Adipose Tissue in Cardiovascular Disease: From Basic Science to Clinical Translation.

The perception of adipose tissue as a metabolically quiescent tissue, primarily responsible for lipid storage and energy balance (with some endocrine, thermogenic, and insulation functions), has changed. It is now accepted that adipose tissue is a crucial regulator of metabolic health, maintaining bidirectional communication with other organs including the cardiovascular system. Additionally, adipose tissue depots are functionally and morphologically heterogeneous, acting not only as sources of bioactive molecules that regulate the physiological functioning of the vasculature and myocardium but also as biosensors of the paracrine and endocrine signals arising from these tissues. In this way, adipose tissue undergoes phenotypic switching in response to vascular and/or myocardial signals (proinflammatory, profibrotic, prolipolytic), a process that novel imaging technologies are able to visualize and quantify with implications for clinical prognosis. Furthermore, a range of therapeutic modalities have emerged targeting adipose tissue metabolism and altering its secretome, potentially benefiting those at risk of cardiovascular disease.

Inflammatory response to retrotransposons drives tumor drug resistance that can be prevented by reverse transcriptase inhibitors.

Activation of endogenous retrotransposons frequently occurs in cancer cells and contributes to tumor genomic instability. To test whether inhibition of retrotranspositions has an anticancer effect, we used treatment with the nucleoside reverse transcriptase inhibitor (NRTI) stavudine (STV) in mouse cancer models, MMTV-HER2/Neu and Th-MYCN, that spontaneously develop breast cancer and neuroblastoma, respectively. In both cases, STV in drinking water did not affect tumor incidence nor demonstrate direct antitumor effects. However, STV dramatically extended progression-free survival in both models following an initial complete response to chemotherapy. To approach the mechanism underlying this phenomenon, we analyzed the effect of NRTI on the selection of treatment-resistant variants in tumor cells in culture. Cultivation of mouse breast carcinoma 4T1 in the presence of STV dramatically reduced the frequency of cells capable of surviving treatment with anticancer drugs. Global transcriptome analysis demonstrated that the acquisition of drug resistance by 4T1 cells was accompanied by an increase in the constitutive activity of interferon type I and NF-κB pathways and an elevated expression of LINE-1 elements, which are known to induce inflammatory responses via their products of reverse transcription. Treatment with NRTI reduced NF-κB activity and reverted drug resistance. Furthermore, the inducible expression of LINE-1 stimulated inflammatory response and increased the frequency of drug-resistant variants in a tumor cell population. These results indicate a mechanism by which retrotransposon desilencing can stimulate tumor cell survival during treatment and suggest reverse transcriptase inhibition as a potential therapeutic approach for targeting the development of drug-resistant cancers.

Phase 1 study of high-dose DFMO, celecoxib, cyclophosphamide and topotecan for patients with relapsed neuroblastoma: a New Approaches to Neuroblastoma Therapy trial.

BACKGROUND: MYC genes regulate ornithine decarboxylase (Odc) to increase intratumoral polyamines. We conducted a Phase I trial [NCT02030964] to determine the maximum tolerated dose (MTD) of DFMO, an Odc inhibitor, with celecoxib, cyclophosphamide and topotecan. METHODS: Patients 2-30 years of age with relapsed/refractory high-risk neuroblastoma received oral DFMO at doses up to 9000 mg/m2/day, with celecoxib (500 mg/m2 daily), cyclophosphamide (250 mg/m2/day) and topotecan (0.75 mg/m2/day) IV for 5 days, for up to one year with G-CSF support. RESULTS: Twenty-four patients (median age, 6.8 years) received 136 courses. Slow platelet recovery with 21-day courses (dose-levels 1 and 2) led to subsequent dose-levels using 28-day courses (dose-levels 2a-4a). There were three course-1 dose-limiting toxicities (DLTs; hematologic; anorexia; transaminases), and 23 serious adverse events (78% fever-related). Five patients (21%) completed 1-year of therapy. Nine stopped for PD, 2 for DLT, 8 by choice. Best overall response included two PR and four MR. Median time-to-progression was 19.8 months, and 3 patients remained progression-free at >4 years without receiving additional therapy. The MTD of DFMO with this regimen was 6750 mg/m2/day. CONCLUSION: High-dose DFMO is tolerable when added to chemotherapy in heavily pre-treated patients. A randomized Phase 2 trial of DFMO added to chemoimmunotherapy is ongoing [NCT03794349].

