Real-world overall survival and characteristics of patients with ER-zero and ER-low HER2-negative breast cancer treated as triple-negative breast cancer: a Swedish population-based cohort study.

Background: Estrogen receptor-low (ER-low) HER2-negative breast cancer has similar pathological and molecular characteristics as triple-negative breast cancer (TNBC), and it is questionable whether it should be considered a separate entity. When the international guidelines lowered the cutoff for ER positivity to ≥1% in 2010, the ≥10% threshold was kept in Sweden. ER-low breast cancer (ER 1-9%) is thus in Sweden treated as TNBC. We aimed to describe patient and tumor characteristics, treatment patterns and overall survival in a Swedish population-based cohort of patients with ER-zero and ER-low HER2-negative breast cancer treated as TNBC. Methods: All TNBC cases diagnosed in Sweden 2008-2020 were included in a population-based cohort study. Patient, tumor and treatment characteristics were analyzed by ER-status (ER 0% vs 1-9%), and associations between subgroups compared using χ2 test. Survival endpoint was overall survival (OS), and Kaplan-Meier curves were estimated. Cox proportional hazards models were used to estimate adjusted hazard ratios comparing ER-low to ER-zero. Findings: Of the 5655 tumors, 90.1% had an ER expression of 0%, while 9.9% were ER-low. ER-low tumors were grade III in 69.4% (80.8% in ER-zero tumors, p-value = 0.001), with a median Ki67 of 60% (63% in ER-zero tumors, p-value = 0.005). There were no significant differences in given chemotherapy (p = 0.546). A pathological complete response (pCR) was achieved in 28.1% of ER-low tumors (25.1% in ER-zero tumors). In the unadjusted analysis of OS, women with ER-low disease had a borderline but not significantly better OS than those with ER-zero disease (HR 0.84 (95% CI 0.71-1.00), p = 0.052). ER-status 1-9% vs 0% was not associated with OS in the multivariable analysis (HR 1.11 (0.90-1.36)). Distant disease-free survival did not differ by ER-status 0% vs 1-9% (HR 0.97 for ER-zero vs ER-low (0.62-1.53), p = 0.905). After preoperative treatment, the impact of pCR for OS did not significantly differ between ER-zero or ER-low disease. Interpretation: ER-low HER2-negative breast cancer has characteristics and prognosis similar to TNBC, when treated in the same way. Therefore, it seems reasonable to use a ≥10% threshold for ER positivity. This would provide patients with ER-low tumors the same treatment opportunities as patients with TNBC, within studies and within clinical routine. Funding: This work was financially supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, in accordance with terms and conditions of a Master Collaboration Agreement between the company and Karolinska Institutet.

Have the recent advancements in cancer therapy and survival benefitted patients of all age groups across the Nordic countries? NORDCAN survival analyses 2002-2021.

BACKGROUND: Since the early 2000s, overall and site-specific cancer survival have improved substantially in the Nordic countries. We evaluated whether the improvements have been similar across countries, major cancer types, and age groups. MATERIAL AND METHODS: Using population-based data from the five Nordic cancer registries recorded in the NORDCAN database, we included a cohort of 1,525,854 men and 1,378,470 women diagnosed with cancer (except non-melanoma skin cancer) during 2002-2021, and followed for death until 2021. We estimated 5-year relative survival (RS) in 5-year calendar periods, and percentage points (pp) differences in 5-year RS from 2002-2006 until 2017-2021. Separate analyses were performed for eight cancer sites (i.e. colorectum, pancreas, lung, breast, cervix uteri, kidney, prostate, and melanoma of skin). RESULTS: Five-year RS improved across nearly all cancer sites in all countries (except Iceland), with absolute differences across age groups ranging from 1 to 21 pp (all cancer sites), 2 to 20 pp (colorectum), -1 to 36 pp (pancreas), 2 to 28 pp (lung), 0 to 9 pp (breast), -11 to 26 pp (cervix uteri), 2 to 44 pp (kidney), -2 to 23 pp (prostate) and -3 to 30 pp (skin melanoma). The oldest patients (80-89 years) exhibited lower survival across all countries and sites, although with varying improvements over time. INTERPRETATION: Nordic cancer patients have generally experienced substantial improvements in cancer survival during the last two decades, including major cancer sites and age groups. Although survival has improved over time, older patients remain at a lower cancer survival compared to younger patients.

