Intratracheal cobinamide (vitamin B12 analog) administration increases survivability in rabbits exposed to a lethal dose of inhaled hydrogen sulfide.

BACKGROUND: Hydrogen sulfide is a highly toxic, flammable, and colorless gas. Hydrogen sulfide has been identified as a potential terrorist chemical threat agent in mass-casualty events. Our previous studies showed that cobinamide, a vitamin B12 analog, effectively reverses the toxicity from hydrogen sulfide poisoning. In this study, we investigate the effectiveness of intratracheally administered cobinamide in treating a lethal dose hydrogen sulfide gas inhalation and compare its performance to saline control administration. METHODS: A total of 53 pathogen-free New Zealand White rabbits were used for this study. Four groups were compared: (i) received no saline solution or drug intratracheally (n = 15), (ii) slow drip saline intratracheally (n = 15), (iii) fast drip saline intratracheally (n = 15), and (iv) slow drip cobinamide intratracheally (n = 8). Blood pressure was continuously monitored, and deoxy- and oxyhemoglobin concentration changes were monitored in real-time in vivo using continuous wave near-infrared spectroscopy. RESULTS: The mean (± standard deviation) weight for all animals (n = 53) was 3.87 ± 0.10 kg. The survival rates of the slow cobinamide and the fast saline groups were 75 percent and 60 percent, respectively, while the survival rates in the slow saline and control groups were 26.7 percent and 20 percent, respectively. A log-rank (Mantel-Cox) test showed that survival in fast saline and slow cobinamide groups were significantly greater than those of no saline control and slow saline groups (P < 0.05). The slow and no saline control groups were not significantly different (P = 0.59). The slow cobinamide group did significantly better than the slow saline group (P = 0.021). DISCUSSION: The ability to use intratracheal cobinamide as an antidote to hydrogen sulfide poisoning is a novel approach to mass-casualty care. The major limitations of this study are that it was conducted in a single species at a single inhaled hydrogen sulfide concentration. Repeated investigations in other species and at varying levels of hydrogen sulfide exposure will be needed before any definitive recommendations can be made. CONCLUSIONS: We demonstrated that intratracheal cobinamide and fast saline drip improved survival for hydrogen sulfide gas inhalation in rabbit models. Although further study is required, our results suggest that intratracheal administration of cobinamide and fast saline may be useful in hydrogen sulfide mass-casualty events.

The splicing factor Prpf31 is required for hematopoietic stem and progenitor cell expansion during zebrafish embryogenesis.

Pre-mRNA splicing is a precise regulated process and is crucial for system development and homeostasis maintenance. Mutations in spliceosomal components have been found in various hematopoietic malignancies (HMs) and have been considered as oncogenic derivers of HMs. However, the role of spliceosomal components in normal and malignant hematopoiesis remains largely unknown. Pre-mRNA processing factor 31 (PRPF31) is a constitutive spliceosomal component, which mutations are associated with autosomal dominant retinitis pigmentosa. PRPF31 was found to be mutated in several HMs, but the function of PRPF31 in normal hematopoiesis has not been explored. In our previous study, we generated a prpf31 knockout (KO) zebrafish line and reported that Prpf31 regulates the survival and differentiation of retinal progenitor cells by modulating the alternative splicing of genes involved in mitosis and DNA repair. In this study, by using the prpf31 KO zebrafish line, we discovered that prpf31 KO zebrafish exhibited severe defects in hematopoietic stem and progenitor cell (HSPC) expansion and its sequentially differentiated lineages. Immunofluorescence results showed that Prpf31-deficient HSPCs underwent malformed mitosis and M phase arrest during HSPC expansion. Transcriptome analysis and experimental validations revealed that Prpf31 deficiency extensively perturbed the alternative splicing of mitosis-related genes. Collectively, our findings elucidate a previously undescribed role for Prpf31 in HSPC expansion, through regulating the alternative splicing of mitosis-related genes.

Relevance of lymphocyte proliferation to PHA in severe combined immunodeficiency (SCID) and T cell lymphopenia.