A scoping review to create a framework for the steps in developing condition-specific preference-based instruments de novo or from an existing non-preference-based instrument: use of item response theory or Rasch analysis.

BACKGROUND: There is no widely accepted framework to guide the development of condition-specific preference-based instruments (CSPBIs) that includes both de novo and from existing non-preference-based instruments. The purpose of this study was to address this gap by reviewing the published literature on CSPBIs, with particular attention to the application of item response theory (IRT) and Rasch analysis in their development. METHODS: A scoping review of the literature covering the concepts of all phases of CSPBI development and evaluation was performed from MEDLINE, Embase, PsychInfo, CINAHL, and the Cochrane Library, from inception to December 30, 2022. RESULTS: The titles and abstracts of 1,967 unique references were reviewed. After retrieving and reviewing 154 full-text articles, data were extracted from 109 articles, representing 41 CSPBIs covering 21 diseases or conditions. The development of CSPBIs was conceptualized as a 15-step framework, covering four phases: 1) develop initial questionnaire items (when no suitable non-preference-based instrument exists), 2) establish the dimensional structure, 3) reduce items per dimension, 4) value and model health state utilities. Thirty-nine instruments used a type of Rasch model and two instruments used IRT models in phase 3. CONCLUSION: We present an expanded framework that outlines the development of CSPBIs, both from existing non-preference-based instruments and de novo when no suitable non-preference-based instrument exists, using IRT and Rasch analysis. For items that fit the Rasch model, developers selected one item per dimension and explored item response level reduction. This framework will guide researchers who are developing or assessing CSPBIs.

Pharmacological labour pain interventions: South African midwives' perspective.

BACKGROUND: Women of childbearing age feel great about giving birth, but the pain could be excruciating depending on their pain tolerances. Midwives requires obstetrical knowledge and skills such as pain management during labour and safety. We explored midwives' perspectives on the utilisation of pharmacological pain alleviation interventions during labour in selected hospitals in Matjhabeng Municipality, Free State province, South Africa. A qualitative study was undertaken, involving a sample of ten midwives, using a semi-structured interview guide. The interviews were audio-recorded and transcribed verbatim. Tesch's open coding data analysis method was applied to analyse the data. The midwives were restricted to use Pethidine and Phenergan prescribed by doctors for labour pain relief, which disrupted labour pain management and obliged them either to wait for a physician or follow telephone instructions. According to the midwives, women taking Pethidine and Phenergan encountered adverse effects and discomfort. Midwives identified high workload, inadequate personnel, lack of skill and knowledge, lack of medication availability, and lack of infrastructure as the primary challenges of administering pharmacological methods to women in labour. The lack of standing orders, which delays the administration of medications pending a physician's prescription, constituted an additional difficulty. In the instance that Pethidine and Phenergan were unavailable or ineffective for some women, the midwives recommended that women be administered alternative pharmacological pain relievers. They also advocated for institutionalization of pharmacological guidelines allowing them to use their discretion when treating labour pain. Midwives can only utilise a few standardised and regulated pharmacological medications for labour pain management. The midwives' ability to administer pharmacological pain relief during labour was hampered by a high workload burden, insufficient staff, lack of skill and understanding, drug unavailability, and inadequate infrastructure. Midwives advocated for supported guidelines that would allow them to treat labour pain at their discretion. Intersectoral stakeholders are required to improve midwife skills and attitudes. Health facilities need to train and supply analgesics to midwives. Midwives ought to be familiar with pharmacological pain relievers.

