Targeting Telomere Biology in Acute Lymphoblastic Leukemia.

Increased cell proliferation is a hallmark of acute lymphoblastic leukemia (ALL), and genetic alterations driving clonal proliferation have been identified as prognostic factors. To evaluate replicative history and its potential prognostic value, we determined telomere length (TL) in lymphoblasts, B-, and T-lymphocytes, and measured telomerase activity (TA) in leukocytes of patients with ALL. In addition, we evaluated the potential to suppress the in vitro growth of B-ALL cells by the telomerase inhibitor imetelstat. We found a significantly lower TL in lymphoblasts (4.3 kb in pediatric and 2.3 kb in adult patients with ALL) compared to B- and T-lymphocytes (8.0 kb and 8.2 kb in pediatric, and 6.4 kb and 5.5 kb in adult patients with ALL). TA in leukocytes was 3.2 TA/C for pediatric and 0.7 TA/C for adult patients. Notably, patients with high-risk pediatric ALL had a significantly higher TA of 6.6 TA/C compared to non-high-risk patients with 2.2 TA/C. The inhibition of telomerase with imetelstat ex vivo led to significant dose-dependent apoptosis of B-ALL cells. These results suggest that TL reflects clonal expansion and indicate that elevated TA correlates with high-risk pediatric ALL. In addition, telomerase inhibition induces apoptosis of B-ALL cells cultured in vitro. TL and TA might complement established markers for the identification of patients with high-risk ALL. Moreover, TA seems to be an effective therapeutic target; hence, telomerase inhibitors, such as imetelstat, may augment standard ALL treatment

Neuropsychosocial profiles of current and future adolescent alcohol misusers

A comprehensive account of the causes of alcohol misuse must accommodate individual differences in biology, psychology and environment, and must disentangle cause and effect. Animal models1 can demonstrate the effects of neurotoxic substances; however, they provide limited insight into the psycho-social and higher cognitive factors involved in the initiation of substance use and progression to misuse. One can search for pre-existing risk factors by testing for endophenotypic biomarkers2 in non-using relatives; however, these relatives may have personality or neural resilience factors that protect them from developing dependence3. A longitudinal study has potential to identify predictors of adolescent substance misuse, particularly if it can incorporate a wide range of potential causal factors, both proximal and distal, and their influence on numerous social, psychological and biological mechanisms4. Here we apply machine learning to a wide range of data from a large sample of adolescents (n = 692) to generate models of current and future adolescent alcohol misuse that incorporate brain structure and function, individual personality and cognitive differences, environmental factors (including gestational cigarette and alcohol exposure), life experiences, and candidate genes. These models were accurate and generalized to novel data, and point to life experiences, neurobiological differences and personality as important antecedents of binge drinking. By identifying the vulnerability factors underlying individual differences in alcohol misuse, these models shed light on the aetiology of alcohol misuse and suggest targets for prevention

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Diagnose und Therapie von Nachgeburtsverhalten, puerperaler Metritis und klinischer Endometritis beim Rind: Ergebnisse einer Online-Umfrage bei Schweizer Tierärzten. I Nachgeburtsverhalten

The aim of this study was to obtain the diagnostic and therapeutic approach among Swiss practitioners in cows with retained fetal membranes (RFM) (part 1). All members of the Association for ruminant health were contacted per email via the newsletter. The survey was completed by 128 veterinarians, partially responded by 140 veterinarians. The manual removal of the fetal membranes is practiced by 129 of the responding veterinarians. Cows with/without fever are treated usually with intrauterine antibiotics. Cows with RFM with/without fever are most commonly treated parenterally with tetracycline or penicillin. The use of cephalosporins and quinolones in cows with fever is more common than in cows without fever. With the present results of the survey veterinarians should critically question the supposed benefits of the manual removal of the placenta and the use of antibiotics in cows with RFM.Ziel der Online-Umfrage war die diagnostische und therapeutische Vorgehensweise bei Kühen mit Nachgeburtsverhalten (Teil 1) in der Praxis zu erfassen. Alle Mitglieder der Vereinigung für Wiederkäuergesundheit wurden per Newsletter kontaktiert. Die Umfrage wurde von 128 Tierärzten1 vollständig und von 140 nur teilweise ausgefüllt. Die manuelle Abnahme der Nachgeburt wird von 129 antwortenden Tierärzten praktiziert. Kühe ohne/mit Fieber werden intrauterin mit Antibiotika- Obletten und parenteral am häufigsten mit den Wirkstoffen Tetracyclin oder Penicillin behandelt. Der Einsatz von Cephalosporinen und Quinolonen ist bei Kühen mit Fieber weiter verbreitet als bei Kühen ohne Fieber. Der vermeintliche Nutzen der manuellen Nachgeburtsabnahme wird diskutiert und der Antibiotikaeinsatz bei Kühen mit Nachgeburtsverhalten kritisch hinterfrag