Severe combined immunodeficiency (SCID) is characterized by a severe deficiency in T cell numbers. We analyzed data collected (n = 307) for PHA-based T cell proliferation from the PIDTC SCID protocol 6901, using either a radioactive or flow cytometry method. In comparing the two groups, a smaller number of the patients tested by flow cytometry had <10% of the lower limit of normal proliferation as compared to the radioactive method (p = 0.02). Further, in patients with CD3+ T cell counts between 51 and 300 cells/µL, there was a higher proliferative response with the PHA flow assay compared to the 3H-T assay (p < 0.0001), suggesting that the method of analysis influences the resolution and interpretation of PHA results. Importantly, we observed many SCID patients with profound T cell lymphopenia having normal T cell proliferation when assessed by flow cytometry. We recommend this test be considered only as supportive in the diagnosis of typical SCID.

Tralokinumab Provides Clinically Meaningful Responses at Week 16 in Adults with Moderate-to-Severe Atopic Dermatitis Who Do Not Achieve IGA 0/1.

BACKGROUND AND OBJECTIVE: Investigator's Global Assessment of clear/almost clear skin (IGA 0/1) is a difficult endpoint to achieve after short-term treatment of chronic moderate-to-severe atopic dermatitis, and does not fully reflect clinically meaningful changes in other parameters. We assessed the impact of tralokinumab versus placebo on other clinically meaningful parameters in patients not achieving IGA 0/1 at week 16 using pooled data from two monotherapy phase III trials, ECZTRA 1 and 2. METHODS: This post hoc analysis included patients (n = 1328) from ECZTRA 1 and 2 who did not achieve the co-primary endpoint, IGA 0/1 at week 16 without rescue medication. Endpoints evaluating atopic dermatitis extent and severity included proportions of patients achieving IGA 0/1, 50%, 75%, and 90% improvement in Eczema Area and Severity Index (EASI-50/75/90); endpoints evaluating patient-reported outcomes included a ≥ 3-point improvement in worst daily pruritus Numerical Rating Scale (NRS), a ≥ 3-point improvement in eczema-related sleep interference (sleep) NRS, a ≥ 4-point improvement in Dermatology Life Quality Index (DLQI), and DLQI ≤ 5. Specifically, clinically meaningful responses were defined as EASI-50, a ≥ 3-point improvement in itch NRS, or a ≥ 4-point improvement in DLQI at week 16. RESULTS: Among ECZTRA 1 and 2 patients who did not achieve IGA 0/1 at week 16 without rescue medication, a significantly greater proportion of patients receiving tralokinumab versus placebo achieved EASI-50 (33.0% vs 13.0%), a ≥ 3-point improvement in itch NRS (22.6% vs 9.4%), or a ≥ 4-point improvement in DLQI (41.2% vs 24.5%) at week 16. In addition, compared with placebo, a numerically greater proportion of tralokinumab-treated patients achieved all three measures of clinically meaningful response (30% vs 18%) or a clinically meaningful change in at least one outcome (48.8% vs 28.5%). Significantly greater proportions of patients receiving tralokinumab versus placebo achieved additional clinician-reported and patient-reported outcomes, such as EASI-75 (13.5% vs 4.1%), EASI-90 (3.5% vs 1.1%), DLQI ≤ 5 (22.5% vs 12.5%), and a ≥ 3-point improvement in sleep NRS (24.5% vs 11.5%). CONCLUSIONS: Tralokinumab provided clinically meaningful responses in patients with moderate-to-severe atopic dermatitis who did not achieve IGA 0/1 at week 16 and/or used rescue medication. Using multiple validated outcome measures of both efficacy and quality of life, alongside IGA scores, can better characterize tralokinumab treatment responses in patients with moderate-to-severe atopic dermatitis. [Video abstract available] CLINICAL TRIAL REGISTRATION: NCT03131648 (ECZTRA 1); study start date: 30 May, 2017; primary completion date: 7 August, 2018; study completion date: 10 October, 2019. NCT03160885 (ECZTRA 2); study start date: 12 June, 2017; primary completion date: 4 September, 2019; study completion date: 14 August, 2019. Video abstract: Tralokinumab provides clinically meaningful responses at week 16 in adults with moderate-to-severe atopic dermatitis who do not achieve IGA 0/1 (MP4 362818 KB).

The Global, Regional, and National Burden of Adult Lip, Oral, and Pharyngeal Cancer in 204 Countries and Territories: A Systematic Analysis for the Global Burden of Disease Study 2019.

Importance: Lip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning. Objective: To analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates. Evidence Review: The incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019. Findings: In 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia. Conclusions and Relevance: In this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.

