1999–2004 and 2010–2011) in 1623 young adult Norwegian twins (63.2% women, aged 19–29 years in wave 1). Results In wave 1, the 12-month prevalence of any mental disorder among people in the twenties was 19.8% (men) and 32.4% (women), anxiety disorders: 9.6% (men) and 26.7% (women), anxiety disorders excluding specific phobias: 2.5% (men) and 6.9% (women), major depressive disorder (MDD): 4.4% (men) and 7.2% (women), and alcohol use disorder (AUD): 8.7% (men) and 4.4% (women). The prevalence of any mental disorder decreased from the twenties to the thirties/forties. This was due to a decrease in AUD and specific phobias. Anxiety disorders in the twenties predicted anxiety disorders and MDD ten years later, even when controlling for the association between these disorders in the twenties. MDD in the twenties predicted MDD ten years later. At both ages, two-week and 12-month prevalence estimates differed markedly for MDD - indicating an episodic course. Conclusions Common mental disorders are highly prevalent among young adults in the twenties, and somewhat less prevalent in the thirties/forties. Those who suffer from one mental disorder in the twenties are at considerably increased risk for suffering from a disorder ten years later as well. This may have significant implications for young people’s ability to attain education, establish a family, and participate in occupational life.

The objective of this study was to characterize changes in metabolic bone parameters following bariatric surgery. Seventy-three obese adult patients who underwent either gastric banding (GB), Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion with duodenal switch (BPD/DS) were followed prospectively for 18 months postoperatively. Changes in the calcium-vitamin D axis (25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D (1,25(OH)(2)D), calcium, parathyroid hormone (PTH)), markers of bone formation (osteocalcin, bone-specific alkaline phosphatase) and resorption (urinary N-telopeptide (NTx)), as well as bone mineral density (BMD) were assessed at 3-month intervals during this time period. Bariatric surgery resulted in significant and progressive weight loss over 18 months. With supplementation, 25OHD levels increased 65.3% (P < 0.0001) by 3 months, but leveled off and decreased <30 ng/ml by 18 months. PTH initially decreased 21.4% (P = 0.01) at 3 months, but later approached presurgery levels. 1,25(OH)(2)D increased significantly starting at month 12 (50.3% increase from baseline, P = 0.008), and was positively associated with PTH (r = 0.82, P = 0.0001). When stratified by surgery type, median PTH and 1,25(OH)(2)D levels were higher following combined restrictive and malabsorptive operations (RYGB and BPD/DS) compared to GB. Bone formation/resorption markers were increased by 3 months (P < 0.05) and remained elevated through 18 months. Radial BMD decreased 3.5% by month 18, but this change was not significant (P = 0.23). Our findings show that after transient improvement, preoperative vitamin D insufficiency and secondary hyperparathyroidism persisted following surgery despite supplementation. Postoperative secondary hyperparathyroidism was associated with increased 1,25(OH)(2)D levels and increased bone turnover markers. [ABSTRACT FROM AUTHOR]

Depression in the elderly too often goes unrecognized and untreated. Look for it in your older patients, and know that treatment can be as effective and life-enhancing for them as it is for the young. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to document the worldwide decline of dracunculiasis (Guinea worm disease, GWD) burden, expressed as disability-adjusted life years (DALYs), from 1990 to 2016, as estimated in the Global Burden of Disease study 2016 (GBD 2016). While the annual number of cases of GWD have been consistently reported by WHO since the 1990s, the burden of disability due to GWD has not previously been quantified in GBD. Methods: The incidence of GWD was modeled for each endemic country using annual national case reports. A literature search was conducted to characterize the presentation of GWD, translate the clinical symptoms into health sequelae, and then assign an average duration to the infection. Prevalence measures by sequelae were multiplied by disability weights to estimate DALYs. Results: The total DALYs attributed to GWD across all endemic countries (n=21) in 1990 was 50,725 (95% UI: 35,265–69,197) and decreased to 0.9 (95% UI: 0.5–1.4) in 2016. A cumulative total of 12,900 DALYs were attributable to GWD from 1990 to 2016. Conclusions: Using 1990 estimates of burden propagated forward, this analysis suggests that between 990,000 to 1.9 million DALYs have been averted as a result of the eradication program over the past 27 years.

