Evaluating mobile harm reduction services for youth and young adults.

The adolescent and young adult (AYA) population has experienced an increase in both emergency room visits and deaths related to substance use. However, AYA are less likely to engage in existing addiction treatment infrastructure. A youth-specific mobile harm reduction program has the potential to reduce substance-related morbidity and mortality including infections, overdose, and death. Launched in 2019, the Community Care in Reach AYA pilot program seeks to address the difference in patterns of substance use between AYA and adults. The results of this evaluation suggest the importance of a youth-oriented program in increasing AYA engagement with harm reduction.

Oxidative Stress is a shared characteristic of ME/CFS and Long COVID.

More than 65 million individuals worldwide are estimated to have Long COVID (LC), a complex multisystemic condition, wherein patients of all ages report fatigue, post-exertional malaise, and other symptoms resembling myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). With no current treatments or reliable diagnostic markers, there is an urgent need to define the molecular underpinnings of these conditions. By studying bioenergetic characteristics of peripheral blood lymphocytes in over 16 healthy controls, 15 ME/CFS, and 15 LC, we find both ME/CFS and LC donors exhibit signs of elevated oxidative stress, relative to healthy controls, especially in the memory subset. Using a combination of flow cytometry, bulk RNA-seq analysis, mass spectrometry, and systems chemistry analysis, we also observed aberrations in ROS clearance pathways including elevated glutathione levels, decreases in mitochondrial superoxide dismutase levels, and glutathione peroxidase 4 mediated lipid oxidative damage. Critically, these changes in redox pathways show striking sex-specific trends. While females diagnosed with ME/CFS exhibit higher total ROS and mitochondrial calcium levels, males with an ME/CFS diagnosis have normal ROS levels, but larger changes in lipid oxidative damage. Further analyses show that higher ROS levels correlates with hyperproliferation of T cells in females, consistent with the known role of elevated ROS levels in the initiation of proliferation. This hyperproliferation of T cells can be attenuated by metformin, suggesting this FDA-approved drug as a possible treatment, as also suggested by a recent clinical study of LC patients. Thus, we report that both ME/CFS and LC are mechanistically related and could be diagnosed with quantitative blood cell measurements. We also suggest that effective, patient tailored drugs might be discovered using standard lymphocyte stimulation assays.

A social-ecological examination of sleep among Airmen in technical training.

Inadequate sleep is an on-going risk to the health and mission readiness of U.S. Armed Forces, with estimates of sleep problems high above U.S. civilian populations. Intervening early in the career of active duty Air Force personnel (or "Airmen") with education and the establishment of healthy behaviors may prevent short and long term-detriments of sleep problems. This paper describes the results of a qualitative study seeking to understand the facilitators and barriers to achieving good sleep in a technical training school during the first year of entry into the United States Air Force. Using the social ecological framework and content analysis, three focus groups with Airmen were conducted to explore themes at the individual, social, environmental, and organizational/policy level. Overall, results indicated a cohort motivated to achieve good sleep, and also struggling with a number of barriers across each level. This paper highlights opportunities for population health interventions during technical training aimed at supporting Airmen in developing healthy sleep behaviors early in the course of their career.

Diagnosis and management of pyruvate kinase deficiency: international expert guidelines.

Pyruvate kinase (PK) deficiency is the most common cause of chronic congenital non-spherocytic haemolytic anaemia worldwide, with an estimated prevalence of one in 100 000 to one in 300 000 people. PK deficiency results in chronic haemolytic anaemia, with wide ranging and serious consequences affecting health, quality of life, and mortality. The goal of the International Guidelines for the Diagnosis and Management of Pyruvate Kinase Deficiency was to develop evidence-based guidelines for the clinical care of patients with PK deficiency. These clinical guidelines were developed by use of GRADE methodology and the AGREE II framework. Experts were invited after consideration of area of expertise, scholarly contributions in PK deficiency, and country of practice for global representation. The expert panel included 29 expert physicians (including adult and paediatric haematologists and other subspecialists), geneticists, laboratory specialists, nurses, a guidelines methodologist, patients with PK deficiency, and caregivers from ten countries. Five key topic areas were identified, the panel prioritised key questions, and a systematic literature search was done to generate evidence summaries that were used in the development of draft recommendations. The expert panel then met in person to finalise and vote on recommendations according to a structured consensus procedure. Agreement of greater than or equal to 67% among the expert panel was required for inclusion of a recommendation in the final guideline. The expert panel agreed on 31 total recommendations across five key topics: diagnosis and genetics, monitoring and management of chronic complications, standard management of anaemia, targeted and advanced therapies, and special populations. These new guidelines should facilitate best practices and evidence-based PK deficiency care into clinical practice.