Tralokinumab Efficacy Over 1 Year in Adults with Moderate-to-Severe Atopic Dermatitis: Pooled Data from Two Phase III Trials.

BACKGROUND: Two phase III trials, ECZTRA 1 and 2, confirmed the efficacy and safety of tralokinumab versus placebo in adults with moderate-to-severe atopic dermatitis (AD). To further explore the long-term efficacy of tralokinumab for AD, a pooled analysis of these trials was conducted. METHODS: ECZTRA 1 and 2 patients (n = 1596 total) were randomized to tralokinumab 300 mg or placebo every 2 weeks (q2w) over 16 weeks. Patients achieving Investigator's Global Assessment of clear/almost clear skin (IGA 0/1) and/or 75% improvement in the Eczema Area and Severity Index (EASI-75) at Week 16, were re-randomized to tralokinumab q2w, every 4 weeks (q4w), or placebo (tralokinumab withdrawal) for another 36 weeks. Patients not achieving the response criteria at Week 16 received open-label tralokinumab q2w plus optional topical corticosteroids (TCS). A pooled, prespecified analysis assessed the proportions of Week 16 responders that maintained IGA 0/1 and/or EASI-75 at Week 52. Pooled data from all patients initiated with tralokinumab, regardless of the response at Week 16 or dosing regimen received thereafter, were analyzed post hoc. RESULTS: In patients who achieved the primary endpoints at Week 16, IGA 0/1 responses were maintained at Week 52 without rescue treatment (including TCS) by 55.9%, 42.4%, and 34.0% of patients re-randomized to tralokinumab q2w, q4w, or placebo (tralokinumab withdrawal), respectively, while EASI-75 responses were maintained by 57.3%, 50.4%, and 26.4%, respectively (prespecified analysis). In a post hoc analysis of all patients initiated with tralokinumab, response rates improved over time with continued tralokinumab treatment beyond Week 16 to Week 52 for EASI-50 (63.1-82.7%), EASI-75 (37.6-61.8%), EASI-90 (20.4-37.3%), and IGA 0/1 (23.0-36.2%). CONCLUSIONS: Tralokinumab treatment provides progressive and sustained improvement over 1 year in the extent and severity of AD in patients with moderate-to-severe AD. CLINICAL TRIAL REGISTRATION: NCT03131648 (ECZTRA 1); study start date: 30 May 2017; primary completion date: 7 August 2018; study completion date: 10 October 2019. NCT03160885 (ECZTRA 2); study start date: 12 June 2017; primary completion date: 4 September 2019; study completion date: 14 August 2019. INFOGRAPHIC.

Atopic dermatitis (AD) is a chronic inflammatory disease characterized by excessively dry and itchy skin, resulting in a considerable burden of disease. Patients with AD often require long-term treatment. Tralokinumab is an injectable antibody treatment that targets a protein called interleukin-13, which substantially contributes to the signs and symptoms of AD. In the ECZTRA 1 and 2 phase III clinical trials, funded by LEO Pharma A/S, adults with moderate-to-severe AD treated with tralokinumab every other week for 16 weeks showed significant improvement in disease extent and severity compared with patients receiving placebo. To further explore the long-term efficacy of tralokinumab for AD, we performed a new analysis combining the almost 1600 patients of ECZTRA 1 and 2. A large proportion of patients treated with tralokinumab who achieved clear or almost clear skin at Week 16 were able to maintain clear or almost clear skin at Week 52 with less frequent dosing (every 4 weeks). Additionally, combining all patients treated with tralokinumab, regardless of Week 16 response or dose frequency thereafter, showed that most patients achieved a significant reduction in disease extent and severity at Week 52. These results demonstrate that many tralokinumab-treated patients continue to improve beyond Week 16, and highlight that efficacy results at Week 16 may not be representative of the outcome of longer-term tralokinumab treatment. These findings may help health care providers better advise patients regarding when to modify treatment with tralokinumab.

Safety and Efficacy of Tralokinumab in Older Adults With Moderate-to-Severe Atopic Dermatitis: A Secondary Analysis.