Determining the effects of Candida utilis-fermented pea starch vs. unfermented pea starch, alone or in whole diets, on palatability and glycemic response in dogs and cats.

Current research suggests yeast fermentation has the potential to improve palatability of pea-based diets for both cats and dogs. However, to be useful, fermentation should not compromise other healthy attributes of peas such as a low glycemic response. Fermentation of uncooked pea starch with Candida utilis (ATCC 9950) appeared to increase crude protein, crude fiber content, inorganic compounds (phosphorus and iron) and phenols. Whole diets were designed with fermented and unfermented pea starch to assess palatability, food intake, and glycemic responses in unacclimated, mixed sex Beagle dogs and mixed breed cats (n = 8 and n = 7, respectively). For palatability testing, a control diet was formulated with 30% corn starch as well as test diets with 30% inclusion of fermented or unfermented pea starch (all lab-made), then compared to a commercial diet containing pea starch (Legacy/Horizon). Fermentation had little effect on rapidly digestible starch either in uncooked starch form or when incorporated into whole diets, but did decrease resistant starch by 15% and increase slowly digestible starch by 20%. Palatability tests using either two choices or four choices at a time revealed a significant preference for the fermented pea starch diet (p < 0.01) in both species. For the glycemic responses, a total of four different pea products were included: unfermented pea starch, fermented pea starch, and 30% inclusion of unfermented and fermented pea starch in whole formulated diets. There were no significant changes in glycemic responses with the fermented pea diet compared to the unfermented diet, demonstrating that healthful low glycemic properties of pea starch were retained after C. utilis fermentation. Overall, C. utilis-fermentation technique was successfully adapted to pea starch where it resulted in increased palatability and food intake in dogs and cats, with potential to positively contribute to overall health benefits for both species.

SWATH-MS Analysis of Blood Plasma and Circulating Small Extracellular Vesicles Enables Detection of Putative Protein Biomarkers of Fertility in Young and Aged Dairy Cows.

The development of biomarkers of fertility could provide benefits for the genetic improvement of dairy cows. Circulating small extracellular vesicles (sEVs) show promise as diagnostic or prognostic markers since their cargo reflects the metabolic state of the cell of origin; thus, they mirror the physiological status of the host. Here, we employed data-independent acquisition mass spectrometry to survey the plasma and plasma sEV proteomes of two different cohorts of Young (Peripubertal; n = 30) and Aged (Primiparous; n = 20) dairy cows (Bos taurus) of high- and low-genetic merit of fertility and known pregnancy outcomes (ProteomeXchange data set identifier PXD042891). We established predictive models of fertility status with an area under the curve of 0.97 (sEV; p value = 3.302e-07) and 0.95 (plasma; p value = 6.405e-08). Biomarker candidates unique to high-fertility Young cattle had a sensitivity of 0.77 and specificity of 0.67 (*p = 0.0287). Low-fertility biomarker candidates uniquely identified in sEVs from Young and Aged cattle had a sensitivity and specificity of 0.69 and 1.0, respectively (***p = 0.0005). Our bioinformatics pipeline enabled quantification of plasma and circulating sEV proteins associated with fertility phenotype. Further investigations are warranted to validate this research in a larger population, which may lead to improved classification of fertility status in cattle.

Inhibition of mitochondrial translocase SLC25A5 and histone deacetylation is an effective combination therapy in neuroblastoma.

The mitochondrion is a gatekeeper of apoptotic processes, and mediates drug resistance to several chemotherapy agents used to treat cancer. Neuroblastoma is a common solid cancer in young children with poor clinical outcomes following conventional chemotherapy. We sought druggable mitochondrial protein targets in neuroblastoma cells. Among mitochondria-associated gene targets, we found that high expression of the mitochondrial adenine nucleotide translocase 2 (SLC25A5/ANT2), was a strong predictor of poor neuroblastoma patient prognosis and contributed to a more malignant phenotype in pre-clinical models. Inhibiting this transporter with PENAO reduced cell viability in a panel of neuroblastoma cell lines in a TP53-status-dependant manner. We identified the histone deacetylase inhibitor, suberanilohydroxamic acid (SAHA), as the most effective drug in clinical use against mutant TP53 neuroblastoma cells. SAHA and PENAO synergistically reduced cell viability, and induced apoptosis, in neuroblastoma cells independent of TP53-status. The SAHA and PENAO drug combination significantly delayed tumour progression in pre-clinical neuroblastoma mouse models, suggesting that these clinically advanced inhibitors may be effective in treating the disease.