Age-dependent natural killer cell and interferon γ deficits contribute to severe pertussis in infant mice.

Many respiratory infections are selectively injurious to infants, yet the etiology of age-associated susceptibility is unknown. One such bacterial pathogen is Bordetella pertussis. In adult mice, innate interferon γ (IFN-γ) is produced by natural killer (NK) cells and restricts infection to the respiratory tract. In contrast, infant pertussis resembles disease in NK cell- and IFN-γ-deficient adult mice that experience disseminated lethal infection. We hypothesized that infants exhibit age-associated deficits in NK cell frequency, maturation, and responsiveness to B. pertussis, associated with low IFN-γ levels. To delineate mechanisms behind age-dependent susceptibility, we compared infant and adult mouse models of infection. Infection in infant mice resulted in impaired upregulation of IFN-γ and substantial bacterial dissemination. B. pertussis-infected infant mice displayed fewer pulmonary NK cells than adult mice. Furthermore, the NK cells in the infant mouse lungs had an immature phenotype, and the infant lung showed no upregulation of the IFN-γ-inducing cytokine IL-12p70. Adoptive transfer of adult NK cells into infants, or treatment with exogenous IFN-γ, significantly reduced bacterial dissemination. These data indicate that the lack of NK cell-produced IFN-γ significantly contributes to infant fulminant pertussis and could be the basis for other pathogen-induced, age-dependent respiratory diseases.

Evaluating patient perspectives of endovascular created arteriovenous fistulas for dialysis access (EndoAVF).

BACKGROUND: Patient reported experience measures are contemporary quality indicators that focus on evaluation of healthcare delivery processes. While surgical arteriovenous fistulas (otherAVF) are preferred for haemodialysis vascular access, fears about surgery and complications often result in refusal/delays. A new technique of endovascular arteriovenous fistula creation (EndoAVF) has been developed and as part of it's ongoing introduction into our unit, the patient perspective was felt critical to its evaluation. The Vascular Access Questionnaire (VAQ) provides a mechanism for identifying and scoring perceptions in this setting. METHOD: Patients who had previously undergone EndoAVF formation were approached to undertake the VAQ as part of a service evaluation of their experience. In addition to the components of the VAQ, data questions relating to the patient's perception of their access were gathered. Results were compared with a matched historical cohort of surgically created fistulas (otherAVF) patients. RESULTS: Patient satisfaction and self-reported ease of use with EndoAVF were high. Overall VAQ scores were similar between the EndoAVF and the surgically created cohort. Functionally, there was no significant difference in perception of their fistula by patients, irrespective of them being created surgically or radiologically. CONCLUSION: Although numbers in this report are small limiting exploration of preserved inherent heterogeneity, we provide a useful initial patient reported experience and perspectives on comparative functional use of radiologically and surgically created AVFs. As real world experience gathers, future larger cohorts with adequate sampling may allow exploration of patient reported experiences and outcome measures.

Relationship between rate of glucose or propionate infusion and milk protein yield and concentration in dairy cows: A meta-regression.