Importance: Older adults with atopic dermatitis (AD) face unique treatment challenges, including comorbidities, polypharmacy, and a higher risk for infections (eg, herpes zoster). Furthermore, limited data are available from clinical trials for treatments in this population. In phase 3 studies, tralokinumab showed superior efficacy in moderate-to-severe AD vs placebo, but results were not stratified by age group. Objective: To evaluate the safety and efficacy of tralokinumab in older (≥65 years) patients with moderate-to-severe AD. Design, Setting, and Participants: A post hoc analysis for adults 65 years or older was conducted from a subset of patients in the US, Canada, Europe, and Asia in 3 randomized, placebo-controlled, phase 3 trials (ECZTRA 1 and 2 [monotherapy] and ECZTRA 3 [tralokinumab + topical corticosteroids as needed]). The post hoc data were analyzed in 2022. Main Outcomes and Measures: Pooled data from up to 16 weeks of treatment from ECZTRA 1, 2, and 3 were used to assess safety. Statistical analyses followed prespecifications of primary end points. Separate efficacy analyses were conducted in these trials respectively at 16 weeks. Results: A total of 75 older adults (42 women [56%]) treated with tralokinumab from the ECZTRA 1, 2, and 3 trials were included in this post hoc analysis. Similar proportions of patients reported adverse events (AEs) with tralokinumab and placebo (44 [58%]). Three patients (4%) in the tralokinumab arm and 3 (10.3%) in the placebo arm experienced severe AEs, and 4 (5.3%) and 2 (6.9%), respectively, had AEs leading to discontinuation. More patients achieved 75% or greater improvement in Eczema Area and Severity Index scores with tralokinumab than placebo (33.9% vs 4.8%; P < .001) in ECZTRA 1 and 2. Similar trends, although not statistically significant, were seen in ECZTRA 3. Safety and efficacy outcomes in this population were similar compared with the younger patient cohorts. The small sample size limited generalizations from this analysis. Conclusion and Relevance: The results of this post hoc analysis suggest that tralokinumab is well tolerated and efficacious in patients 65 years or older with moderate-to-severe AD.

The COVID-19 Vaccine Conundrum: An Assessment of Vaccine Hesitancy Amongst Patients at a Federally Qualified Health Center.

Background: With three COVID-19 vaccines currently authorized for use in the US, vaccine hesitancy has the potential to sabotage COVID-19 vaccination efforts and be detrimental to overall health outcomes. In order to realize the extent of vaccine hesitancy, an adequate understanding of the role that self-identified barriers and epidemiologic factors may play is timely and important. Objectives: The objectives of this study were to 1) determine if there is a relationship between vaccine hesitancy and epidemiologic factors, and 2) identify perceived patient-reported barriers associated with receiving a COVID-19 vaccine. Methods: A written questionnaire was utilized to collect data from eligible patients over a 15-week period between October 2020 and February 2021. A combination of non-parametric tests and descriptive statistics were used to analyze this data. Results: A majority of patients were either very strongly in support of (28.2%) or very strongly against (29.7%) receiving a COVID-19 vaccine. Notable findings included the comparison of patients with advanced degrees being more likely to get vaccinated (48.1%) to those without advanced degrees (38.8%) (P = .032). There was also a significant difference between races regarding their interest in receiving a COVID-19 vaccine. Blacks were much more likely to answer very strongly against receiving the vaccine (60.9%) compared to Caucasians (22.1%) and Hispanics (30.4%) (P <.001). The most reported barrier to receiving a COVID-19 vaccine was concern for side effects. Conclusion: This study provides a glimpse into possible correlations between vaccine hesitancy and epidemiologic factors as well as patient-reported barriers to receiving a COVID-19 vaccine. With widespread vaccination underway, it is imperative that we learn about and address concerns about receiving the COVID-19 vaccine to ensure community protection against this serious life-threatening infectious disease.

Dhx38 is required for the maintenance and differentiation of erythro-myeloid progenitors and hematopoietic stem cells by alternative splicing.

Mutations that occur in RNA-splicing machinery may contribute to hematopoiesis-related diseases. How splicing factor mutations perturb hematopoiesis, especially in the differentiation of erythro-myeloid progenitors (EMPs), remains elusive. Dhx38 is a pre-mRNA splicing-related DEAH box RNA helicase, for which the physiological functions and splicing mechanisms during hematopoiesis currently remain unclear. Here, we report that Dhx38 exerts a broad effect on definitive EMPs as well as the differentiation and maintenance of hematopoietic stem and progenitor cells (HSPCs). In dhx38 knockout zebrafish, EMPs and HSPCs were found to be arrested in mitotic prometaphase, accompanied by a 'grape' karyotype, owing to the defects in chromosome alignment. Abnormal alternatively spliced genes related to chromosome segregation, the microtubule cytoskeleton, cell cycle kinases and DNA damage were present in the dhx38 mutants. Subsequently, EMPs and HSPCs in dhx38 mutants underwent P53-dependent apoptosis. This study provides novel insights into alternative splicing regulated by Dhx38, a process that plays a crucial role in the proliferation and differentiation of fetal EMPs and HSPCs.