Impact of direct-acting antiviral treatment on health utility in patients with chronic hepatitis C in hospital and community settings.

BACKGROUND: Direct-acting antiviral agents (DAAs) have transformed chronic hepatitis C (CHC) treatment. Continued affordable access to DAAs requires updated cost-effectiveness analyses (CEA). Utility is a preference-based measure of health-related quality of life (HRQoL) used in CEA. This study evaluated the impact of DAAs on utilities for patients with CHC in two clinical settings. METHODS: This prospective longitudinal study included patients aged ≥18 years, diagnosed with CHC and scheduled to begin DAA treatment, from two tertiary care hospital clinics and four community clinics in Toronto, Calgary, and Montreal. Patients completed two utility instruments (EQ-5D-5L and Health Utilities Index 2/3 (HUI2/3)) before treatment, 6 weeks after treatment initiation, and 12 weeks and 1 year after treatment completion. We measured utilities for all patients, and for hospital-based and community-based groups. RESULTS: Between 2017 and 2020, 209 patients (126 hospital-based, 83 community-based; average age 53 years; 65% male) were recruited, and 143 completed the 1-year post-treatment assessment. Pre-treatment, utilities were (mean ± standard deviation) 0.77 ± 0.21 (EQ-5D-5L), 0.69 ± 0.24 (HUI2) and 0.58 ± 0.34 (HUI3). The mean changes at 1-year post-treatment were 0.035, 0.038 and 0.071, respectively. While utilities for hospital-based patients steadily improved, utilities for the community-based cohort improved between baseline and 12-weeks post-treatment, but decreased thereafter. DISCUSSION: This study suggests that utilities improve after DAA treatment in patients with CHC in a variety of settings. However, community-based patients may face challenges related to comorbid health and social conditions that are not meaningfully addressed by treatment. Our study is essential for valuing health outcomes in CHC-related CEA.

Community First Responders' Contribution to Emergency Medical Service Provision in the United Kingdom.

STUDY OBJECTIVE: We aimed to investigate community first responders' contribution to emergency care provision in terms of number, rate, type, and location of calls and characteristics of patients attended. METHODS: We used a retrospective observational design analyzing routine data from electronic clinical records from 6 of 10 ambulance services in the United Kingdom during 2019. Descriptive statistics, including numbers and frequencies, were used to illustrate characteristics of incidents and patients that the community first responders attended first in both rural and urban areas. RESULTS: The data included 4.5 million incidents during 1 year. The community first responders first attended a higher proportion of calls in rural areas compared with those in urban areas (3.90% versus 1.48 %). In rural areas, the community first responders also first attended a higher percentage of the most urgent call categories, 1 and 2. The community first responders first attended more than 9% of the total number of category 1 calls and almost 5% of category 2 calls. The community first responders also attended a higher percentage of the total number of cardiorespiratory and neurological/endocrine conditions. They first attended 6.5% of the total number of neurological/endocrine conditions and 5.9% of the total number of cardiorespiratory conditions. Regarding arrival times in rural areas, the community first responders attended higher percentages (more than 6%) of the total number of calls that had arrival times of less than 7 minutes or more than 60 minutes. CONCLUSION: In the United Kingdom, community first responders contribute to the delivery of emergency medical services, particularly in rural areas and especially for more urgent calls. The work of community first responders has expanded from their original purpose-to attend to out-of-hospital cardiac arrests. The future development of community first responders' schemes should prioritize training for a range of conditions, and further research is needed to explore the contribution and potential future role of the community first responders from the perspective of service users, community first responders' schemes, ambulance services, and commissioners.