Diagnose und Therapie von Nachgeburtsverhalten, puerperaler Metritis und klinischer Endometritis beim Rind: Ergebnisse einer Online-Umfrage bei Schweizer Tierärzten. II Puerperale Metritis und klinische Endometritis

The aim of the study was to obtain the diagnostic and therapeutic approach among Swiss practitioners in cows with puerperal metritis and clinical endometritis (part 2). All members of the Association for ruminant health were contacted per email via the newsletter. The survey was completed by 128 veterinarians, partially responded by 140 veterinarians. The following main symptoms of puerperal metritis were stated by the practitioners: purulent vaginal discharge, fever and reduced appetite. A vaginal and rectal examination was performed to diagnose the disease. Usually, an intrauterine treatment with tetracycline or cefapirin was done. Parenteral administration of tetracycline or penicillin was often combined with PGF(2α), NSAIDS or cortisone. Clinical endometritis was also diagnosed by vaginal and rectal examination and the main symptom indicated was purulent vaginal discharge. The therapy consisted of the administration of PGF(2α), uterine infusions predominantly with cefapirin, and rarely with parenteral administration of antibiotics. Further diagnostic tools were not used and normally cows were not rechecked. The success of the therapy of puerperal metritis and clinical endometritis was judged to be satisfactory to excellent.Ziel der Online-Umfrage war die diagnostische und therapeutische Vorgehensweise bei Kühen mit puerperaler Metritis und klinischer Endometritis (Teil 2) in der Praxis zu erfassen. Alle Mitglieder der Vereinigung für Wiederkäuergesundheit wurden per Newsletter kontaktiert. Die Umfrage wurde von 128 Tierärzten1 vollständig und von 140 nur teilweise ausgefüllt. Als Hauptsymptome der puerperalen Metritis werden stinkender Vaginalausfluss, Fieber und Inappetenz genannt. Die Diagnostik schliesst eine vaginale und rektale Untersuchung ein. Die betroffenen Kühe werden intrauterin mit Tetracyclin- Obletten oder Cefapirin behandelt, parenteral am häufigsten mit den Wirkstoffen Tetracyclin oder Penicillin. Unterstützend werden Prostaglandin F2a (PGF2a), nicht-steroidale Entzündungshemmer (NSAIDS) oder Kortison verabreicht. Die Diagnose der klinischen Endometritis stützt sich ebenfalls auf eine vaginale und rektale Untersuchung ab. Als Hauptsymptom wird ein veränderter Vaginalausfluss vermerkt. Die Therapie besteht aus PGF2a, Uterusinfusionen, am ehesten mit dem Wirkstoff Cefapirin und selten aus parenteraler Antibiotikagabe. Die Kühe werden nicht routinemässig nachkontrolliert, weiterführende Abklärungen finden ebenfalls kaum statt. Der Behandlungserfolg wird bei puerperaler Metritis wie bei klinischer Endometritis als gut angesehen

Prediction of SARS-CoV-2 epitopes across 9360 HLA class I alleles.