Background Preeclampsia is a severe pregnancy disorder often complicated by reduced fetal growth or preterm delivery and is associated with long‐term maternal morbidity and mortality. We aimed to assess the association between preeclampsia phenotypes and risk of subsequent coronary heart disease and maternal cardiovascular mortality. Methods and Results Women aged 16 to 49 years who gave birth during 1980–2002 and registered in the Medical Birth Registry of Norway were followed prospectively (1–29 years) for an incident major coronary event and mortality through linkage with the Cardiovascular Disease in Norway 1994–2009 (CVDNOR) project and the Norwegian Cause of Death Registry. Preeclampsia was subdivided based on the presence of a child born small for gestational age or preterm delivery. Among 506 350 women with 1 to 5 singleton births, there were 1275 (0.3%) occurrences of major coronary event, 468 (0.1%) cardiovascular deaths, and 5411 (1.1%) deaths overall. Compared with women without preeclampsia, the hazard ratio (95% CI) for major coronary event was 2.1 (1.73–2.65) after preeclampsia alone, 3.3 (2.37–4.57) after preeclampsia in combination with small for gestational age, and 5.4 (3.74–7.74) after preeclampsia in combination with preterm delivery. Analyses distinguishing women with 1 (n=61 352) or >1 (n=281 069) lifetime pregnancy and analyses with cardiovascular mortality as outcome followed the same pattern. Conclusions The occurrence of major coronary events was increased among women with preeclampsia and highest for preeclampsia combined with a child born small for gestational age and/or preterm delivery.

Background Heart failure (HF) is a serious complication of acute myocardial infarction (AMI). We explored the excess mortality associated with HF as an early or late complication of AMI and describe changes over time in such excess mortality. Methods and Results All patients hospitalized with an incident AMI and without history of prior HF hospitalization were followed up to 1 year after AMI discharge for episodes of HF. New HF episodes were classified as in‐hospital HF if diagnosed during the AMI hospitalization or postdischarge HF if diagnosed within 1 year after discharge from the incident AMI. Logistic and Cox regression models were used to explore the excess mortality associated with HF categories. Changes over time in the excess mortality were assessed by testing the interaction between HF status and study year. In‐hospital HF increased in‐hospital mortality 1.79 times (odds ratio [OR], 1.79; 95% CI: 1.68–1.91). The excess mortality associated with HF increased by 4.3 times from 2001 to 2009 (P interaction

BackgroundRecent time trends and educational gradients characterizing out‐of‐hospital coronary deaths (OHCD) are poorly described. Methods and ResultsWe identified all deaths from coronary heart disease occurring outside the hospital in Norway during 1995 to 2009. Time trends were explored using Poisson regression analysis with year as the independent, continuous variable. Information on the highest achieved education was obtained from The National Education Database and classified as primary (up to 10 years of compulsory education), secondary (high school or vocational school), or tertiary (college/university). Educational gradients in OHCD were explored using Poisson regression, stratified by sex and age (

BackgroundCoronary heart disease (CHD) represents often the underlying conditions for the development of heart failure (HF). We aimed at exploring the burden and timing of HF complicating an acute myocardial infarction (AMI), using the total population of AMI patients hospitalized during 2001–2009 in Norway. Methods and ResultsA total of 86 771 patients with a first AMI during 2001–2009 and without previous HF were identified in the “Cardiovascular Disease in Norway” project and followed until HF development, death, or December 31, 2009. In 16 219 patients (18.7%), HF was present on admission or developed during hospitalization for the incident AMI. HF occurrence varied according to age (8.9%, 15.2%, and 25.6% among men and 10.2%, 16.8%, and 27.1% among women ages 25–54, 55–74, and 75–85 years). Among 63 853 patients discharged alive without HF, 8058 (12.6%) were hospitalized with or died because of HF during a median follow‐up time of 3.2 years. HF incidence rates (IRs) per 1000 person‐years during follow‐up were 31 (95% CI, 30–32) for men and 46 (95% CI, 44–47) for women (P

Focuses on stock price distributions that arise when prices follow a diffusion process with a stochastically varying volatility parameter. Use of analytic techniques to derive an explicit closed-form solution for the case where volatility is driven by an arithmetic Ornstein-Uhlenbeck process; Problems in the finance literature.