Development and validation of a prognostic model for death 30 days after adult emergency laparotomy.

The probability of death after emergency laparotomy varies greatly between patients. Accurate pre-operative risk prediction is fundamental to planning care and improving outcomes. We aimed to develop a model limited to a few pre-operative factors that performed well irrespective of surgical indication: obstruction; sepsis; ischaemia; bleeding; and other. We derived a model with data from the National Emergency Laparotomy Audit for patients who had emergency laparotomy between December 2016 and November 2018. We tested the model on patients who underwent emergency laparotomy between December 2018 and November 2019. There were 4077/40,816 (10%) deaths 30 days after surgery in the derivation cohort. The final model had 13 pre-operative variables: surgical indication; age; blood pressure; heart rate; respiratory history; urgency; biochemical markers; anticipated malignancy; anticipated peritoneal soiling; and ASA physical status. The predicted mortality probability deciles ranged from 0.1% to 47%. There were 1888/11,187 deaths in the test cohort. The scaled Brier score, integrated calibration index and concordance for the model were 20%, 0.006 and 0.86, respectively. Model metrics were similar for the five surgical indications. In conclusion, we think that this prognostic model is suitable to support decision-making before emergency laparotomy as well as for risk adjustment for comparing organisations.

Mitotic Dysregulation at Tumor Initiation Creates a Therapeutic Vulnerability to Combination Anti-Mitotic and Pro-Apoptotic Agents for MYCN-Driven Neuroblastoma.

MYCN amplification occurs in approximately 20-30% of neuroblastoma patients and correlates with poor prognosis. The TH-MYCN transgenic mouse model mimics the development of human high-risk neuroblastoma and provides strong evidence for the oncogenic function of MYCN. In this study, we identified mitotic dysregulation as a hallmark of tumor initiation in the pre-cancerous ganglia from TH-MYCN mice that persists through tumor progression. Single-cell quantitative-PCR of coeliac ganglia from 10-day-old TH-MYCN mice revealed overexpression of mitotic genes in a subpopulation of premalignant neuroblasts at a level similar to single cells derived from established tumors. Prophylactic treatment using antimitotic agents barasertib and vincristine significantly delayed the onset of tumor formation, reduced pre-malignant neuroblast hyperplasia, and prolonged survival in TH-MYCN mice. Analysis of human neuroblastoma tumor cohorts showed a strong correlation between dysregulated mitosis and features of MYCN amplification, such as MYC(N) transcriptional activity, poor overall survival, and other clinical predictors of aggressive disease. To explore the therapeutic potential of targeting mitotic dysregulation, we showed that genetic and chemical inhibition of mitosis led to selective cell death in neuroblastoma cell lines with MYCN over-expression. Moreover, combination therapy with antimitotic compounds and BCL2 inhibitors exploited mitotic stress induced by antimitotics and was synergistically toxic to neuroblastoma cell lines. These results collectively suggest that mitotic dysregulation is a key component of tumorigenesis in early neuroblasts, which can be inhibited by the combination of antimitotic compounds and pro-apoptotic compounds in MYCN-driven neuroblastoma.

Whole-genome sequencing facilitates patient-specific quantitative PCR-based minimal residual disease monitoring in acute lymphoblastic leukaemia, neuroblastoma and Ewing sarcoma.