Survival trends for patients diagnosed with cutaneous malignant melanoma in the Nordic countries 1990-2016: The NORDCAN survival studies.

BACKGROUND: The survival in patients diagnosed with cutaneous malignant melanoma (CMM) has improved in the Nordic countries in the last decades. It is of interest to know if these improvements are observed in all ages and for both women and men. METHODS: Patients diagnosed with CMM in the Nordic countries in 1990-2016 were identified in the NORDCAN database. Flexible parametric relative survival models were fitted, except for Iceland where a non-parametric Pohar-Perme approach was used. A range of survival metrics were estimated by sex, both age-standardised and age-specific. RESULTS: The 5-year relative survival improved in all countries, in both women and men and across age. While the improvement was more pronounced in men, women still had a higher survival at the end of the study period. The survival was generally high, with age-standardised estimates of 5-year relative survival towards the end of the study period ranging from 85% in Icelandic men to 95% in Danish women. The age-standardised and reference-adjusted 5-year crude probability of death due to CMM ranged from 5% in Danish and Swedish women to 13% in Icelandic men. CONCLUSION: Although survival following CMM was relatively high in the Nordic countries in 1990, continued improvements in survival were observed throughout the study period in both women and men and across age.

Childbirth rates in women with myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPN) are associated with inferior pregnancy outcome, however, little is known about fertility and childbearing potential in women with MPN. In this study we aimed to describe reproductive patterns, as well as to quantify risk of miscarriage and stillbirth. Women aged 15-44 years with an MPN diagnosis 1973-2018, were identified in Swedish health care registers, and age-matched 1:4 to population controls. We identified 1141 women with MPN and 4564 controls. Women with MPN had a lower rate of childbirth (hazard ratio [HR] with 95% confidence interval was 0.78 (0.68-0.90)). Subgroup analysis showed that the rate was not significantly reduced in essential thrombocythemia, HR 1.02 (0.86-1.22) while the HR was 0.50 (0.33-0.76) in PV and 0.45 (0.28-0.74) in PMF. The risk of miscarriage was not significantly increased before MPN diagnosis, the HR during follow-up after diagnosis was 1.25 (0.89-1.76). Women with MPN were more likely to have had a previous stillbirth. Women with MPN had fewer children at diagnosis, and fewer children in total. In conclusion, the childbirth rate was lower among women with MPN than controls, but not among women with essential thrombocythemia.

Time trends in the use of curative treatment in men 70 years and older with nonmetastatic prostate cancer.

BACKGROUND: Undertreatment of otherwise healthy men in their seventies with prostate cancer has been reported previously. MATERIAL AND METHODS: Using information in a Swedish prostate cancer research database, patterns of management and cancer-specific mortality were compared across age groups in over 70,000 men diagnosed with intermediate- or high-risk nonmetastatic prostate cancer between 2008 and 2020. Crude probabilities of death were estimated non-parametrically. Staging procedures, primary treatment, and cancer death were compared using regression models, adjusting for patient and tumor characteristics. RESULTS: During the study period, the proportion of men treated with curative intent increased in ages 70-74 (intermediate-risk from 45% to 72% and high-risk from 49% to 84%), 75-79 (intermediate-risk from 11% to 52% and high-risk from 12% to 70%), and 80-84 years (intermediate-risk from < 1% to 14% and high-risk from < 1% to 30%). Older age was associated with lower likelihoods of staging investigations and curative treatment, also after adjustment for tumor characteristics and comorbidity. Men treated with curative intent and those initially managed conservatively had lower crude risks of prostate cancer death than men receiving androgen deprivation treatment (ADT). In adjusted analyses, ADT was associated with higher prostate cancer mortality than curative treatment across ages and risk groups. Among men managed conservatively, prostate cancer mortality was higher in ages 70 and above. INTERPRETATION: Use of curative treatment increased substantially in older men with prostate cancer between 2008 and 2020. Our findings suggest reduced age-bias and under-treatment, likely reflecting improved individualized decision-making and adherence to guidelines recommending more active management of older men.

Prediction of pregnancy-related complications in women undergoing assisted reproduction, using machine learning methods.