Elucidating antiviral CD8 T lymphocyte responses to SARS-CoV-2 may shed light on the heterogeneity of clinical outcomes and inform vaccine or therapeutic approaches. To facilitate the evaluation of antiviral CD8 T cell responses to SARS-CoV-2, we generated a publicly accessible database of epitopes predicted to bind any class I HLA protein across the entire SARS-CoV-2 proteome. While a subset of epitopes from earlier betacoronaviruses, such as SARS-CoV (SARS), have been validated experimentally, validation systems are often biased toward specific HLA haplotypes (notably HLA-A*02:01) that only account for a fraction of the haplotypes of individuals affected by the SARS-CoV-2 pandemic. To enable evaluation of epitopes across individuals with a variety of HLA haplotypes, we computed the predicted binding affinities between 9-mer peptides derived from the annotated SARS-CoV-2 peptidome across 9,360 MHC class I HLA-A, -B, and -C alleles. There were 6,748 unique combinations of peptides and HLA alleles (pMHCs) with a predicted binding affinity of less than 500nM, including 1,103 unique peptides and 1,022 HLA alleles, spanning 11 annotated superfamilies. These peptides were derived from all 11 proteins spanning the SARS-CoV-2 peptidome, including peptides that have previously been validated experimentally. We also show evidence that these previously validated epitopes may be relevant in other HLA contexts. This complete dataset is available publicly: gs://pici-covid19-data-resources/mhci/peptide_predictions

Prediction of SARS-CoV-2 epitopes across 9360 HLA class I alleles.

Elucidating antiviral CD8 T lymphocyte responses to SARS-CoV-2 may shed light on the heterogeneity of clinical outcomes and inform vaccine or therapeutic approaches. To facilitate the evaluation of antiviral CD8 T cell responses to SARS-CoV-2, we generated a publicly accessible database of epitopes predicted to bind any class I HLA protein across the entire SARS-CoV-2 proteome. While a subset of epitopes from earlier betacoronaviruses, such as SARS-CoV (SARS), have been validated experimentally, validation systems are often biased toward specific HLA haplotypes (notably HLA-A*02:01) that only account for a fraction of the haplotypes of individuals affected by the SARS-CoV-2 pandemic. To enable evaluation of epitopes across individuals with a variety of HLA haplotypes, we computed the predicted binding affinities between 9-mer peptides derived from the annotated SARS-CoV-2 peptidome across 9,360 MHC class I HLA-A, -B, and -C alleles. There were 6,748 unique combinations of peptides and HLA alleles (pMHCs) with a predicted binding affinity of less than 500nM, including 1,103 unique peptides and 1,022 HLA alleles, spanning 11 annotated superfamilies. These peptides were derived from all 11 proteins spanning the SARS-CoV-2 peptidome, including peptides that have previously been validated experimentally. We also show evidence that these previously validated epitopes may be relevant in other HLA contexts. This complete dataset is available publicly: gs://pici-covid19-data-resources/mhci/peptide_predictions

Immunization against gonadotropin-releasing hormone in dairy cattle: Antibody titers, ovarian function, hormonal levels, and reversibility

Suppression of cyclic activity in cattle is often desired in alpine farming and for feedlot cattle not intended for breeding. A cattle-specific anti-GnRH vaccination (Bopriva, Zoetis Australia Ltd., West Ryde, Australia) is approved for use in heifers and bulls in New Zealand, Australia, Mexico, Brazil, Argentina, Turkey, and Peru. Eleven healthy, cyclic Swiss Fleckvieh cows were included in the study and vaccinated twice with Bopriva 4wk apart. Injection site, rectal body temperature, and heart and respiratory rates were recorded before and 3d following each vaccination. Blood samples were taken weekly for progesterone and estrogen analysis and to determine GnRH antibody titer. Ovaries were examined weekly, using ultrasound to count the number of follicles and identify the presence of a corpus luteum. Thirty weeks after the first vaccination, the cows were subjected to a controlled internal drug-releasing device-based Select-Synch treatment. The GnRH antibody titers increased after the second vaccination and peaked 2wk later. Estrogen levels were not influenced by vaccination, and progesterone level decreased in 7 of 11 cows up to 3wk after the second vaccination and remained low for 10 to 15wk following the second vaccination. The number of class I follicles (diameter ≤5mm) was not influenced by vaccination, whereas the number of class II follicles (diameter 6-9mm) decreased between 7 and 16wk after the first vaccination. Class III follicles (diameter >9mm) were totally absent during this period in most cows. The median period until recurrence of class III follicles was 78d from the day of the second vaccination (95% confidence interval: 60-92d). After vaccination, all cows showed swelling and pain at the injection site, and these reactions subsided within 2wk. Body temperature and heart and respiratory rates increased after the first and second vaccinations and returned to normal values within 2d of each vaccination. The cows in our study were not observed to display estrus behavior until 30wk after the first vaccination. Therefore, a Select-Synch protocol was initiated at that time. Ten cows became pregnant after the first insemination (the remaining cow was reinseminated once until confirmed pregnancy). Bopriva induced a reliable and reversible suppression of reproductive cyclicity for more than 2mo. The best practical predictor for the length of the anestrus period was the absence of class III follicles