BACKGROUND: Minimal residual disease (MRD) measurement is a cornerstone of contemporary acute lymphoblastic leukaemia (ALL) treatment. The presence of immunoglobulin (Ig) and T cell receptor (TCR) gene recombinations in leukaemic clones allows widespread use of patient-specific, DNA-based MRD assays. In contrast, paediatric solid tumour MRD remains experimental and has focussed on generic assays targeting tumour-specific messenger RNA, methylated DNA or microRNA. METHODS: We examined the feasibility of using whole-genome sequencing (WGS) data to design tumour-specific polymerase chain reaction (PCR)-based MRD tests (WGS-MRD) in 18 children with high-risk relapsed cancer, including ALL, high-risk neuroblastoma (HR-NB) and Ewing sarcoma (EWS) (n = 6 each). RESULTS: Sensitive WGS-MRD assays were generated for each patient and allowed quantitation of 1 tumour cell per 10-4 (0.01%)-10-5 (0.001%) mononuclear cells. In ALL, WGS-MRD and Ig/TCR-MRD were highly concordant. WGS-MRD assays also showed good concordance between quantitative PCR and droplet digital PCR formats. In serial clinical samples, WGS-MRD correlated with disease course. In solid tumours, WGS-MRD assays were more sensitive than RNA-MRD assays. CONCLUSIONS: WGS facilitated the development of patient-specific MRD tests in ALL, HR-NB and EWS with potential clinical utility in monitoring treatment response. WGS data could be used to design patient-specific MRD assays in a broad range of tumours.

Measurable residual disease analysis in paediatric acute lymphoblastic leukaemia patients with ABL-class fusions.

BACKGROUND: ABL-class fusions including NUP214-ABL1 and EBF1-PDGFRB occur in high risk acute lymphoblastic leukaemia (ALL) with gene expression patterns similar to BCR-ABL-positive ALL. Our aim was to evaluate new DNA-based measurable residual disease (MRD) tests detecting these fusions and IKZF1-deletions in comparison with conventional immunoglobulin/T-cell receptor (Ig/TCR) markers. METHODS: Precise genomic breakpoints were defined from targeted or whole genome next generation sequencing for ABL-fusions and BCR-ABL1. Quantitative PCR assays were designed and used to re-measure MRD in remission bone marrow samples previously tested using Ig/TCR markers. All MRD testing complied with EuroMRD guidelines. RESULTS: ABL-class patients had 46% 5year event-free survival and 79% 5year overall survival. All had sensitive fusion tests giving high concordance between Ig/TCR and ABL-class fusion results (21 patients, n = 257 samples, r2 = 0.9786, P < 0.0001) and Ig/TCR and IKZF1-deletion results (9 patients, n = 143 samples, r2 = 0.9661, P < 0.0001). In contrast, in BCR-ABL1 patients, Ig/TCR and BCR-ABL1 tests were discordant in 32% (40 patients, n = 346 samples, r2 = 0.4703, P < 0.0001) and IKZF1-deletion results were closer to Ig/TCR (25 patients, n = 176, r2 = 0.8631, P < 0.0001). CONCLUSIONS: MRD monitoring based on patient-specific assays detecting gene fusions or recurrent assays for IKZF1-deletions is feasible and provides good alternatives to Ig/TCR tests to monitor MRD in ABL-class ALL.

No exponential rise in revision knee replacement surgery over the past 15 years: an analysis from the National Joint Registry.

OBJECTIVE: To investigate trends in the incidence rate and the main indication for revision knee replacement (rKR) over the past 15 years in the UK. METHOD: Repeated national cross-sectional study from 2006 to 2020 using data from the National Joint Registry (NJR). Crude incidence rates were calculated using population statistics from the Office for National Statistics. RESULTS: Annual total counts of rKR increased from 2,743 procedures in 2006 to 6,819 procedures in 2019 (149% increase). The incidence rate of rKR increased from 6.3 per 100,000 adults in 2006 (95% CI 6.1 to 6.5) to 14 per 100,000 adults in 2019 (95% CI 14 to 14) (122% increase). Annual increases in the incidence rate of rKR became smaller over the study period. There was a 43.6% reduction in total rKR procedures in 2020 (during the Covid-19 pandemic) compared to 2019. Aseptic loosening was the most frequent indication for rKR overall (20.7% procedures). rKR for aseptic loosening peaked in 2012 and subsequently decreased. rKR for infection increased incrementally over the study period to become the most frequent indication in 2019 (2.7 per 100,000 adults [95% CI 2.6 to 2.9]). Infection accounted for 17.1% first linked rKR, 36.5% second linked rKR and 49.4% third or more linked rKR from 2014 to 2019. CONCLUSIONS: Recent trends suggest slowing of the rate of increase in the incidence of rKR. Infection is now the most common indication for rKR, following recent decreases in rKR for aseptic loosening. Infection was prevalent in re-revision KR procedures.