Lower bone mineral density (BMD) in smokers may be attributable to lower body weight or fat mass, rather than to a direct effect of smoking. We analyzed the effects of smoking exposure, assessed by plasma cotinine, and body fat on BMD and the risk of subsequent hip fracture. In the community-based Hordaland Health Study (HUSK), 3003 participants 46-49 years and 2091 subjects 71-74 years were included. Cotinine was measured in plasma and information on health behaviors was obtained from self-administered questionnaires. BMD and total body soft tissue composition were measured by dual X-ray absorptiometry. Information on hip fracture was obtained from computerized records containing discharge diagnoses for hospitalizations between baseline examinations 1997-2000 through December 31st, 2009. In the whole cohort, moderate and heavy smokers had stronger positive associations between fat mass and BMD compared to never smokers (differences in regression coefficient (95% CI) per % change in fat mass = 1.38 (0.24, 2.52) and 1.29 (0.17, 2.4), respectively). In moderate and heavy smokers there was a nonlinear association between BMD and fat mass with a stronger positive association at low compared to high levels of fat mass (Davies segmented test, p

Increasing differences in cardiovascular disease (CVD) mortality across levels of education have been reported in Norway. The aim of the study was to investigate educational inequalities in acute myocardial infarction (AMI) incidence and whether such inequalities have changed during the past decade using a nationwide longitudinal study design.Data on 141 332 incident (first) AMIs in Norway during 2001-2009 were obtained through the Cardiovascular Disease in Norway (CVDNOR) project. Educational inequalities in AMI incidence were assessed in terms of age-standardised incidence rates stratified on educational level, incidence rate ratios (IRR), relative index of inequality (RII) and slope index of inequality (SII). All calculations were conducted in four gender and age strata: Men and women aged 35-69 and 70-94 years.AMI Incidence rates decreased during 2001-2009 for all educational levels except in women aged 35-69 among whom only those with basic education had a significant decrease. In all gender and age groups; those with the highest educational level had the lowest rates. The strongest relative difference was found among women aged 35-69, with IRR (95% CI) for basic versus tertiary education 3.04 (2.85-3.24)) and RII (95% CI) equal to 4.36 (4.03-4.71). The relative differences did not change during 2001-2009 in any of the four gender and age groups, but absolute inequalities measured as SII decreased among the oldest men and women.There are substantial educational inequalities in AMI incidence in Norway, especially for women aged 35-69. Relative inequalities did not change from 2001 to 2009.

Etter at forskning på begynnelsen av 1990-tallet viste at B-vitaminet folat (også kalt folsyre; tidligere folinsyre) alene eller sammen med multivitaminer kunne redusere forekomsten av enkelte medfødte misdannelser, ble det i Norge et økende fokus på folat og svangerskap. I 1996 ble situasjonen rundt helse- og ernæringsmyndighetenes håndtering av folat-problematikken betegnet som "sikker kunnskap, usikker praksis" (1). Vi skal i det følgende forsøke å beskrive situasjonen 11 år senere. Noen spørsmål er avklart, andre er kommet til, praksis er klart endret, resultatene har latt vente på seg, og det knytter seg fortsatt usikkerhet til hva som er den beste helsepolitikken på dette området

Osteoclasts are the sole bone-resorbing cells and are formed by the fusion of osteoclast precursor cells (OCPs) derived from myeloid lineage cells. Animal studies reveal that circulating OCPs (cOCPs) in blood travel to bone and fuse with bone-resident osteoclasts. However, the characteristics of human cOCPs and their association with bone diseases remain elusive. We have identified and characterized human cOCPs and found a positive association between cOCPs and osteoclast activity. Sorted cOCPs have a higher osteoclastogenic potential than other myeloid cells and effectively differentiate into osteoclasts. cOCPs exhibit distinct morphology and transcriptomic signatures. The frequency of cOCPs in the blood varies among treatment-naive postmenopausal women and has an inverse correlation with lumbar spine bone density and a positive correlation with serum CTX, a bone resorption marker. The increased cOCPs in treatment-naive patients with osteoporosis were significantly diminished by denosumab, a widely used antiresorptive therapy. Our study reveals the distinctive identity of human cOCPs and the potential link between the dynamic regulation of cOCPs and osteoporosis and its treatment. Taken together, our study enhances our understanding of human cOCPs and highlights a potential opportunity to measure cOCPs through a simple blood test, which could potentially identify high-risk individuals.