Although postruminal glucose infusion into dairy cows has increased milk protein yield in some past experiments, the same trend has not been observed in others. A meta-regression of 64 sets of observations from 29 previously published glucose and propionate infusion studies in dairy cattle, treating study and experiment (study) as random effects, was performed to establish the general effects of glucose equivalent (GlcE) infusion rate on milk true protein (MTP) yield and content, if any, and to identify independent, fixed-effect variables that accounted for the changes in MTP yield and content that were observed. Candidate explanatory variables included rate and site of infusion, diet composition and intake, body weight and lactation stage of the cows, and the change in nutrient intake between GlcE and control treatments. Across all studies, according to a model containing only the random effects of study and experiment, GlcE infusion at an average of 954 g/d increased MTP yield by 26 g/d, on average, whereas mean MTP content was not affected. Backward stepwise elimination of potential explanatory variables from a full mixed model produced a final, reduced model for MTP yield that retained a positive, second-order quadratic effect of infusion rate of GlcE and a positive, linear effect of the change in crude protein intake (CPI) between GlcE treatment and control. This change in CPI due to GlcE infusion ranged from -0.546 to 0.173 kg/d in the dataset. The model fit indicated that when CPI was allowed to drop during GlcE infusion, the effect of GlcE on MTP yield was smaller than when CPI was maintained or increased, in a manifestation of the classic protein:energy interaction. The final reduced model for MTP content contained the same explanatory variables as for MTP yield, plus a negative effect of intravenous compared with gastrointestinal infusion. Overall, the meta-analysis revealed that both MTP yield, and content were positively related to GlcE infusion rate and to the change in CPI between glucose treatment and control.

Disparate pathways for extrachromosomal DNA biogenesis and genomic DNA repair.

Oncogene amplification on extrachromosomal DNA (ecDNA) is a pervasive driver event in cancer, yet our understanding of how ecDNA forms is limited. Here, we couple a CRISPR-based method for induction of ecDNA with extensive characterization of newly formed ecDNA to examine ecDNA biogenesis. We find that DNA circularization is efficient, irrespective of 3D genome context, with formation of a 1 Mb and 1.8 Mb ecDNA both reaching 15%. We show non-homologous end joining and microhomology mediated end joining both contribute to ecDNA formation, while inhibition of DNA-PKcs and ATM have opposing impacts on ecDNA formation. EcDNA and the corresponding chromosomal excision scar form at significantly different rates and respond differently to DNA-PKcs and ATM inhibition. Taken together, our results support a model of ecDNA formation in which double strand break ends dissociate from their legitimate ligation partners prior to joining of illegitimate ends to form the ecDNA and excision scar.

SNAPIG: a model to study nutrient digestion and absorption kinetics in growing pigs based on diet and ingredient properties.

Current feed formulation and evaluation practices rely on static values for the nutritional value of feed ingredients and assume additivity. Hereby, the complex interplay among nutrients in the diet and the highly dynamic digestive processes are ignored. Nutrient digestion kinetics and diet × animal interactions should be acknowledged to improve future predictions of the nutritional value of complex diets. Therefore, an in silico nutrient-based mechanistic digestion model for growing pigs was developed: "SNAPIG" (Simulating Nutrient digestion and Absorption kinetics in PIGs). Aiming to predict the rate and extent of nutrient absorption from diets varying in ingredient composition and physicochemical properties, the model represents digestion kinetics of ingested protein, starch, fat, and non-starch polysaccharides, through passage, hydrolysis, absorption, and endogenous secretions of nutrients along the stomach, proximal small intestine, distal small intestine, and caecum + colon. Input variables are nutrient intake and the physicochemical properties (i.e. solubility, and rate and extent of degradability). Data on the rate and extent of starch and protein hydrolysis of different ingredients per digestive segment were derived from in vitro assays. Passage of digesta from the stomach was modelled as a function of feed intake level, dietary nutrient solubility and diet viscosity. Model evaluation included testing against independent data from in vivo studies on nutrient appearance in (portal) blood of growing pigs. When simulating diets varying in physicochemical properties and nutrient source, SNAPIG can explain variation in glucose absorption kinetics (postprandial time of peak, TOP: 20-100 min observed vs 25-98 min predicted), and predict variation in the extent of ileal protein and fat digestion (root mean square prediction errors (RMSPE) = 12 and 16%, disturbance error = 12 and 86%, and concordance correlation coefficient = 0.34 and 0.27). For amino acid absorption, the observed variation in postprandial TOP (61 ± 11 min) was poorly predicted despite accurate mean predictions (58 ± 34 min). Recalibrating protein digestion and amino acid absorption kinetics require data on net-portal nutrient appearance, combined with observations on digestion kinetics, in pigs fed diets varying in ingredient composition. Currently, SNAPIG can be used to forecast the time and extent of nutrient digestion and absorption when simulating diets varying in ingredient and nutrient composition. It enhances our quantitative understanding of nutrient digestion kinetics and identifies knowledge gaps in this field of research. Already useful as research tool, SNAPIG can be coupled with a postabsorptive metabolism model to predict the effects of dietary and feeding-strategies on the pig's growth response.