OBJECTIVE: To use machine learning methods to develop prediction models of pregnancy complications in women who conceived with assisted reproductive techniques (ART). DESIGN: A nation-wide register-based cohort study with prospectively collected data. SETTING: Swedish national registers and nationwide quality IVF register. PATIENT(S): all nulliparous women who achieved birth within the first 3 ART treatment cycles between 2008 and 2016 in Sweden. INTERVENTION(S): Characteristics before the use of ART, such as demographics and medical history, were considered potential predictors in the development of before treatment prediction models. ART treatment details were further included in after treatment prediction models. MAIN OUTCOME MEASURE(S): Potential diagnoses of preeclampsia, placental complications (previa, accreta, and abruption), and postpartum hemorrhage were identified using the International Classification of Diseases recorded in the Swedish Medical Birth and Patient registers, respectively. Multiple prediction model algorithms were performed and compared for each outcome and treatment cycle, including logistic regression, decision tree model, naïve Bayes classification, support vector machine, random forest, and gradient boosting. The performance of each model was assessed with C statistic, and nested cross-validation was used to aid model selection and hyperparameter tuning. RESULT(S): A total of 14,732 women gave birth after the first (N = 7,302), second (N = 4,688), or third (N = 2,742) ART cycle, representing birth rates of 24.1%, 23.8%, and 22.0%. Overall prediction performance did not vary much across the different methods used. In the first cycle, the before treatment prediction performance was at best 66%, 66%, and 60% for preeclampsia, placental complications, and postpartum hemorrhage, respectively. Inclusion of after treatment characteristics conferred slight improvement (approximately 1%-5%), as did prediction in later cycles (approximately 1%-5%). The top influential and consistent predictors included age, region of residence, infertility diagnosis, and type of embryo transfer (fresh or frozen) in the later (2nd and 3rd) cycles. Body mass index was a top predictor of preeclampsia and was also influential for placental complications but not for postpartum hemorrhage. CONCLUSION(S): The combined use of demographics, medical history, and ART treatment information was not enough to confidently predict serious pregnancy complications in women who conceived with ART. Future studies are needed to assess if additional longitudinal follow-up during pregnancy can improve the prediction to allow clinical protocol development.

Whole genome case-control study of central nervous system toxicity due to antimicrobial drugs.

A genetic predisposition to central nervous system (CNS) toxicity induced by antimicrobial drugs (antibiotics, antivirals, antifungals, and antiparasitic drugs) has been suspected. Whole genome sequencing of 66 cases and 833 controls was performed to investigate whether antimicrobial drug-induced CNS toxicity was associated with genetic variation. The primary objective was to test whether antimicrobial-induced CNS toxicity was associated with seventeen efflux transporters at the blood-brain barrier. In this study, variants or structural elements in efflux transporters were not significantly associated with CNS toxicity. Secondary objectives were to test whether antimicrobial-induced CNS toxicity was associated with genes over the whole genome, with HLA, or with structural genetic variation. Uncommon variants in and close to three genes were significantly associated with CNS toxicity according to a sequence kernel association test combined with an optimal unified test (SKAT-O). These genes were LCP1 (q = 0.013), RETSAT (q = 0.013) and SFMBT2 (q = 0.035). Two variants were driving the LCP1 association: rs6561297 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51-8.46]) and the regulatory variant rs10492451 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51-8.46]). No common genetic variant, HLA-type or structural variation was associated with CNS toxicity. In conclusion, CNS toxicity due to antimicrobial drugs was associated with uncommon variants in LCP1, RETSAT and SFMBT2.

Fasting plasma metabolites reflecting meat consumption and their associations with incident type 2 diabetes in two Swedish cohorts.

