Cancer Prevention as the Key to Long Term Population Health: An Interview with Dr. Carolyn Gotay

Dr. Carolyn Gotay is Professor and Canadian Cancer Society Chair in Cancer Primary Prevention at the University of British Columbia (UBC). Her training began at Duke University and continued with a PhD in Psychology from the University of Maryland. During her first position at the University of Calgary, she became interested in the relationship between psychology and cancer, which would become the focus of her subsequent work. Dr. Gotay has held positions at Gettysburg College, the University of Calgary, and the National Cancer Institute (U.S.) where she acted as a Health Scientist Administrator. Following these positions, she began at the University of Hawaii, where she worked as the Director of the Cancer Prevention and Control Program. Throughout these various roles, her primary prevention interests were multi-faceted; they included a focus on clinical trials investigating quality of life as well as understanding end-of-life care and the psychosocial wellbeing of patients. Dr. Gotay joined UBC in 2008 where she continued her primary prevention research through the School of Population and Public Health and the B.C. Cancer Agency. Currently, Dr. Gotay is a leader in the Cancer Prevention Centre where she and her colleagues look at modifiable cancer risk factors and the application and assessment of interven­tions to modify these behaviours in the population. Dre Carolyn Gotay est professeure et elle siège au sein de la Société canadienne du cancer dans le domaine de la prévention primaire du cancer à l’Université de la Colombie-Britannique. Son éducation universitaire a débuté à l’Université de Duke et elle a continué ses études doctorales en psychologie à l’Université de Maryland. Son premier poste fut à l’Université de Calgary et elle concentre ses recherches sur la relation entre la psychologie et le cancer. Dre Gotay a obtenu des postes à l’Université de Gettysburg, à l’Université de Calgary et à l’institut national du cancer (É.U.) où elle était administratrice scientifique de la santé. Par la suite, elle a travaillé à l’Université d’Hawaii, où elle a oeuvré en tant que directrice du programme de prévention et de contrôle du cancer. À travers son cheminement professionnel, Dre Gotay a étudié les soins primaires préventifs en lien avec la qualité de vie, les soins de fin de vie et le bien-être psychosocial des patients. En 2008, elle a eu la chance de continuer sa recherche en soins préventifs primaires à l’Université de la Colombie-Britannique dans le département de santé publique ainsi qu’à l’agence de cancer de la Colombie-Britannique. Dre Go­tay demeure une leader au centre de prévention du cancer où elle travaille présentement avec ses collègues pour trouver des facteurs de risque modifiables du cancer et l’application d’interventions pour modifier ces comportements dans la population

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

An Unusual Case of Deep Brain Stimulation Wound Infection Secondary to COVID-19 Mask-Related Friction

This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements

GNAO1 Mutation–Induced Pediatric Dystonic Storm Rescue With Pallidal Deep Brain Stimulation

Dystonic storm or status dystonicus is a life-threatening hyperkinetic movement disorder with biochemical alterations due to the excessive muscle contractions. The medical management can require pediatric intensive care unit admission and a combination of medications while the underlying trigger is managed. Severe cases may require general anesthesia and paralytic agents with intubation and may relapse when these drugs are weaned. Deep brain stimulation of the globus pallidum has been reported to terminate dystonic storm in several pediatric cases. We present a 10-year-old boy with a de novo GNAO1 mutation–induced dystonic storm who required a 2-month pediatric intensive care unit admission and remained refractory to all medical treatments. Deep brain stimulation was performed under general anesthetic without complication. His dyskinetic movements stopped with initiation of stimulation. He was discharged from the pediatric intensive care unit after 4 days. We present prospectively evaluated changes in dystonia symptoms and quality of life for a patient with GNAO1 mutation treated with deep brain stimulation

Nanoscale Reaction Vessels Designed for Synthesis of Copper-Drug Complexes Suitable for Preclinical Development

The development of copper-drug complexes (CDCs) is hindered due to their very poor aqueous solubility. Diethyldithiocarbamate (DDC) is the primary metabolite of disulfiram, an approved drug for alcoholism that is being repurposed for cancer. The anticancer activity of DDC is dependent on complexation with copper to form copper bis-diethyldithiocarbamate (Cu(DDC)(2)), a highly insoluble complex that has not been possible to develop for indications requiring parenteral administration. We have resolved this issue by synthesizing Cu(DDC)(2) inside liposomes. DDC crosses the liposomal lipid bilayer, reacting with the entrapped copper; a reaction that can be observed through a colour change as the solution goes from a light blue to dark brown. This method is successfully applied to other CDCs including the anti-parasitic drug clioquinol, the natural product quercetin and the novel targeted agent CX-5461. Our method provides a simple, transformative solution enabling, for the first time, the development of CDCs as viable candidate anticancer drugs; drugs that would represent a brand new class of therapeutics for cancer patients