Editorial: Clinical Education Research and Dental Public Health.

The central premise of Dental Public Health (DPH) is striving to change the oral health of the nation for the better and as Leo Buscaglia, the 19th century historian, elegantly stated; 'Change is the end result of all true learning'. The two primary goals of DPH; promoting oral health and preventing oral disease, have at their very heart the education of the general public and patients. Similarly, in seeking to recruit, train and retain an effective dental workforce, with a focus on oral health-related quality of life improvements, close attention to the education of those practitioners is imperative.

Comparison of imputation methods for missing production data of dairy cattle.

Nowadays, vast amounts of data representing feed intake, growth, and environmental impact of individual animals are being recorded in on-farm settings. Despite their apparent use, data collected in real-world applications often have missing values in one or several variables, due to reasons including human error, machine error, or sampling frequency misalignment across multiple variables. Since incomplete datasets are less valuable for downstream data analysis, it is important to address the missing value problem properly. One option may be to reduce the dataset to a subset that contains only complete data, but considerable data may be lost via this process. The current study aimed to compare imputation methods for the estimation of missing values in a raw dataset of dairy cattle including 454 553 records collected from 629 cows between 2009 and 2020. The dataset was subjected to a cleaning process that reduced its size to 437 075 observations corresponding to 512 cows. Missing values were present in four variables: concentrate DM intake (CDMI, missing percentage = 2.30%), forage DM intake (FDMI, 8.05%), milk yield (MY, 15.12%), and BW (64.33%). After removing all missing values, the resulting dataset (n = 129 353) was randomly sampled five times to create five independent subsets that exhibit the same missing data percentages as the cleaned dataset. Four univariate and nine multivariate imputation methods (eight machine learning methods and the MissForest method) were applied and evaluated on the five repeats, and average imputation performance was reported for each repeat. The results showed that Random Forest was overall the best imputation method for this type of data and had a lower mean squared prediction error and higher concordance correlation coefficient than the other imputation methods for all imputed variables. Random Forest performed particularly well for imputing CDMI, MY, and BW, compared to imputing FDMI.

Novel therapeutics and future directions for refractory immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder affecting approximately 1 in 20 000 people. While most patients with ITP are successfully managed with the current set of standard and approved therapeutics, patients who cannot be adequately managed with these therapies, considered to have refractory ITP, are not uncommon. Therefore, there remains an ongoing need for novel therapeutics and drug development in ITP. Several agents exploiting novel targets and mechanisms in ITP are presently under clinical development, with trials primarily recruiting heavily pretreated patients and those with otherwise refractory disease. Such agents include the neonatal Fc receptor antagonist efgartigimod, the Bruton tyrosine kinase inhibitor rilzabrutinib, the complement inhibitors sutimlimab and iptacopan and anti-CD38 monoclonal antibodies such as daratumumab and mezagitamab, among others. Each of these agents exploits therapeutic targets or other aspects of ITP pathophysiology currently not targeted by the existing approved agents (thrombopoietin receptor agonists and fostamatinib). This manuscript offers an in-depth review of the current available data for novel therapeutics in ITP presently undergoing phase 2 or 3 studies in patients with heavily pretreated or refractory ITP. It additionally highlights the future directions for drug development in refractory ITP, including discussion of innovative clinical trial designs, health-related quality of life as an indispensable clinical trial end-point and balancing potential toxicities of drugs with their potential benefits in a bleeding disorder in which few patients suffer life-threatening bleeding.