BACKGROUND: Consumption of processed red meat has been associated with increased risk of developing type 2 diabetes (T2D), but challenges in dietary assessment call for objective intake biomarkers. OBJECTIVES: This study aimed to investigate metabolite biomarkers of meat intake and their associations with T2D risk. METHODS: Fasting plasma samples were collected from a case-control study nested within Västerbotten Intervention Program (VIP) (214 females and 189 males) who developed T2D after a median follow-up of 7 years. Panels of biomarker candidates reflecting the consumption of total, processed, and unprocessed red meat and poultry were selected from the untargeted metabolomics data collected on the controls. Observed associations were then replicated in Swedish Mammography clinical subcohort in Uppsala (SMCC) (n = 4457 females). Replicated metabolites were assessed for potential association with T2D risk using multivariable conditional logistic regression in the discovery and Cox regression in the replication cohorts. RESULTS: In total, 15 metabolites were associated with ≥1 meat group in both cohorts. Acylcarnitines 8:1, 8:2, 10:3, reflecting higher processed meat intake [r > 0.22, false discovery rate (FDR) < 0.001 for VIP and r > 0.05; FDR < 0.001 for SMCC) were consistently associated with higher T2D risk in both data sets. Conversely, lysophosphatidylcholine 17:1 and phosphatidylcholine (PC) 15:0/18:2 were associated with lower processed meat intake (r < -0.12; FDR < 0.023, for VIP and r < -0.05; FDR < 0.001, for SMCC) and with lower T2D risk in both data sets, except for PC 15:0/18:2, which was significant only in the VIP cohort. All associations were attenuated after adjustment for BMI (kg/m2). CONCLUSIONS: Consistent associations of biomarker candidates involved in lipid metabolism between higher processed red meat intake with higher T2D risk and between those reflecting lower intake with the lower risk may suggest a relationship between processed meat intake and higher T2D risk. However, attenuated associations after adjusting for BMI indicates that such a relationship may at least partly be mediated or confounded by BMI.

Genetic diversity and recent ancestry based on whole-genome sequencing of endangered Swedish cattle breeds.

Several indigenous cattle breeds in Sweden are endangered. Conservation of their genetic diversity and genomic characterization is a priority.Whole-genome sequences (WGS) with a mean coverage of 25X, ranging from 14 to 41X were obtained for 30 individuals of the breeds Fjällko, Fjällnära, Bohuskulla, Rödkulla, Ringamåla, and Väneko. WGS-based genotyping revealed 22,548,028 variants in total, comprising 18,876,115 single nucleotide polymorphisms (SNPs) and 3,671,913 indels. Out of these, 1,154,779 SNPs and 304,467 indels were novel. Population stratification based on roughly 19 million SNPs showed two major groups of the breeds that correspond to northern and southern breeds. Overall, a higher genetic diversity was observed in the southern breeds compared to the northern breeds. While the population stratification was consistent with previous genome-wide SNP array-based analyses, the genealogy of the individuals inferred from WGS based estimates turned out to be more complex than expected from previous SNP-array based estimates. Polymorphisms and their predicted phenotypic consequences were associated with differences in the coat color phenotypes between the northern and southern breeds. Notably, these high-consequence polymorphisms were not represented in SNP arrays, which are used routinely for genotyping of cattle breeds.This study is the first WGS-based population genetic analysis of Swedish native cattle breeds. The genetic diversity of native breeds was found to be high. High-consequence polymorphisms were linked with desirable phenotypes using whole-genome genotyping, which highlights the pressing need for intensifying WGS-based characterization of the native breeds.

Risk of obstetric and perinatal complications in women presenting with breast cancer during pregnancy and the first year postpartum in Sweden 1973-2017: A population-based matched study.

INTRODUCTION: For women presenting with breast cancer during pregnancy, treatment guidelines were historically restricted to only surgical treatment. Over the past decades, chemotherapy administered during pregnancy has been gradually introduced. Although breast cancer treatments during ongoing pregnancy have been deemed safe, detailed information on potential obstetric risks is lacking. We aimed to assess the risk of adverse obstetric and perinatal outcomes of breast cancer in pregnancy and within 1 year postpartum and in relation to trimester at breast cancer diagnosis, tumor stage, and cancer treatment during pregnancy. MATERIAL AND METHODS: Population-based matched study. Women diagnosed with breast cancer during pregnancy in 1973-2017 were identified in the Swedish Cancer Register and the Medical Birth Register, with additional information from the National Quality Register for Breast Cancer. Each birth with maternal breast cancer (n = 208 pregnant, n = 672 postpartum) was matched by age, calendar year, and birth order to 10 unexposed births from cancer-free women in the population (n = 2080 and n = 6720). Adjusted conditional logistic and multinomial regression models were used to estimate odds ratios and relative risk ratios, commonly denoted relative risks (RR) with 95% confidence intervals (CI), of adverse obstetric and perinatal outcomes. RESULTS: Breast cancer during pregnancy was associated with higher risks of preterm birth, both planned (RR 67.1, 95% CI 33.2-135.6) and spontaneous preterm birth (RR 3.8, 95% CI 2.0-7.5), and low birthweight (<2500 g: RR 7.5, 95% CI 4.9-11.3). The associated risks were higher if the breast cancer was diagnosed in the second trimester, and of similar magnitude irrespective of stage and treatment groups. There was a higher risk of low birthweight for gestational age (<25th centile) if breast cancer was diagnosed in the first trimester (RR 2.8, 95% CI 1.1-7.3). Risks of other pregnancy complications were similar to those of unexposed women, as were risks of neonatal mortality and malformations. Postpartum breast cancer was only associated with bleeding during pregnancy (RR 1.6, 95% CI 1.0-2.8). CONCLUSIONS: Preterm birth and related adverse outcomes were more common in women diagnosed with breast cancer during pregnancy. Reassuringly, breast cancer was not associated with other maternal pregnancy complications or adverse outcomes in children.