Challenges and opportunities in designing dementia-friendly communities with local governments

Background: Communities that do not accommodate the needs and preferences of people with dementia can exacerbate disability and isolation. Although dementia-friendly communities (DFCs) were established to foster understanding and acceptance of dementia, the built environment remains underexplored. We identified the challenges and opportunities for fostering dementia-enabling environments among community planners. Method: This study is set in South-West Sydney, Australia, where a DFC is being established. The policies of seven local governments were analysed for actions that aligned with Dementia Australia’s 41 DFC recommendations: 13 for social, 14 for outdoor, and 14 for indoor environments. An online workshop was then held with 30 community planners to raise awareness for dementia-enabling environments. Participants were surveyed about their dementia beliefs and attitudes. Facilitated discussions identified challenges and opportunities for designing DFCs. Qualitative and quantitative data across all sources were triangulated. Result: Although none of the local government policies specifically mentioned dementia, up to 20/41 DFC actions were met. Most of these were in social engagement (with ≤10/13 recommendations met by each local government). Less action was taken on outdoor and indoor environments (with ≤9/14 outdoor and ≤4/14 indoor recommendations met by up to six local governments). Although beliefs and attitudes about dementia among planners were generally positive, only 48% indicated that they had a good understanding of it and nearly 80% noted they would feel anxious and depressed about a diagnosis. Key DFC challenges included a lack of awareness and conflicting priorities between government bodies. Opportunities included engaging with universities to conduct demographically relevant awareness raising, facilitate multisectoral collaboration, developing an evidence-base, and involving service providers to engage with the dementia community. Conclusion: This study triangulated data to identify gaps in community planning efforts, confirming that more action is required to design dementia-friendly communities. We are now leading a multisectoral collaboration to educate community planners and the public, and are advocating for the recognition of dementia-friendly environments in government plans. This study provides practical guidance to assist planners with DFC designs

Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections

Background: Subcutaneous allergen-specific immunotherapy frequently causes allergic side effects and requires 30 to 80 injections over 3 to 5 years. Objective: We sought to improve immunotherapy by using intralymphatic allergen administration (intralymphatic immunotherapy [ILIT]) and by targeting allergen to the MHC class II pathway. Methods: Recombinant major cat dander allergen Fel d 1 was fused to a translocation sequence (TAT) and to part of the human invariant chain, generating a modular antigen transporter (MAT) vaccine (MAT–Fel d 1). In a randomized double-blind trial ILIT with MAT–Fel d 1 in alum was compared with ILIT with placebo (saline in alum) in allergic patients (ClinicalTrials.gov NCT00718679). Results: ILIT with MAT–Fel d 1 elicited no adverse events. After 3 placebo injections within 2 months, nasal tolerance increased less than 3-fold, whereas 3 intralymphatic injections with MAT–Fel d 1 increased nasal tolerance 74-fold (P < .001 vs placebo). ILIT with MAT–Fel d 1 stimulated regulatory T-cell responses (P = .026 vs placebo) and increased cat dander–specific IgG4 levels by 5.66-fold (P = .003). The IgG4 response positively correlated with IL-10 production (P < .001). Conclusion: In a first-in-human clinical study ILIT with MAT–Fel d 1 was safe and induced allergen tolerance after 3 injections