Bibliometric analysis of parasite vaccine research from 1990 to 2019.

Bibliometric and bibliographic analyses are popular tools for investigating publication metrics and thematic transitions in an expanding codex of biomedical literature. Bibliometric techniques have been employed in parasitology and vaccinology, with only a few malaria-specific literature analyses being reported specifically on parasite vaccines. The pursuit of parasite prophylactics is an important, global endeavour both medically and economically. As such, a comprehensive understanding of the research topics would be a valuable tool in assessing the current status and future directions of parasite vaccine development. Consequently, this study investigated parasite vaccinology from 1990 to 2019 by analysing literature exported from the Web of Science and Dimensions databases using two, commonly used, bibliometric programs: SciMAT and VOSviewer. The results of this study show the common, emerging, and transient themes within the discipline, and where the future lies as vaccine development moves further into the age of omics and informatics.

The impact of long haul travel on the sleep of elite athletes.

In order to manage and implement strategies to alleviate the symptoms of jet lag it is essential to assess the impact of jet lag in athletes. The aim of this study was to assess the impact of long haul eastward travel on elite athletes' (n = 7 elite national track cyclists; male n = 3, and female n = 4) sleep. The athletes' sleep was monitored before, during and after travel using both actigraphy and self-report measures. Participants wore an activity monitor for 5 days prior to travel, during the long haul travel and 5 days upon arrival at their destination and completed a daily online sleep diary Actigraphy highlighted significant reductions in time in bed, total sleep time and sleep efficiency (%) due to long haul eastward travel, particularly in the 48 h after travel. Sleep diary data exhibited significant reductions in time in bed, total sleep time, sleep efficiency, sleep quality and a significant increase in fatigue going to bed as a result of long haul eastward travel. In order to facilitate the development of interventions to reduce the symptoms and severity of jet lag objective and subjective assessments of sleep should be coupled with assessments of chronotype and perceived sleep need.

Simoctocog alfa (Nuwiq®) in previously untreated patients with severe haemophilia A-Final efficacy and safety results from the NuProtect study.

INTRODUCTION: Simoctocog alfa (Nuwiq®) is a 4th generation recombinant FVIII with proven efficacy for the prevention and treatment of bleeding episodes (BEs) in previously treated patients with severe haemophilia A. The NuProtect study assessed the immunogenicity, efficacy and safety of simoctocog alfa in 108 previously untreated patients (PUPs). The incidence of high-titre inhibitors was 16.2% and no patients with non-null F8 mutations developed inhibitors. AIM: To report the efficacy and safety results from the NuProtect study. METHODS: PUPs received simoctocog alfa for prophylaxis, treatment of BEs, or as surgical prophylaxis. The efficacy of prophylaxis (during inhibitor-free periods) was assessed using annualised bleeding rates (ABRs). The efficacy in treating BEs and in surgical prophylaxis was assessed using a 4-point scale. Adverse events were recorded throughout the study. RESULTS: Of 108 PUPs treated with simoctocog alfa, 103 received at least one prophylactic dose and 50 received continuous prophylaxis for at least 24 weeks. In patients on continuous prophylaxis, the median ABR was 0 (mean 0.5) for spontaneous BEs and 2.5 (mean 3.6) for all BEs. In 85 patients who had BEs, efficacy of BE treatment was excellent or good for 92.9% (747/804) of rated BEs; 92.3% of BEs were treated with 1 or 2 infusions. The efficacy of surgical prophylaxis was excellent or good for 94.7% (18/19) of rated procedures. There were no safety concerns and no thromboembolic events. CONCLUSION: Simoctocog alfa was efficacious and well tolerated as prophylaxis, surgical prophylaxis and for the treatment of BEs in PUPs with severe haemophilia A.

Review: When worlds collide - poultry modeling in the 'Big Data' era.