Risk factors for the increasing incidence of pregnancy-associated cancer in Sweden - a population-based study.

INTRODUCTION: The incidence of cancer during pregnancy and within first year post-delivery, ie pregnancy-associated cancer (PAC), is increasing in many countries, but little is known about risk factors for these trends. This study quantified incidence of PAC by trimesters and post-delivery periods, and assessed the role of maternal age, parity, immigrant status, education, smoking and body mass index for the risk and incidence trends of PAC. MATERIAL AND METHODS: We used data from the national birth and cancer registers in Sweden during 1973-2017 to define a register-based cohort of women aged 15-44 years. Incidence rates of PAC during pregnancy and up to 1 year post-delivery were calculated per 100 000 deliveries per year. Poisson regression with multiple imputation estimated incidence rate ratios with 95% confidence intervals adjusted by year, age, previous parity, immigrant status, education, smoking and BMI during 1990-2017, when information on risk factors was available. RESULTS: Among 4 557 284 deliveries, a total of 1274 (during pregnancy) and 3355 (within 1 year post-delivery) cases of PAC were diagnosed, with around 50 cases/year diagnosed during pregnancy and 110 cases/year during the first year post-delivery in the latest period 2015-2017. The most common cancer types during pregnancy were malignant melanoma, breast and cervical cancer, together accounting for 57% of cases during pregnancy and 53% during the first year post-delivery. The numbers of PAC were lower during pregnancy than during post-delivery for all tumor types with lowest numbers during first trimester. The PAC incidence rates increased over calendar time. High maternal age at diagnosis, smoking, nulliparity and non-immigrant background were associated with significantly higher risks of PAC. The increasing PAC incidence was in part explained by higher maternal age over time, but not by the other factors. CONCLUSIONS: High maternal age is the strongest risk factor for PAC. We show for the first time that smoking, nulliparity and non-immigrant background are also contributing risk factors for PAC. However, only high maternal age contributed significantly to the increasing incidence. Further studies on other potential risk factors for PAC are warranted, since our results indicate that age on its own does not fully explain the increase.

Genetic diversity and historical demography of underutilised goat breeds in North-Western Europe.

In the last decade, several studies aimed at dissecting the genetic architecture of local small ruminant breeds to discover which variations are involved in the process of adaptation to environmental conditions, a topic that has acquired priority due to climate change. Considering that traditional breeds are a reservoir of such important genetic variation, improving the current knowledge about their genetic diversity and origin is the first step forward in designing sound conservation guidelines. The genetic composition of North-Western European archetypical goat breeds is still poorly exploited. In this study we aimed to fill this gap investigating goat breeds across Ireland and Scandinavia, including also some other potential continental sources of introgression. The PCA and Admixture analyses suggest a well-defined cluster that includes Norwegian and Swedish breeds, while the crossbred Danish landrace is far apart, and there appears to be a close relationship between the Irish and Saanen goats. In addition, both graph representation of historical relationships among populations and f4-ratio statistics suggest a certain degree of gene flow between the Norse and Atlantic landraces. Furthermore, we identify signs of ancient admixture events of Scandinavian origin in the Irish and in the Icelandic goats. The time when these migrations, and consequently the introgression, of Scandinavian-like alleles occurred, can be traced back to the Viking colonisation of these two isles during the Viking Age (793-1066 CE). The demographic analysis indicates a complicated history of these traditional breeds with signatures of bottleneck, inbreeding and crossbreeding with the improved breeds. Despite these recent demographic changes and the historical genetic background shaped by centuries of human-mediated gene flow, most of them maintained their genetic identity, becoming an irreplaceable genetic resource as well as a cultural heritage.

Were cancer patients worse off than the general population during the COVID-19 pandemic? A population-based study from Norway, Denmark and Iceland during the pre-vaccination era.