Abstract: The European LeukemiaNet (ELN) genetic risk classifications were developed based on data from younger adults receiving intensive chemotherapy. Emerging analyses from patients receiving less-intensive therapies prompted a proposal for an ELN genetic risk classification specifically for this patient population., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Treatment of acute leukemia is gradually moving away from a "one-size-fits-all" approach, as scientific and clinical advances expand the arsenal of available targeted therapies. One of the recent additions is the group of menin inhibitors; oral, selective, small molecules that disrupt the interaction between the chromatin adapter menin, and an epigenetic regulator, the lysine methyltransferase 2A (KMT2A) complex. Two susceptible leukemia subtypes have been identified: (i) acute myeloid leukemia with a mutation in nucleophosmin 1 (NPM1), and (ii) any acute leukemia, myeloid or lymphoid, with a translocation resulting in the rearrangement of KMT2A. These leukemias share a distinct genetic expression, maintained by the KMT2A-menin interaction. Together they account for approximately 40% of patients with acute myeloid leukemia and 10% of patients with acute lymphoblastic leukemia. This spotlight review follows the journey of revumenib, as a representative of menin inhibitors, from bench to bedside. It focuses on the pathophysiology of leukemias sensitive to menin inhibition, delineation of how this understanding led to targeted drug development, and data from clinical trials. The important discovery of resistance mechanisms is also explored, as well as future directions in the use of menin inhibitors for treating leukemia.

Abstract: Although the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML aged ≥60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-, 11% intermediate-, and 78% had adverse-risk AML. ELN risk was prognostic for overall survival (OS) (P < .001) but did not stratify favorable- from intermediate-risk (P = .71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (n = 316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P < .05). A "mutation score" was calculated for each combination of these mutations, assigning adverse-risk patients to 2 risk groups: -1 to 0 points ("Beat-AML intermediate") vs 1+ points ("Beat-AML adverse"). In the final refined risk classification, ELN favorable- and intermediate-risk were combined into a newly defined "Beat-AML favorable-risk" group, in addition to mutation scoring within the ELN adverse-risk group. This approach redefines risk for older patients with ND AML and proposes refined Beat-AML risk groups with improved discrimination for OS (2-year OS, 48% vs 33% vs 11%, respectively; P < .001), providing patients and providers additional information for treatment decision-making., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Hypomethylating agents (HMA) and venetoclax (VEN) are commonly used in patients with IDH -mutated ( IDH m) acute myeloid leukemia (AML) ineligible for induction chemotherapy. While prior studies demonstrated high response and survival rates with HMA/VEN in IDH m AML, the impact of treatment modifications in real-world settings is unclear. We retrospectively reviewed 89 IDH m AML patients treated with HMA/VEN from January 2018 to June 2023. CR/CRi rates were 76% in newly diagnosed (ND) and 55% in relapsed/refractory (R/R) patients, and median overall survival was 29.2 months (ND) and 17.1 months (R/R), respectively. Treatment modifications were common. Early VEN reductions were associated with lower response rates but not worse survival. Prolonged cycles were not associated with worse response rates or survival. Significant neutropenia and ED visits or unplanned hospitalizations were considerable before and after CR/CRi, though febrile neutropenia decreased afterward. HMA/VEN is efficacious, with treatment modifications not affecting survival, though long-term toxicities are notable.