Within poultry production systems, models have provided vital decision support, opportunity analysis, and performance optimization capabilities to nutritionists and producers for decades. In recent years, due to the advancement of digital and sensor technologies, 'Big Data' streams have emerged, optimally positioned to be analyzed by machine-learning (ML) modeling approaches, with strengths in forecasting and prediction. This review explores the evolution of empirical and mechanistic models in poultry production systems, and how these models may interact with new digital tools and technologies. This review will also examine the emergence of ML and Big Data in the poultry production sector, and the emergence of precision feeding and automation of poultry production systems. There are several promising directions for the field, including: (1) application of Big Data analytics (e.g., sensor-based technologies, precision feeding systems) and ML methodologies (e.g., unsupervised and supervised learning algorithms) to feed more precisely to production targets given a 'known' individual animal, and (2) combination and hybridization of data-driven and mechanistic modeling approaches to bridge decision support with improved forecasting capabilities.

A dynamic model to measure retention of solid and liquid digesta fractions in chickens fed diets with differing fibre sources.

Dietary fibres impact multiple digestive processes, and insights into the effects of various types of fibre on digesta retention time are required to optimise current feed formulation systems. Therefore, the objective of this study was to apply a dynamic modelling approach to generate estimates for the retention time of solid and liquid digesta in broilers fed different fibre sources. A maize-wheat-soybean meal control diet was compared against three diets in which wheat was partially substituted with oat hulls, rice husks, or sugar beet pulp (3% w/w). Non-starch polysaccharide (NSP) digestibility was evaluated in broilers between 23 and 25 days of age (n = 60 birds/treatment) using titanium dioxide (TiO2, 0.5 g/kg) as a marker, after feeding the experimental diets for 21 days. Digesta mean retention time (MRT) was measured in another 108 birds at 30 days of age by the administration of an oral pulse dose of chromium sesquioxide (Cr2O3) as solid marker and Cobalt-EDTA as liquid marker, and subsequent measurement of marker recovery in compartments of the digestive tract (n = 2 or 3 replicate birds/time point/treatment). Marker recovery models to estimate fractional passage rates for solid and liquid digesta in crop, gizzard, small intestine, and caeca compartments of the gastrointestinal tract were developed to predict MRT of solid and liquid digesta for each dietary treatment. The models were composed of a series of first-order differential equations, representing the variation of marker concentration in a compartment over time. Estimated MRT of solid and liquid digesta in the gizzard varied from 20 min for oat hulls and 34 min for rice husks diets to 14 min for sugar beet pulp and 12 min for control diets. In the caeca, liquid MRT was decreased compared to the control diet (989 min) for the sugar beet pulp diet (516 min), while it was increased for both the oat hulls and rice husks diets (≈1 500 min). Overall, these estimates are greater than those previously reported, suggesting that liquid digesta retention in the caeca previously has been underestimated. Digestibility of total NSP was increased by dietary fibre inclusion, regardless of the fibre type, although degradation of constituent sugars of NSP varied among diets. In conclusion, the inclusion of fibre sources at a low level (3% w/w) in the diet of broiler modulated retention time mainly in the gizzard and caeca, and increased digestibility of NSP.

HostSeq: a Canadian whole genome sequencing and clinical data resource.

HostSeq was launched in April 2020 as a national initiative to integrate whole genome sequencing data from 10,000 Canadians infected with SARS-CoV-2 with clinical information related to their disease experience. The mandate of HostSeq is to support the Canadian and international research communities in their efforts to understand the risk factors for disease and associated health outcomes and support the development of interventions such as vaccines and therapeutics. HostSeq is a collaboration among 13 independent epidemiological studies of SARS-CoV-2 across five provinces in Canada. Aggregated data collected by HostSeq are made available to the public through two data portals: a phenotype portal showing summaries of major variables and their distributions, and a variant search portal enabling queries in a genomic region. Individual-level data is available to the global research community for health research through a Data Access Agreement and Data Access Compliance Office approval. Here we provide an overview of the collective project design along with summary level information for HostSeq. We highlight several statistical considerations for researchers using the HostSeq platform regarding data aggregation, sampling mechanism, covariate adjustment, and X chromosome analysis. In addition to serving as a rich data source, the diversity of study designs, sample sizes, and research objectives among the participating studies provides unique opportunities for the research community.