Background: In a population-based setting, we investigated the risks of testing positive for SARS-CoV-2 and developing severe COVID-19 outcomes among cancer patients compared with the general population. Methods: In nationwide cohorts, we identified all individuals in Norway, Denmark and Iceland who tested positive for SARS-CoV-2 or had a severe COVID-19 outcome (hospitalisation, intensive care, and death) from March until December 2020, using data from national health registries. We estimated standardised incidence ratios (SIRs) with 95% confidence intervals (CIs) comparing cancer patients with the general population. Findings: During the first wave of the pandemic, cancer patients in Norway and Denmark had higher risks of testing SARS-CoV-2 positive compared to the general population. Throughout 2020, recently treated cancer patients were more likely to test SARS-CoV-2 positive. In Iceland, cancer patients experienced no increased risk of testing positive. The risk of COVID-19-related hospitalisation was higher among cancer patients diagnosed within one year of hospitalisation (Norway: SIR = 2.43, 95% CI 1.89-3.09; Denmark: 2.23, 1.96-2.54) and within five years (Norway: 1.58, 1.35-1.83; Denmark: 1.54, 1.42-1.66). Risks were higher in recently treated cancer patients and in those diagnosed with haematologic malignancies, colorectal or lung cancer. Risks of COVID-19-related intensive care and death were higher among cancer patients. Interpretation: Cancer patients were at increased risk of testing positive for SARS-CoV-2 during the first pandemic wave when testing availability was limited, while relative risks of severe COVID-19 outcomes remained increased in cancer patients throughout 2020. Recent cancer treatment and haematologic malignancy were the strongest risk factors. Funding: Nordic Cancer Union.

Genome-wide association study on abdomen depth, head width, hip width, and withers height in native cattle of Guilan (Bos indicus).

Native breeds in any country are a national capital, and their preservation is of great importance. Native Cattle of Guilan (NCG) is one of the few pure native breeds in Iran and the West Asia region. During the last decade, NCG population has decreased by more than 40%. This study aimed to identify significant single nucleotide polymorphisms (SNPs) and candidate genes associated with meat production traits in NCG using a genome-wide association study (GWAS). The blood and hair samples were collected from 72 NCG individuals and genotyped using the Illumina Bovine SNP50 chip. The results of the genomic scan showed that several SNPs were associated with abdominal depth, head width, hip width, and withers height in NCG. Several candidate genes were identified, including multiple epidermal growth factor-like domains 11 (MEGF11), Methionine Sulfoxide Reductase A (MSRA), chondroitin sulfate synthase 3 (CHSY3), Cyclin-Dependent Kinase 7 (CDK7), and Parkin (PRKN) genes, which are involved in muscle growth, meat tenderness, differentiation of fat cells, fat metabolism, and adipogenesis. These genes can contribute to meat quantity and quality in NCG. This study provided valuable insights into the genetics of NCG and the identification of effective genes associated with meat production traits. The results of this study could be used for the preservation and sustainable use of this breed of native cattle, as an important genetic resource in Iran.

Relation between αS1-casein, genotype, and quality traits of milk from Swedish dairy goats.

Locally produced food is becoming popular among Swedish consumers. One product that has increased in popularity is artisan-manufactured goat cheese, and although the dairy goat industry in Sweden is small-scale, production is gradually increasing. In goats, the CSN1S1 gene regulates expression of the protein αS1-casein (αS1-CN), which has been found to be important for cheese yield. Over the years, breeding animals have been imported to Sweden from Norway. Historically, a high frequency of the Norwegian goat population carried a polymorphism at the CSN1S1 gene. This polymorphism, called the Norwegian null allele (D), leads to zero or significantly reduced expression of αS1-CN. Using milk samples from 75 goats, this study investigated associations between expression of αS1-CN and genotype at the CSN1S1 gene on milk quality traits from Swedish Landrace goats. Milk samples were grouped according to relative level of αS1-CN (low: 0-6.9% of total protein; medium-high: 7-25% of total protein) and genotype (DD, DG, DA/AG/AA). While the D allele leads to extremely low expression of αS1-CN, the G allele is low expressing and the A allele is highly expressing for this protein. Principal component analysis was used to explore the total variation in milk quality traits. To evaluate the effect of different allele groups on milk quality attributes, 1-way ANOVA and Tukey pairwise comparison tests were used. The majority (72%) of all goat milk samples investigated showed relative αS1-CN content of 0% to 6.82% of total protein. The frequency of individuals homozygous for the Norwegian null allele (DD) was 59% in the population of sampled goats, and only 15% carried at least one A allele. A low relative concentration of αS1-CN was associated with lower total protein, higher pH, and higher relative concentration of ß-casein and levels of free fatty acids. Milk from goats homozygous for the null allele (DD) showed a similar pattern as milk with low relative concentration of αS1-CN, but total protein was only numerically lower, and somatic cell count and αS2-CN were higher than for the other genotypes. The associations between levels of αS1-CN and the investigated genotype at the CSN1S1 gene indicate a need for a national breeding program for Swedish dairy goats.