Aberrant expression of HOX and MEIS1 family genes, as seen in KMT2A-rearranged, NUP98-rearranged, or NPM1-mutated leukemias leads to arrested differentiation and leukemia development. HOX family genes are essential gatekeepers of physiologic hematopoiesis, and their expression is regulated by the interaction between KMT2A and menin. Menin inhibitors block this interaction, downregulate the abnormal expression of MEIS1 and other transcription factors and thereby release the differentiation block. Menin inhibitors show significant clinical efficacy against KMT2A-rearranged and NPM1-mutated acute leukemias, with promising potential to address unmet needs in various pediatric leukemia subtypes. In this collaborative initiative, pediatric and adult hematologists/oncologists, and stem cell transplant physicians have united their expertise to explore the potential of menin inhibitors in pediatric leukemia treatment internationally. Our efforts aim to provide a comprehensive clinical overview of menin inhibitors, integrating preclinical evidence and insights from ongoing global clinical trials. Additionally, we propose future international, inclusive, and efficient clinical trial designs, integrating pediatric populations in adult trials, to ensure broad access to this promising therapy for all children and adolescents with menin-dependent leukemias., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Comprehensive genomic sequencing is becoming a critical component in the assessment of hematologic malignancies, with broad implications for patients' management. In this context, unequivocally discriminating somatic from germline events is challenging but greatly facilitated by matched analysis of tumor:normal pairs of samples. In contrast to solid tumors, in hematologic malignancies conventional sources of normal control material (peripheral blood, buccal swabs, saliva) could be highly involved by the neoplastic process, rendering them unsuitable. In this work we describe our real-world experience using cell-free DNA (cfDNA) isolated from nail clippings as an alternate source of normal control material, through the dedicated review of 2,610 tumor:nail pairs comprehensively sequenced by MSK-IMPACT-heme. Overall, we found that nail cfDNA is a robust germline control for paired genomic studies. In a subset of patients, nail DNA may be contaminated by tumor DNA, reflecting unique attributes of the hematologic disease and transplant history. Contamination is generally low level, but significantly more common among patients with myeloid neoplasms (20.5%; 304/1,482) than among those with lymphoid diseases (5.4%; 61/1,128) and particularly enriched in myeloproliferative neoplasms with marked myelofibrosis. When identified in patients with lymphoid and plasma-cell neoplasms, mutations commonly reflected a myeloid profile and correlated with a concurrent/evolving clonal myeloid neoplasm. Donor DNA was identified in 22% (11/50) of nails collected after allogeneic stem-cell transplantation. In this cohort, an association with a recent history of graft-versus-host disease was identified. These findings should be considered as a potential limitation to the use of nails as a source of normal control DNA but could also provide important diagnostic information regarding the disease process.