"Bring the Hoses to Where the Fire Is!": Differential Impacts of Marginalization and Socioeconomic Status on COVID-19 Case Counts and Healthcare Costs.

OBJECTIVES: Local health leaders and the Director General of the World Health Organization alike have observed that COVID-19 "does not discriminate." Nevertheless, the disproportionate representation of people of low socioeconomic status among those infected resembles discrimination. This population-based retrospective cohort study examined COVID-19 case counts and publicly funded healthcare costs in Ontario, Canada, with a focus on marginalization. METHODS: Individuals with their first positive severe acute respiratory syndrome coronavirus 2 test from January 1, 2020 to June 30, 2020, were linked to administrative databases and matched to negative/untested controls. Mean net (COVID-19-attributable) costs were estimated for 30 days before and after diagnosis, and differences among strata of age, sex, comorbidity, and measures of marginalization were assessed using analysis of variance tests. RESULTS: We included 28 893 COVID-19 cases (mean age 54 years, 56% female). Most cases remained in the community (20 545, 71.1%) or in long-term care facilities (4478, 15.5%), whereas 944 (3.3%) and 2926 (10.1%) were hospitalized, with and without intensive care unit, respectively. Case counts were skewed across marginalization strata with 2 to 7 times more cases in neighborhoods with low income, high material deprivation, and highest ethnic concentration. Mean net costs after diagnosis were higher for males ($4752 vs $2520 for females) and for cases with higher comorbidity ($1394-$7751) (both P < .001) but were similar across levels of most marginalization dimensions (range $3232-$3737, all P ≥ .19). CONCLUSIONS: This study suggests that allocating resources unequally to marginalized individuals may improve equality in outcomes. It highlights the importance of reducing risk of COVID-19 infection among marginalized individuals to reduce overall costs and increase system capacity.

Patient and Provider Perspectives on HIV Stigma in Healthcare Settings in Underserved Areas of the US South: A Mixed Methods Study.

Stigma experienced in healthcare settings is a barrier to ending the HIV epidemic. Using a convergent parallel mixed methods approach, we collected qualitative data from 14 focus groups with People with HIV (PWH) and Healthcare workers (HCW) and quantitative survey data (N = 762 PWH and N = 192 HCW) from seven HIV healthcare clinics outside of major urban areas in the southeastern US. Four key themes emerged: (1) HIV-related stigma and discrimination in healthcare settings; (2) experiences of intersectional stigma; (3) disclosure concerns in healthcare settings; and (4) impact of stigma on HIV-related health behavior. Implications for future stigma interventions in healthcare settings include the importance of engaging PWH in the development of interventions, the need for interventions in settings that do not specialize in HIV care, and the importance of engaging all staff when addressing HIV-related stigma.

RESUMEN: El estigma experimentado en los entornos de atención médica es una barrera para poner fin a la epidemia del VIH. Utilizando un enfoque convergente de métodos mixtosparalelos, recopilamos datos cualitativos de 14 grupos focales con personas con VIH y trabajadores de la salud y datos de encuestas cuantitativas (N = 762 personas con VIH y N = 192 trabajadores de la salud) de siete clínicas de atención médica de VIH fuera de las principales áreas urbanas en el sureste de los Estados Unidos. Surgieron cuatro temas clave: (1) el estigma y la discriminación relacionados con el VIH en los entornos de atención médica; (2) experiencias de estigma interseccional; (3) preocupaciones de divulgación en entornos de atención médica; y (4) el impacto del estigma en el comportamiento de salud relacionado con el VIH. Las implicaciones para futuras intervenciones de estigma en entornos de atención médica incluyen la importancia de involucrar a las personas con VIH en el desarrollo de intervenciones, la necesidad de intervenciones en entornos que no se especializan en la atención del VIH y la importancia de involucrar a todo el personal al abordar el estigma relacionado con el VIH.