Improving communication of cancer survival statistics-feasibility of implementing model-based algorithms in routine publications.

BACKGROUND: Routine reporting of cancer patient survival is important, both to monitor the effectiveness of health care and to inform about prognosis following a cancer diagnosis. A range of different survival measures exist, each serving different purposes and targeting different audiences. It is important that routine publications expand on current practice and provide estimates on a wider range of survival measures. We examine the feasibility of automated production of such statistics. METHODS: We used data on 23 cancer sites obtained from the Cancer Registry of Norway (CRN). We propose an automated way of estimating flexible parametric relative survival models and calculating estimates of net survival, crude probabilities, and loss in life expectancy across many cancer sites and subgroups of patients. RESULTS: For 21 of 23 cancer sites, we were able to estimate survival models without assuming proportional hazards. Reliable estimates of all desired measures were obtained for all cancer sites. DISCUSSION: It may be challenging to implement new survival measures in routine publications as it can require the application of modeling techniques. We propose a way of automating the production of such statistics and show that we can obtain reliable estimates across a range of measures and subgroups of patients.

Rilmazafone: A designer benzodiazepine pro-drug involved in fatal intoxications.

Rilmazafone is a pro-drug that can be prescribed in Japan to treat insomnia. Rilmazafone metabolizes into active compounds by a ring closure resulting in a triazolo benzodiazepine structure similar to alprazolam. In mid-2022, the National Board of Forensic Medicine in Sweden were requested to investigate two separate deaths with the suspected use of pagoclone. Packages labeled "Pagoclone" were found at each scene that was suspected to contain rilmazafone based on website information. During screening by high resolution mass spectrometry, rilmazafone metabolites were presumptively identified. Due to the lack of reference material for the active metabolites, the metabolites were synthesized in house and quantification of the compounds identified in the two autopsy cases was prompted. In Case 1, femoral blood concentrations of 7.9, 65 and 170 ng/g of the metabolites rilmazolam, N-desmethyl rilmazolam and di-desmethyl rilmazolam, respectively, were detected. Additional toxicological findings included the medications haloperidol, alimemazine, fluoxetine, olanzapine and acetaminophen. In Case 2, femoral blood concentrations of 1.7, 1.4 and 70 ng/g of rimazolam, N-desmethyl rilmazolam and di-desmethyl rilmazolam, respectively, were detected. Additional toxicological findings included loperamide, alimemazine and pregabalin. The intake of rilmazafone was determined as the cause of death in Case 1 and contributed in the Case 2.

Influence of various assumptions for the individual TNM components on the TNM stage using Nordic cancer registry data.

BACKGROUND: The stage at diagnosis is one of the most important predictors for cancer survival. TNM stage is constructed from T (tumor size), N (nodal spread), and M (distant metastasis) components. In many notifications to cancer registries, TNM information is incomplete with unknown N and/or M. We aimed to evaluate the influence of various assumptions for recoding missing N (NX) and M (MX) as N0 and M0 on the proportion with available TNM stage, stage-distribution, and stage-specific relative survival. MATERIAL AND METHODS: We identified 140,201 patients diagnosed with incident cancer of the colon, rectum, lung, breast, or kidney during 2014-2016 in Denmark, Norway, Sweden, or Iceland. Information on TNM were obtained from cancer registry records used for an update of the Nordic cancer statistics database NORDCAN. Patients were followed for death or emigration through 2017. We calculated proportions of available TNM stage, stage distribution, and stage-specific relative survival under different approaches for each cancer site and country. RESULTS: Application of the assumptions yielded higher numbers of cases with available TNM stage for stages 0-I, II, and III. We observed only minor differences in stage-specific one-year relative survival when applying N0M0 for missing N and M, especially for high completeness of TNM registrations, whereas relative survival for remaining cases with missing TNM stage declined substantially. CONCLUSION: We found no major changes in stage-specific one-year relative survival applying N0M0 for NXMX. We conclude that complete TNM information is preferable to making assumptions, but it seems reasonable to consider assuming N0M0 for missing N and M in future studies based on the Nordic cancer registries. An automatic algorithm, though, is not recommended without considering potential area-specific reasons for frequent use of NX and MX. Clinicians should be urged to report complete TNM information to improve surveillance of the TNM stage.