Epidural steroid injections (ESIs) are a common and often effective treatment for radicular back pain. While oral glucocorticoids increase fracture incidence, little is known regarding fracture risk after ESI. This study investigated the incidence of fractures among individuals who received ESI and those who did not. We hypothesized that ESI exposure would be associated with an increased incidence of osteoporotic fracture and specifically vertebral fractures. Using 2005-2018 5% Medicare data, individuals with radicular pain who had ≥1 ESI and those who did not (non-ESI) were matched 1:10 by age, sex, and month of radicular pain diagnosis using exposure density sampling (EDS). Using a high-dimensional propensity score (HDPS) calculated based on the top 500 covariates across multiple data dimensions, ESI and non-ESI individuals were matched 1:1. Fractures were identified using validated ICD-9/10 diagnosis codes. Fracture incidence rate (IR) was calculated by group, and hazard ratios (HR) compared using Cox regression. 25 062 ESI patients and 221 735 non-ESI patients who met eligibility criteria were identified using EDS. Mean age was 76 years (74% female). Among ESI-treated individuals, there were 2296 fractures, IR 49.1 (95% CI: 47.2-51.2) per 1000 person years. For non-ESI individuals, there were 11 917 fractures, IR 35.2 (95% CI: 34.5-35.8). Individuals who received ESI had a greater hazard of fracture at typical osteoporotic sites, HR 1.39 (95% CI 1.33-1.46) by EDS and 1.32 (1.12-1.54) by HDPS, and greater hazard of vertebral fracture, 1.54 (1.45-1.64) by EDS and 1.69 (1.38-2.07) by HDPS. Patients who received greater cumulative ESI doses (≥3 in 1 year) had a higher risk of fractures within the first six months of follow-up. ESI exposure in older individuals is associated with an increased risk of fracture, suggesting there may be lasting detrimental skeletal effects of ESI. Further research into strategies to reduce fracture risk in this population is warranted., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Abstract: Although intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remission among older patients with nucleophosmin 1 (NPM1) mutations. Whether IC or HMA/VEN is superior in patients aged ≥60 years with NPM1-mutant AML is unknown. We performed an international, multicenter retrospective cohort study of 221 patients (147 IC and 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR) (defined as CR + CR with incomplete count recovery) rate was similar for IC and HMA/VEN (cCR, 85% vs 74%; P = .067). Although overall survival (OS) was favorable with IC in unselected patients compared with HMA/VEN (24-month OS, 59% [95% confidence interval (CI), 52-69%] vs 38% [95% CI, 27-55%]; P = .013), it was not statistically different among patients aged 60-75 years (60% [95% CI, 52-70%] vs 44% [95% CI, 29-66%]; P = .069) and patients who received an allogeneic stem cell transplant (70% [95% CI, 58-85%] vs 66% [95% CI, 44-100%]; P = .56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS, 65% [95% CI, 56-74%] with IC vs 40% [95% CI, 26-60%] with HMA/VEN; P = .009) and without FLT3 internal tandem duplication mutations might benefit from IC compared with HMA/VEN (24-month OS, 68% [95% CI, 59-79%] vs 43% [95% CI, 29-63%]; P = .008). In multivariable analysis, OS was not statistically different between patients treated with IC and HMA/VEN (hazard ratio for death with HMA/VEN vs IC, 0.71; 95% CI, 0.40-1.27; P = .25)., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Symptoms of obstructive sleep apnoea (OSA) overlap significantly with those of psychiatric disorders, making accurate diagnosis of OSA challenging within psychiatric settings. Diagnosing OSA in psychiatric patients is crucial because untreated OSA can exacerbate psychiatric symptoms, reduce treatment efficacy, and impair overall quality of life. This study aimed to determine the diagnostic accuracy of a readily accessible procedure for psychiatric patients in a real-world clinical setting by comparing the Somnocheck micro CARDIO ® (SCm) portable cardiorespiratory polygraphy device with the gold standard polysomnography (PSG)., Methods: This observational cohort study included consecutive psychiatric patients at intermediate to high risk for OSA based on screening with the STOP-Bang questionnaire, admitted to a single tertiary care centre between June 1, 2016 and December 31, 2022. The Apnoea-Hypopnoea-Index (AHI), Apnoea-Index (AI), Oxygen-Desaturation-Index (ODI), and minimum oxygen saturation were measured sequentially by SCm and PSG., Results: A total of 57 patients were analysed (median age 62.0 [Interquartile Range (IQR), 51.5-72.5] years; 34 [59.6%] men). Regarding AHI, no significant differences (AHI measured by PSG, median, 16.6 [IQR, 6.2-26.7] vs. AHI measured by SCm, median, 14.9 [IQR, 10.0-22.8]; p = 0.812; r = 0.71) were found between SCm and PSG. AI, ODI and minimum oxygen saturation differed significantly between SCm and PSG. Using optimised cut-off values (any OSA: AHI SCm ≥ 9.25), SCm showed high sensitivity (0.894) and high specificity (0.800) for the diagnosis of OSA, with an area under the receiver operating characteristic curve of 0.877., Conclusions: This study found that the SCm portable device was accurate in identifying psychiatric patients with OSA. AHI measurement by SCm provided reliable diagnostic performance in comparison with the gold standard polysomnography. These findings support the integration of polygraphic measurements into the routine sleep assessment of psychiatric patients. Early and accurate diagnosis of OSA in this population can significantly improve the management of both sleep disorders and psychiatric conditions, potentially enhancing overall treatment outcomes and quality of life for these patients., (© 2024. The Author(s).)