Behavioural adjustments of predators and prey to wind speed in the boreal forest.

Wind speed can have multifaceted effects on organisms including altering thermoregulation, locomotion, and sensory reception. While forest cover can substantially reduce wind speed at ground level, it is not known if animals living in forests show any behavioural responses to changes in wind speed. Here, we explored how three boreal forest mammals, a predator and two prey, altered their behaviour in response to average daily wind speeds during winter. We collected accelerometer data to determine wind speed effects on activity patterns and kill rates of free-ranging red squirrels (n = 144), snowshoe hares (n = 101), and Canada lynx (n = 27) in Kluane, Yukon from 2015 to 2018. All 3 species responded to increasing wind speeds by changing the time they were active, but effects were strongest in hares, which reduced daily activity by 25%, and lynx, which increased daily activity by 25%. Lynx also increased the number of feeding events by 40% on windy days. These results highlight that wind speed is an important abiotic variable that can affect behaviour, even in forested environments.

Patient-maintained versus anaesthetist-controlled propofol sedation during elective primary lower-limb arthroplasty performed under spinal anaesthesia: a randomised controlled trial.

BACKGROUND: Patient-maintained propofol TCI sedation (PMPS) allows patients to titrate their own target-controlled infusion (TCI) delivery of propofol sedation using a handheld button. The aim of this RCT was to compare PMPS with anaesthetist-controlled propofol TCI sedation (ACPS) in patients undergoing elective primary lower-limb arthroplasty surgery under spinal anaesthesia. METHODS: In this single-centre open-label investigator-led study, adult patients were randomly assigned to either PMPS or ACPS during their surgery. Both sedation regimes used Schnider effect-site TCI modelling. The primary outcome measure was infusion rate adjusted for weight (expressed as mg kg-1 h-1). Secondary outcomes measures included depth of sedation, occurrence of sedation-related adverse events and time to medical readiness for discharge from the postanaesthsia care unit (PACU). RESULTS: Eighty patients (48 female) were randomised. Subjects using PMPS used 39.3% less propofol during the sedation period compared with subjects in group ACPS (1.56 [0.57] vs 2.57 [1.33] mg kg-1 h-1; P<0.001), experienced fewer discrete episodes of deep sedation (0 vs 6; P=0.0256), fewer airway/breathing adverse events (odds ratio [95% confidence interval]: 2.94 [1.31-6.64]; P=0.009) and were ready for discharge from PACU more quickly (8.94 [5.5] vs 13.51 [7.2] min; P=0.0027). CONCLUSIONS: Patient-maintained propofol sedation during lower-limb arthroplasty under spinal anaesthesia results in reduced drug exposure and fewer episodes of sedation-related adverse events compared with anaesthetist-controlled propofol TCI sedation. To facilitate further investigation of this procedural sedation technique, PMPS-capable TCI infusion devices should be submitted for regulatory approval for clinical use. CLINICAL TRIAL REGISTRATION: ISRCTN29129799.

Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma) in the setting of cowden syndrome: a case report and literature review on COLD syndrome.

Lhermitte-Duclos Disease is a rare clinical entity involving a dysplastic lesion of the cerebellum. The dysplastic cerebellar ganglioblastoma is often seen in association with Cowden Syndrome, an autosomal dominant disorder consisting of a mutation in the phosphatase and homologous tensin (PTEN) gene. Characteristic findings on neuroimaging allow for a pre-operative diagnosis to be made, which guides further management of the condition. This report describes the diagnosis and management of Lhermitte-Duclos Disease in a 51-year-old lady, spanning a period of almost seven years. The characteristic radiological and histological findings are presented, along with the clinical features associated with Cowden Syndrome. This patient ultimately underwent surgical intervention for symptomatic relief, which is described here.