Tralokinumab Plus Topical Corticosteroids as Needed Provides Progressive and Sustained Efficacy in Adults with Moderate-to-Severe Atopic Dermatitis Over a 32-Week Period: An ECZTRA 3 Post Hoc Analysis.

BACKGROUND: The efficacy and safety of tralokinumab, a fully human monoclonal antibody that specifically neutralizes interleukin-13, plus topical corticosteroids (TCS) as needed were evaluated over 32 weeks in the phase III ECZTRA 3 trial. Significantly more tralokinumab- versus placebo-treated patients achieved the primary endpoints of Investigator's Global Assessment (IGA) score of 0/1 and 75% improvement in Eczema Area and Severity Index (EASI-75) and all confirmatory endpoints at Week 16. OBJECTIVE: This post hoc analysis investigated the impact of tralokinumab plus TCS on atopic dermatitis (AD) severity, symptoms, and health-related quality of life (QoL) over the entire 32-week treatment period of ECZTRA 3, including all patients initiated on tralokinumab irrespective of the response achieved at Week 16. METHODS: Patients were randomized 2:1 to receive subcutaneous tralokinumab 300 mg or placebo every 2 weeks (q2w) with TCS as needed for an initial 16 weeks. At Week 16, patients who achieved the clinical response criteria (IGA 0/1 and/or EASI-75) with tralokinumab were re-randomized 1:1 to tralokinumab q2w or every 4 weeks (q4w), with TCS as needed, for another 16 weeks. Patients not achieving the clinical response criteria with tralokinumab received tralokinumab q2w plus TCS from Week 16. All patients randomized to tralokinumab in the initial treatment period were pooled for this analysis, irrespective of response at Week 16 or dosing regimen beyond Week 16. RESULTS: Continued tralokinumab (q2w, N = 164; q4w, N = 69) plus TCS treatment provided progressive improvements from Week 16 onwards in AD signs, with 70.2% (177/252) of patients achieving EASI-75 and 50.4% (127/252) achieving EASI-90 at Week 32. Improvements in patient-reported outcomes were observed within the first few weeks of tralokinumab q2w plus TCS treatment and were sustained throughout the 32-week period. At Week 32, patients initiated on tralokinumab q2w plus TCS achieved a relative improvement versus baseline of 70.8% (standard error (SE), 2.4) in eczema-related sleep interference numeric rating scale (NRS) and 66.8% (SE, 3.1) in Dermatology Life Quality Index (DLQI). Mean TCS use during Weeks 16-32 ranged from 9.2 to 13.6 g (SE, 1.2-2.0) q2w. Most patients (89.9% (222/247)) initiated on tralokinumab q2w plus TCS achieved a meaningful improvement in at least one of the three disease domains, including AD signs (EASI-50), symptoms (pruritus NRS improvement ≥ 3), and QoL (DLQI improvement ≥ 4) at Week 16. Of patients initiated on tralokinumab q2w plus TCS, 53.4% (132/247) achieved a clinically meaningful improvement in all three domains at Week 16 (vs. placebo, 28.5% (35/123); p < 0.001). CONCLUSIONS: Continued tralokinumab treatment plus TCS as needed provides progressive and sustained improvements in AD signs, symptoms, and health-related QoL over 32 weeks. CLINICAL TRIAL REGISTRATION: NCT03363854; study start date: 22 February 2018; primary completion date: 8 March 2019; study completion date: 26 September 2019.