Pre-Injury Antiplatelet Therapy and Risk of Adverse Outcomes after Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

There is an increasing number of trauma patients presenting on pre-injury antiplatelet (AP) agents attributable to an aging population and expanding cardio- or cerebrovascular indications for antithrombotic therapy. The effects of different AP regimens on outcomes after traumatic brain injury (TBI) have yet to be elucidated, despite the implications on patient/family counseling and the potential need for better reversal strategies. The goal of this systematic review and meta-analysis was to assess the impact of different pre-injury AP regimens on outcomes after TBI. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the OVID Medline, Embase, BIOSIS, Scopus, and Cochrane databases were searched from inception to February 2022 using a combination of terms pertaining to TBI and use of AP agents. Baseline demographics and study characteristics as well as outcome data pertaining to intracerebral hematoma (ICH) progression, need for neurosurgical intervention, hospital length of stay, mortality, and functional outcome were extracted. Pooled odds ratios (ORs) and mean differences comparing groups were calculated using random-effects models. Thirteen observational studies, totaling 1244 patients receiving single AP therapy with acetylsalicylic acid or clopidogrel, 413 patients on dual AP therapy, and 3027 non-AP users were included. No randomized controlled trials were identified. There were significant associations between dual AP use and ICH progression (OR, 2.81; 95% confidence interval [CI], 1.19-6.61; I 2, 85%; p = 0.02) and need for neurosurgical intervention post-TBI (OR, 1.61; 95% CI, 1.15-2.28; I 2, 15%; p = 0.006) compared to non-users, but not between single AP therapy and non-users. There were no associations between AP use and hospital length of stay or mortality after trauma. Pre-injury dual AP use, but not single AP use, is associated with higher rates of ICH progression and neurosurgical intervention post-TBI. However, the overall quality of studies was low, and this association should be further investigated in larger studies

A simple passive equilibration method for loading carboplatin into pre-formed liposomes incubated with ethanol as a temperature dependent permeability enhancer.

A passive equilibration method which relies on addition of candidate drugs to pre-formed liposomes is described as an alternative method for preparing liposome encapsulated drugs. The method is simple, rapid and applicable to liposomes prepared with high (45mol%) or low (<20mol%) levels of cholesterol. Passive equilibration is performed in 4-steps: (i) formation of liposomes, (ii) addition of the candidate drug to the liposomes in combination with a permeability enhancing agent, (iii) incubation at a temperature that facilitates diffusion of the added compound across the lipid bilayer, and (iv) quenching the enhanced membrane permeability by reduction in temperature and/or removal of the permeabilization enhancer. The method is fully exemplified here using ethanol as the permeabilization enhancer and carboplatin (CBDCA) as the drug candidate. It is demonstrated that ethanol can be added to liposomes prepared with 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and Cholesterol (Chol) (55:45mol ratio) in amounts up to 30% (v/v) with no change in liposome size, even when incubated at temperatures>60°C. Super-saturated solutions of CBDCA (40mg/mL) can be prepared at 70°C and these are stable in the presence of ethanol even when the temperature is reduced to <30°C. maximum CBDCA encapsulation is achieved within 1h after the CBDCA solution is added to pre-formed DSPC/Chol liposomes in the presence of 30% (v/v) ethanol at 60°C. When the pre-formed liposomes are mixed with ethanol (30% v/v) at or below 40°C, the encapsulation efficiency is reduced by an order of magnitude. The method was also applied to liposomes prepared from other compositions include a cholesterol free formulations (containing 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000] (DSPE-PEG2000)) and a low Chol (<20mol%) formulations prepared with the distearoyl-sn-glycero-3-phospho-(1'-rac-glycerol) DSPG)). The cytotoxic activity of CBDCA was unaffected when prepared in this manner and two of the resultant formulations exhibited good stability in vitro and in vivo. The cytotoxic activity of CBDCA was unaffected when prepared in this manner and the resultant formulations exhibited good stability in vitro and in vivo. Pharmacokinetics studies in CD-1 mice indicated that the resulting formulations increased the circulation half life of the associated CBDCA significantly (AUC0-24h of CBDCA=0.016μg·hr/mL; AUC0-24h of the DSPC/Chol CBDCA formulation=1014.0μg·hr/mL and AUC0-24h of the DSPC/DSPG/Chol CBDCA formulation=583.96μg·hr/mL). Preliminary efficacy studies in Rag-2M mice with established subcutaneous H1975 and U-251 tumors suggest that the therapeutic activity of CBDCA is improved when administered in liposomal formulations. The encapsulation method described here has not been disclosed previously and will have broad applications to drugs that would normally be encapsulated during liposome manufacturing

Diethyldithiocarbamate (DDC) loading into DSPC/Chol (55:45) liposomes prepared with encapsulated 300 mM CuSO₄.

