SCYX-7158, an Orally-Active Benzoxaborole for the Treatment of Stage 2 Human African Trypanosomiasis

Human African trypanosomiasis (HAT) is caused by infection with the parasite Trypanosoma brucei and is an important public health problem in sub-Saharan Africa. New, safe, and effective drugs are urgently needed to treat HAT, particularly stage 2 disease where the parasite infects the brain. Existing therapies for HAT have poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. Through an integrated drug discovery project, we have discovered and optimized a novel class of boron-containing small molecules, benzoxaboroles, to deliver SCYX-7158, an orally active preclinical drug candidate. SCYX-7158 cured mice infected with T. brucei, both in the blood and in the brain. Extensive pharmacokinetic characterization of SCYX-7158 in rodents and non-human primates supports the potential of this drug candidate for progression to IND-enabling studies in advance of clinical trials for stage 2 HAT

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

How Do Restaurants Grapple with Stress when Attempting to Achieve and Keep the Michelin Star? A Qualitative Investigation in the Canadian Market

With The Michelin Guide’s recent expansion into the Canadian market, and the highly stressful environment associated with the restaurant industry, this qualitative study looks to understand the stress that comes from trying to acquire and retain a Michelin star rating, along with the strategies restaurants employ to mitigate these stressors

Prevalence of xylazine among people who inject drugs seeking medical care at a syringe services program clinic: Miami, Florida, 2023

Background: We aimed to report the preliminary xylazine prevalence among people who inject drugs (PWID) treated at a student-run free clinic in Miami, FL, USA and to identify characteristics associated with screening positive for xylazine. Methods: A retrospective chart review of 59 patients presenting to a syringe services program (SSP) clinic in was conducted between April 27th and August 17th, 2023. We measured presence of xylazine with rapid visual immunoassay strips on patient urine samples. Results: Xylazine was present in 55.9 % (33/59) of urine samples including 2 without detected opioids. Xylazine presence was significantly associated with unsheltered homelessness (p = 0.018), presence of wound(s) (p = 0.008), and testing positive for hepatitis C antibody (p = 0.014), fentanyl (p = 0.005) and MDMA (p = 0.002). Conclusions: A high prevalence of xylazine in the Southeastern United States furthers evidence of the geographical spread of xylazine and rapidly evolving illicit drug supply. Widespread xylazine screening is urgently needed to inform people who inject drugs and to studyinterventions to minimize harms associated with xylazine

Simulated patient training to improve youth engagement in HIV care in Kenya: A stepped wedge cluster randomized controlled trial

Youth living with HIV (YLHIV) report that negative interactions with health care workers (HCWs) affects willingness to return to care. This stepped wedge randomized trial evaluated effectiveness of a standardized patient actor (SP) HCW training intervention on adolescent engagement in care in Kenya. HCWs caring for YLHIV at 24 clinics received training on adolescent care, values clarification, communication, and motivational interviewing, with 7 SP encounters followed by facilitated feedback of videotaped interactions. Facilities were randomized to timing of the intervention. The primary outcome was defined as return within 3 months after first visit (engagement) among YLHIV who were either newly enrolled or who returned to care after >3 months out of care. Visit data was abstracted from electronic medical records. Generalized linear mixed models adjusted for time, being newly enrolled, and clustering by facility. YLHIV were surveyed regarding satisfaction with care. Overall, 139 HCWs were trained, and medical records were abstracted for 4,595 YLHIV. Median YLHIV age was 21 (IQR 19–23); 82% were female, 77% were newly enrolled in care, and 75% returned within 3 months. Half (54%) of trained HCWs remained at their clinics 9 months post-training. YLHIV engagement improved over time (global Wald test, p = 0.10). In adjusted models, the intervention showed no significant effect on engagement [adjusted Prevalence Ratio (aPR) = 0.95, 95% Confidence Interval (CI): 0.88–1.02]. Newly enrolled YLHIV had significantly higher engagement than those with prior lapses in care (aPR = 1.18, 95%CI: 1.05–1.33). Continuous satisfaction with care scores were significantly higher by wave 3 compared to baseline (coefficient = 0.38, 95%CI: 0.19–0.58). Despite provider skill improvement, there was no effect of SP training on YLHIV engagement in care. This may be due to temporal improvements or turnover of trained HCWs. Strategies to retain SP-training benefits need to address HCW turnover. YLHIV with prior gaps in care may need more intensive support. Registration CT #: NCT02928900. https://clinicaltrials.gov/ct2/show/NCT02928900

Simulated patient training to improve youth engagement in HIV care in Kenya: A stepped wedge cluster randomized controlled trial.

Youth living with HIV (YLHIV) report that negative interactions with health care workers (HCWs) affects willingness to return to care. This stepped wedge randomized trial evaluated effectiveness of a standardized patient actor (SP) HCW training intervention on adolescent engagement in care in Kenya. HCWs caring for YLHIV at 24 clinics received training on adolescent care, values clarification, communication, and motivational interviewing, with 7 SP encounters followed by facilitated feedback of videotaped interactions. Facilities were randomized to timing of the intervention. The primary outcome was defined as return within 3 months after first visit (engagement) among YLHIV who were either newly enrolled or who returned to care after >3 months out of care. Visit data was abstracted from electronic medical records. Generalized linear mixed models adjusted for time, being newly enrolled, and clustering by facility. YLHIV were surveyed regarding satisfaction with care. Overall, 139 HCWs were trained, and medical records were abstracted for 4,595 YLHIV. Median YLHIV age was 21 (IQR 19-23); 82% were female, 77% were newly enrolled in care, and 75% returned within 3 months. Half (54%) of trained HCWs remained at their clinics 9 months post-training. YLHIV engagement improved over time (global Wald test, p = 0.10). In adjusted models, the intervention showed no significant effect on engagement [adjusted Prevalence Ratio (aPR) = 0.95, 95% Confidence Interval (CI): 0.88-1.02]. Newly enrolled YLHIV had significantly higher engagement than those with prior lapses in care (aPR = 1.18, 95%CI: 1.05-1.33). Continuous satisfaction with care scores were significantly higher by wave 3 compared to baseline (coefficient = 0.38, 95%CI: 0.19-0.58). Despite provider skill improvement, there was no effect of SP training on YLHIV engagement in care. This may be due to temporal improvements or turnover of trained HCWs. Strategies to retain SP-training benefits need to address HCW turnover. YLHIV with prior gaps in care may need more intensive support. Registration CT #: NCT02928900. https://clinicaltrials.gov/ct2/show/NCT02928900