Purpose: Revumenib, an oral, small molecule inhibitor of the menin-lysine methyltransferase 2A (KMT2A) interaction, showed promising efficacy and safety in a phase I study of heavily pretreated patients with KMT2A -rearranged ( KMT2Ar ) acute leukemia. Here, we evaluated the activity of revumenib in individuals with relapsed/refractory (R/R) KMT2Ar acute leukemia., Methods: AUGMENT-101 is a phase I/II, open-label, dose-escalation and expansion study of revumenib conducted across 22 clinical sites in five countries (ClinicalTrials.gov identifier: NCT04065399). We report results from the phase II, registration-enabling portion. Individuals age ≥30 days with R/R KMT2Ar acute leukemia or with AML and nucleophosmin 1 ( NPM1 ) mutation were enrolled. Revumenib was administered once every 12 hours, at 163 mg (95 mg/m 2 if weight <40 kg) with a strong cytochrome P450 inhibitor, in 28-day cycles. The primary end points were the rate of complete remission (CR) or CR with partial hematologic recovery (CR + CRh) and safety. At a prespecified interim analysis, safety was assessed in all KMT2Ar treated patients; efficacy was assessed in those with centrally confirmed KMT2Ar . The separate NPM1 cohort of the trial is ongoing., Results: From October 1, 2021, to July 24, 2023, N = 94 patients (median [range] age, 37 [1.3-75] years) were treated. Grade ≥3 adverse events included febrile neutropenia (37.2%), differentiation syndrome (16.0%), and QTc prolongation (13.8%). In the efficacy-evaluable patients (n = 57), the CR + CRh rate was 22.8% (95% CI, 12.7 to 35.8), exceeding the null hypothesis of 10% ( P = .0036). Overall response rate was 63.2% (95% CI, 49.3 to 75.6), with 15 of 22 patients (68.2%) having no detectable residual disease., Conclusion: Revumenib led to high remission rates with a predictable safety profile in R/R KMT2Ar acute leukemia. To our knowledge, this trial represents the largest evaluation of a targeted therapy for these patients.

The FLT3 inhibitor quizartinib has been shown to improve overall survival when added to intensive induction chemotherapy ("7 + 3") in patients 18-75 years old with newly diagnosed AML harboring a FLT3- ITD mutation. However, the health economic implications of this approval are unknown. We evaluated the cost-effectiveness of quizartinib using a partitioned survival analysis model. One-way and probabilistic sensitivity analyses were conducted. In the base case scenario, the addition of quizartinib to 7 + 3 resulted in incremental costs of $289,932 compared with 7 + 3 alone. With an incremental gain of 0.84 quality-adjusted life years (QALYs) with quizartinib + 7 + 3 induction vs. 7 + 3 alone, the incremental cost-effectiveness ratio for the addition of quizartinib to standard 7 + 3 was $344,039/QALY. Only an 87% reduction in the average wholesale price of quizartinib or omitting quizartinib continuation therapy after completion of consolidation therapy and allogeneic hematopoietic cell transplant would make quizartinib a cost-effective option.

Background: Axial spondyloarthritis (AxSpA) is a chronic rheumatic disease characterized by spine inflammation, abnormal bone growth, and paradoxically osteoporosis and vertebral fractures. The pathogenesis of skeletal deficits in this disease is poorly understood., Purpose: We sought to evaluate volumetric bone mineral density (vBMD) and bone microarchitecture in patients with AxSpA and to identify disease-related factors associated with skeletal abnormalities., Methods: We enrolled patients between 2018 and 2021 as part of a 2-year prospective study at a single institution investigating skeletal health and the skeletal effects of interleukin-17 (IL-17) treatment. Patients with AxSpA who met Assessment in SpondyloArthritis International Society (ASAS) classification criteria by X-ray or had evidence of active inflammation on magnetic resonance imaging suggestive of sacroiliitis were referred to the study by their rheumatologists. We excluded those with a history of fragility fracture, multiple myeloma, Cushing's disease, primary hyperparathyroidism, osteomalacia, untreated vitamin D deficiency, secondary osteoporosis, or other systemic rheumatic diseases, as well as use of oral steroids for 2 or more weeks in the 6 months prior or current use of hormone replacement therapy, current oral bisphosphonate, past or current intravenous bisphosphonate, teriparatide, or denosumab therapies. A total of 1606 patients were screened for eligibility. Of these, 30 participants were enrolled (mean age 43 years, 50% male). Patients with AxSpA had dual-energy X-ray absorptiometry (DXA) measurements of areal BMD (aBMD) and high-resolution peripheral quantitative computed tomography (HR-pQCT) measurements of vBMD microarchitecture and failure load by finite element analysis. Standardized disease assessment tools used included the Bath Ankylosing Spondylitis Disease Activity (BASDAI), Metrology Index (BASMI), and Functional Index (BASFI)., Results: In the 30 included patients, mean DXA and HR-pQCT Z-scores were within 1 standard deviation (SD) of normal for all indices, except for total vBMD in males (-1.2 SD below mean). Mean symptom duration was 11.7 years and mean scores for BASDAI, BASFI, and BASMI were 4.6, 3.6, and 2.7, respectively (range 1-10, 10 = severe limitation). Longer disease duration was associated with more severe skeletal deficits at the hip and tibia-specifically, lower hip aBMD, lower meta- and inner-trabecular vBMD, lower trabecular number, and higher trabecular separation and heterogeneity., Conclusion: This study of 30 patients with AxSpA found that abnormalities in bone density and microarchitecture at weightbearing sites were associated with longer disease duration. Because of its small sample size, larger studies are needed to better characterize the pathogenic disease factors that govern skeletal damage in AxSpA., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: WY, MD, declares a relationship with Novartis. SMG, MD, reports relationships with UCB and Novartis. EMS, MD, reports a relationship with Radius Pharmaceuticals. The other authors declare no potential conflicts of interest., (© The Author(s) 2024.)