<p><b>(A)</b> Photograph of solutions consisting of DDC (5mg/mL) and added to CuSO₄-containing DSPC/Chol (55:45) liposomes (20 mM liposomal lipid) over a 1 hour at 25°C. <b>(B)</b> Formation of Cu(DDC)₂ inside DSPC/Chol liposomes (20 mM) as a function of time over 1 hour at 4(●), 25(■) and 40(▲)°C following addition of DDC at a final DDC concentration of (5 mM); Cu(DDC)₂ was measured using a UV-Vis spectrophotometer and lipid was measured using scintillation counting. <b>(C)</b> Cu(DDC)₂ formation inside DSPC/Chol (55:45) liposomes over time where the external pH was 7.4 (▲) and 3.5 (▼). <b>(D)</b> Measured Cu(DDC)₂ as a function of increasing DDC added, represented as the theoretical Cu(DDC)₂ to total liposomal lipid ratio; where the lipid concentration was fixed at 20 mM and final DDC concentration was varied. <b>(E)</b> Cryo-electron microscopy photomicrograph of CuSO₄- containing DSPC/Chol (55:45) liposomes and the same liposomes after formation of encapsulated Cu(DDC)₂. <b>(F)</b> Size of the CuSO₄- containing liposomes and liposomes with encapsulated Cu(DDC)₂ as determined by quasi-electric light scattering and cryo-electron microscopy; data points are given as mean ± SD.</p

Preliminary tolerability and plasma elimination profiles for liposomal formulations of Cu(DDC)₂, Cu(CQ)₂, CuQu and CuCX-5461 after intravenous injection into CD-1 mice.

<p>Mice were injected with a single dose of 15 mg/kg Cu(DDC)₂ (-●-), 30mg/kg Cu(CQ)₂ (-■-), 70mg/kg CuQu (-▲-) and 50 mg/kg Cu-CX-5461 (-▼-). <b>(A)</b> Changes in body weight following administration of the indicated liposomal formulation where body weights were measured over 14 days after injection (n = 3). <b>(B)</b> Preliminary plasma elimination profiles of the indicated liposomal formulations where the copper-complexed compound was measured at 1, 4, 8 and 24 hrs after administration (n = 4); concentrations were measured using HPLC or AAS as described in the Methods.</p

Factors associated with acute respiratory distress syndrome in brain-injured patients: A systematic review and meta-analysis

Purpose: Acute respiratory distress syndrome (ARDS) is common in patients with acute brain injury admitted to the ICU. We aimed to identify factors associated with ARDS in this population. Methods: We searched MEDLINE, Embase, Cochrane Central, Scopus, and Web of Science from inception to January 14, 2022. Three reviewers independently screened articles and selected English-language studies reporting risk factors for ARDS in brain-injured adult patients. Data were extracted on ARDS incidence, adjusted and unadjusted risk factors, and clinical outcomes. Risk of bias was reported using the Quality in Prognostic Studies tool. Certainty of evidence was assessed using GRADE. Results: We selected 23 studies involving 6,961,284 patients with acute brain injury. The pooled cumulative incidence of ARDS after brain injury was 17.0% (95%CI 10.7–25.8). In adjusted analysis, factors associated with ARDS included sepsis (odds ratio (OR) 4.38, 95%CI 2.37–8.10; high certainty), history of hypertension (OR 3.11, 95%CI 2.31–4.19; high certainty), pneumonia (OR 2.69, 95%CI 2.35–3.10; high certainty), acute kidney injury (OR 1.44, 95%CI 1.30–1.59; moderate certainty), admission hypoxemia (OR 1.67, 95%CI 1.29–2.17; moderate certainty), male sex (OR 1.30, 95%CI 1.06–1.58; moderate certainty), and chronic obstructive pulmonary disease (OR 1.27, 95%CI 1.13–1.44; moderate certainty). Development of ARDS was independently associated with increased odds of in-hospital mortality (OR 3.12, 95% CI 1.39–7.00). Conclusions: Multiple risk factors are associated with ARDS in brain-injured patients. These findings could be used to develop prognostic models for ARDS or as prognostic enrichment strategies for patient enrolment in future clinical trials