Atopic dermatitis (AD) is a chronic inflammatory disease that causes excessively dry and itchy skin that can negatively impact sleep and overall quality of life for patients. Topical corticosteroids (TCS) are the most common medication used for AD, but they are not able to control the most severe cases. Tralokinumab is a treatment injected under the skin that targets an immune messenger protein called interleukin 13, which plays a key role in driving the signs and symptoms of AD. The ECZTRA 3 clinical trial, funded by LEO Pharma, compared the use of TCS as needed with either tralokinumab or placebo in over 350 adult patients with moderate-to-severe AD over a 32-week period. After 16 weeks, more patients taking tralokinumab plus TCS had clear or almost clear skin compared with patients taking placebo plus TCS. Patients taking tralokinumab also used less TCS than patients taking placebo. In new analyses presented here, we found that the proportion of patients with clear or almost clear skin continued to increase with on-going treatment from Week 16 to Week 32. Tralokinumab plus TCS treatment also led to clinically meaningful improvements in outcomes important to patients, including itch, sleep, and quality of life. Improvements occurred early, within the first few weeks of therapy, and lasted through Week 32. Our assessment of multiple outcomes over time clearly demonstrates the positive impact of tralokinumab on different aspects of AD.

From epistemology to policy: reorienting philosophy courses for science students.

Philosophy of science has traditionally focused on the epistemological dimensions of scientific practice at the expense of the ethical and political questions scientists encounter when addressing questions of policy in advisory contexts. In this article, I will explore how an exclusive focus on epistemology and theoretical reason can function to reinforce common, yet flawed assumptions concerning the role of scientific knowledge in policy decision making when reproduced in philosophy courses for science students. In order to address this concern, I will argue that such courses should supplement the traditional focus on theoretical reason with an analysis of the practical reasoning employed by scientists in advisory contexts. Later sections of this paper outline a teaching strategy by which this can be achieved that consists of two steps: the first examines idealized examples of scientific advising in order to highlight the irreducible role played by moral reasoning in justifying policy recommendations. The second employs argument analysis to reveal implicit moral assumptions in actual advisory reports that form the basis for class discussion. This paper concludes by examining some of the wider benefits that can be expected from adopting such an approach.

Microdialysis techniques and microdialysis-based patient-near diagnostics.

This article will debate the usefulness of POCT measurements and the contribution microdialysis can make to generating valuable information. A particular theme will be the rarely considered difference between ex vivo sampling, which typically generates only a static measure of concentration, and in vivo measurements that are subject to dynamic changes due to mass transfer. Those dynamic changes provide information about the patients' physiological state.

Hospitalization costs with degludec versus glargine U100 for patients with type 2 diabetes at high cardiovascular risk: Canadian costs applied to SAEs from a randomized outcomes trial.

OBJECTIVES: The present cost-consequence analysis compared estimated hospitalization costs in a Canadian setting with insulin degludec (degludec) versus insulin glargine 100 units/mL (glargine U100) in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk. METHODS: Medical terms were mapped across the different vocabularies, in order to assign unit costs from eligible hospital abstracts in Canadian Institute for Health Information data (International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Canada) to serious adverse events (SAEs; Medical Dictionary for Regulatory Activities) from the randomized DEVOTE trial comparing the two insulins degludec and glargine. Mean annual costs of SAE-related hospitalizations were estimated by treatment, the cost difference (degludec - glargine U100) was bootstrapped to compute confidence intervals (CIs) and p-values, and the cost ratio (degludec/glargine U100) was estimated using a Tweedie distribution. RESULTS: The mean annual cost per patient for SAE-related hospitalizations was 4,074 CAD with degludec and 4,569 CAD with glargine U100 (cost difference: -495, 95% confidence interval [CI]: -966; -24, p = .039), for a cost ratio of 0.89 (95% CI: 0.81; 0.98, p = .016). Overall, cost ratios from sensitivity analyses varying individual methodological assumptions were consistent with the main analysis. Of the system organ classes from DEVOTE SAEs, cardiac disorders were the largest contributor to the costs savings with degludec versus glargine U100. CONCLUSIONS: In patients with T2D at high CV risk, our findings suggest that there are likely to be lower hospitalization costs with degludec versus glargine U100 based on the SAEs observed in DEVOTE and in a Canadian setting.

Nicotinamide Adenine Dinucleotide Phosphate Oxidases in Glucose Homeostasis and Diabetes-Related Endothelial Cell Dysfunction.