An increasing number of acute myeloid leukemia (AML) therapeutics have been developed, not as cytotoxic therapies, but rather as targeted agents able to restore the aberrant and leukemogenic "block" in normal differentiation. All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are classic examples of differentiating agents for treatment of acute promyelocytic leukemia (APL); newer therapies functioning through differentiation include isocitrate dehydrogenase (IDH) 1 and 2 inhibitors, FMS-like tyrosine kinase 3 (FLT3) inhibitors, and menin inhibitors. The terminal differentiation of leukemic blasts via differentiating agent therapy can lead to a constellation of signs and symptoms, originally referred to as "retinoic acid syndrome" and now termed "differentiation syndrome" (DS), characterized predominantly by systemic inflammatory response system (SIRS)-like features of dyspnea, pulmonary infiltrates, pleural and pericardial effusions, unexplained fevers, hypotension, edema, and renal insufficiency. DS in patients with newly diagnosed APL is generally straightforward to identify, however DS in patients with multiply relapsed AML can be more challenging to diagnose, due to non-specific signs and symptoms which can be mistakenly attributed to infectious etiologies or the underlying refractory leukemia itself. Prompt consideration of DS, rapid initiation of systemic corticosteroids, and early cytoreduction in the setting of concomitant hyperleukocytosis, are essential for optimal management., (Copyright © 2024 American Society of Hematology.)

Abstract: Treatment with enasidenib, a selective mutant isocitrate dehydrogenase isoform 2 (IDH2) inhibitor, has been associated with the development of differentiation syndrome (DS) in patients with acute myeloid leukemia (AML). Studies on the incidence and clinical features of DS are limited in this setting, and diagnosis is challenging because of nonspecific symptoms. This study assessed the incidence, diagnostic criteria, risk factors, and correlation with clinical response of DS based on the pooled analysis of 4 clinical trials in patients with IDH2-mutated AML treated with enasidenib as monotherapy, or in combination with azacitidine or with chemotherapy. Across the total AML population, 67 of 643 (10.4%) had ≥1 any-grade DS event, with highest incidence in patients who received enasidenib plus azacitidine and lowest incidence in patients who received enasidenib plus chemotherapy (13/74 [17.6%] and 2/93 [2.2%]). The most common symptoms of DS were dyspnea/hypoxia (80.6%) and pulmonary infiltrate (73.1%). Median time to onset of first DS event across all studies was 32 days (range, 4-129). Most patients (88.1%) received systemic steroids for treatment of DS. Evaluation of baseline risk factors for DS identified higher levels of bone marrow blasts and lactate dehydrogenase as independent factors associated with increased grade 3 to 5 DS risk. Overall, these results suggest that DS associated with IDH inhibition is manageable, given the benefits of enasidenib treatment in IDH2-mutated AML. We further characterized enasidenib-related DS in these patients and identified risk factors, which could be used for DS management in clinical practice. These trials were registered at www.ClinicalTrials.gov as # NCT01915498, NCT02577406, NCT02677922, and NCT02632708., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)