Understanding the Intricacies of Delivering Compassionate Care in the Intensive Care Unit and What Hinders It: A Qualitative Study of Members of 2 Critical Care Societies.

BACKGROUND: Patient-centered care is increasing in importance especially in the post-coronavirus disease 2019 (COVID-19) pandemic era. We sought to understand factors affecting compassionate care faced by intensivists in the intensive care unit (ICU). METHODS: Using survey methodology incorporating 3 real-life case vignettes, responses were elicited to difficult ethical and moral dilemmas in the ICU setting. Members of 2 critical care societies in the United States and Europe were included in the survey. RESULTS: Responses from 323 intensivists (32% out of 1000 members who opened the initial email invitation) around the world were analyzed thematically. Conflicts between patient choices and suggested medical care, institutional/work constraints restricting compassionate care and leading to burnout, and personal variables influencing compassionate care were the themes that emerged from our investigation. The results demonstrate that intensivists have compassion for their patients and want to provide patient-centered care, but also experience stress due to their limited ability to improve their patients' conditions. CONCLUSIONS: Compassionate attitudes can be hindered by an underlying worry about the decision made by the patient and their family, a lack of confidence in making hard moral decisions, and the burdens of burnout.

Early Life Environmental Exposure to Cadmium, Lead, and Arsenic and Age at Menarche: A Longitudinal Mother-Child Cohort Study in Bangladesh.

BACKGROUND: Several metals act as endocrine disruptors, but there are few large longitudinal studies about associations with puberty onset. OBJECTIVES: We evaluated whether early life cadmium, lead, and arsenic exposure was associated with timing of menarche. METHODS: In a mother-child cohort in rural Bangladesh (n=935), the exposure was assessed by concentrations in maternal erythrocytes in early pregnancy and in girls' urine at 5 and 10 years of age using inductively coupled plasma mass spectrometry. The girls were interviewed twice, at average ages 13.3 [standard deviation (SD)=0.43] and 13.8 (SD=0.43) y, and the date of menarche, if present, was recorded. Associations were assessed using Kaplan-Meier analysis and multivariable-adjusted Cox regression. RESULTS: In total, 77% of the girls (n=717) had reached menarche by the second follow-up. The median age of menarche among all girls was 13.0 y (25th-75th percentiles: 12.4-13.7 y). At 10 years of age, median urinary cadmium was 0.25µg/L (5th-95th percentiles: 0.087-0.72µg/L), lead 1.6µg/L (0.70-4.2µg/L), and arsenic 54µg/L (19-395µg/L). Given the same age, girls in the highest quartile of urinary cadmium at 5 and 10 years of age had a lower rate of menarche than girls in the lowest quartile, with an adjusted hazard ratio of (HR) 0.80 (95% CI: 0.62, 1.01) at 5 years of age, and 0.77 (95% CI: 0.60, 0.98) at 10 years of age. This implies that girls in the highest cadmium exposure quartile during childhood had a higher age at menarche. Comparing girls in the highest to the lowest quartile of urinary lead at 10 years of age, the former had a higher rate of menarche [adjusted HR = 1.23 (95% CI: 0.97, 1.56)], implying lower age at menarche, whereas there was no association with urinary lead at 5 years of age. Girls born to mothers in the highest quartile of erythrocyte arsenic during pregnancy were less likely to have attained menarche than girls born to mothers in the lowest quartile [adjusted HR= 0.79 (95% CI: 0.62, 0.99)]. No association was found with girls' urinary arsenic exposure. DISCUSSION: Long-term childhood cadmium exposure was associated with later menarche, whereas the associations with child lead exposure were inconclusive. Maternal exposure to arsenic, but not cadmium or lead, was associated with later menarche. https://doi.org/10.1289/EHP11121.