Oxidative stress within the vascular endothelium, due to excess generation of reactive oxygen species (ROS), is thought to be fundamental to the initiation and progression of the cardiovascular complications of type 2 diabetes mellitus. The term ROS encompasses a variety of chemical species including superoxide anion (O2•-), hydroxyl radical (OH-) and hydrogen peroxide (H2O2). While constitutive generation of low concentrations of ROS are indispensable for normal cellular function, excess O2•- can result in irreversible tissue damage. Excess ROS generation is catalysed by xanthine oxidase, uncoupled nitric oxide synthases, the mitochondrial electron transport chain and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. Amongst enzymatic sources of O2•- the Nox2 isoform of NADPH oxidase is thought to be critical to the oxidative stress found in type 2 diabetes mellitus. In contrast, the transcriptionally regulated Nox4 isoform, which generates H2O2, may fulfil a protective role and contribute to normal glucose homeostasis. This review describes the key roles of Nox2 and Nox4, as well as Nox1 and Nox5, in glucose homeostasis, endothelial function and oxidative stress, with a key focus on how they are regulated in health, and dysregulated in type 2 diabetes mellitus.

Segmental Bone Defects and the History of Bone Transport.

SUMMARY: This article describes the etiology of segmental bone defects and reviews the options of care, past and present. A brief description of distraction osteogenesis and how the Ilizarov method was used to treat bone defects with circular external fixation leading to the latest method of transport with motorized internal lengthening nails is presented.

Prediction of antimicrobial resistance in clinical Campylobacter jejuni isolates from whole-genome sequencing data.

Campylobacter jejuni is recognised as the leading cause of bacterial gastroenteritis in industrialised countries. Although the majority of Campylobacter infections are self-limiting, antimicrobial treatment is necessary in severe cases. Therefore, the development of antimicrobial resistance (AMR) in Campylobacter is a growing public health challenge and surveillance of AMR is important for bacterial disease control. The aim of this study was to predict antimicrobial resistance in C. jejuni from whole-genome sequencing data. A total of 516 clinical C. jejuni isolates collected between 2014 and 2017 were subjected to WGS. Resistance phenotypes were determined by standard broth dilution, categorising isolates as either susceptible or resistant based on epidemiological cutoffs for six antimicrobials: ciprofloxacin, nalidixic acid, erythromycin, gentamicin, streptomycin, and tetracycline. Resistance genotypes were identified using an in-house database containing reference genes with known point mutations and the presence of resistance genes was determined using the ResFinder database and four bioinformatical methods (modified KMA, ABRicate, ARIBA, and ResFinder Batch Upload). We identified seven resistance genes including tet(O), tet(O/32/O), ant(6)-Ia, aph(2″)-If, blaOXA, aph(3')-III, and cat as well as mutations in three genes: gyrA, 23S rRNA, and rpsL. There was a high correlation between phenotypic resistance and the presence of known resistance genes and/or point mutations. A correlation above 98% was seen for all antimicrobials except streptomycin with a correlation of 92%. In conclusion, we found that WGS can predict antimicrobial resistance with a high degree of accuracy and have the potential to be a powerful tool for AMR surveillance.

Risk factors for kidney disorders in patients with type 2 diabetes at high cardiovascular risk: An exploratory analysis (DEVOTE 12).

AIM: To investigate risk factors associated with kidney disorders in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk. METHODS: In DEVOTE, a cardiovascular outcomes trial, 7637 patients were randomised to insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100), with standard of care. In these exploratory post hoc analyses, serious adverse event reports were searched using Standardised MedDRA® Queries related to chronic kidney disease (CKD) or acute kidney injury (AKI). Baseline predictors of CKD, AKI and change in estimated glomerular filtration rate (eGFR) were identified using stepwise selection and Cox or linear regression. RESULTS: Over 2 years, eGFR (mL/min/1.73 m2) decline was small and similar between treatments (degludec: 2.70; glargine U100: 2.92). Overall, 97 and 208 patients experienced CKD and AKI events, respectively. A history of heart failure was a risk factor for CKD (hazard ratio [HR] 1.97 [95% confidence interval [CI] 1.41; 2.75]) and AKI (HR 2.28 [95% CI 1.64; 3.17]). A history of hepatic impairment was a significant predictor of CKD (HR 3.28 [95% CI 2.12; 5.07]) and change in eGFR (estimate: -8.59 [95% CI -10.20; -7.00]). CONCLUSION: Our findings indicate that traditional, non-modifiable risk factors for kidney disorders apply to insulin-treated patients with T2D at high CV risk. TRIAL REGISTRATION: NCT01959529 (ClinicalTrials.gov).