Age and frailty are independently associated with increased COVID-19 mortality and increased care needs in survivors: results of an international multi-centre study

INTRODUCTION: Increased mortality has been demonstrated in older adults with COVID-19, but the effect of frailty has been unclear.METHODS: This multi-centre cohort study involved patients aged 18years and older hospitalised with COVID-19, using routinely collected data. We used Cox regression analysis to assess the impact of age, frailty, and delirium on the risk of inpatient mortality, adjusting for sex, illness severity, inflammation, and co-morbidities. We used ordinal logistic regression analysis to assess the impact of age, Clinical Frailty Scale (CFS), and delirium on risk of increased care requirements on discharge, adjusting for the same variables.RESULTS: Data from 5,711 patients from 55 hospitals in 12 countries were included (median age 74, IQR 54-83; 55.2% male). The risk of death increased independently with increasing age (>80 vs 18-49: HR 3.57, CI 2.54-5.02), frailty (CFS 8 vs 1-3: HR 3.03, CI 2.29-4.00) inflammation, renal disease, cardiovascular disease, and cancer, but not delirium. Age, frailty (CFS 7 vs 1-3: OR 7.00, CI 5.27-9.32), delirium, dementia, and mental health diagnoses were all associated with increased risk of higher care needs on discharge. The likelihood of adverse outcomes increased across all grades of CFS from 4 to 9.CONCLUSIONS: Age and frailty are independently associated with adverse outcomes in COVID-19. Risk of increased care needs was also increased in survivors of COVID-19 with frailty or older age

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance.

Investment in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing in Africa over the past year has led to a major increase in the number of sequences that have been generated and used to track the pandemic on the continent, a number that now exceeds 100,000 genomes. Our results show an increase in the number of African countries that are able to sequence domestically and highlight that local sequencing enables faster turnaround times and more-regular routine surveillance. Despite limitations of low testing proportions, findings from this genomic surveillance study underscore the heterogeneous nature of the pandemic and illuminate the distinct dispersal dynamics of variants of concern-particularly Alpha, Beta, Delta, and Omicron-on the continent. Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve while the continent faces many emerging and reemerging infectious disease threats. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Abstract DDT02-02: Preclinical development of LFA102, a highly potent and selective neutralizing antibody against the prolactin receptor

Abstract The prolactin receptor (PRLR) is a class I cytokine receptor frequently expressed in breast and prostate cancer. The polypeptide hormone prolactin (PRL) has been demonstrated to induce PRLR signaling through the Jak/Stat, PI3-kinase/AKT and MAPK pathways, leading to cell proliferation and survival. Breast- and prostate-specific overexpression of PRL in transgenic mice leads to a higher incidence of mammary and prostate tumors, respectively. In addition, the PRLR locus is the site of frequent viral integrations in MMTV-derived mammary tumors. Elevated serum PRL levels in humans have been correlated with an increased risk for breast cancer, and an analysis of more than 3000 breast tumor specimens indicates that PRLR is expressed with high prevalence (60-70% of tumors) across all breast cancer subtypes. In prostate cancer specimens, the presence of prolactin and phosphorylated Stat5 have been reported to be associated with high-grade tumors and poor clinical outcomes, suggesting a role of the PRL/PRLR signaling pathway in the pathology of this disease as well. All of these lines of evidence support the hypothesis that targeting the PRL/PRLR axis may be a new approach for addressing unmet medical need in these tumor types. LFA102 is a Human Engineered™ anti-PRLR antibody of the IgG1 isotype that neutralizes the function of PRLR through a nonligand competitive binding interaction. LFA102 blocks PRL-induced signaling and proliferation in T47D and MCF7 human breast cancer cells in vitro, and abolishes PRL-induced phospho-Stat5 signaling in T47D xenograft tumors in vivo. This antibody also cross-reacts with and neutralizes rat PRLR and is capable of potently regressing PRL-dependent Nb2-C11 pre-T cell lymphoma tumors in vivo. In vitro studies have shown that LFA102 can mediate antibody-dependent cellular cytotoxicity (ADCC) and inhibit the PRL-dependent release of the proangiogenic factor VEGF from breast cancer cells. Thus, there are multiple potential mechanisms through which LFA102 could show antitumor activity in vivo. Preclinical toxicological studies of LFA102 indicate that this therapeutic is well tolerated and exhibits a normal pharmacokinetic profile in relevant animal species. The safety and pharmacokinetics of LFA102 in humans are currently being evaluated in a phase I healthy volunteer trial. A phase 1b trial in breast and prostate cancer is planned to evaluate the efficacy of this antibody in patient populations predicted to have the highest probability of benefiting from an anti-PRLR therapeutic. This presentation will provide a summary of the preclinical data supporting the clinical development of LFA102. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr DDT02-02. doi:10.1158/1538-7445.AM2011-DDT02-02</jats:p

WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation

AbstractMetastatic breast cancer remains a major cause of cancer related deaths in women and there are few effective therapies against this advanced disease. Emerging evidence suggests that key steps of tumor progression and metastasis are controlled by reversible epigenetic mechanisms. Using an in vivo genetic screen, we identified WDR5 as an actionable epigenetic regulator that is required for metastatic progression in models of triple-negative breast cancer. We found that knockdown of WDR5 in breast cancer cells independently impaired their tumorigenic as well as metastatic capabilities. Mechanistically, WDR5 promotes cell growth by increasing ribosomal gene expression and translation efficiency in a KMT2-independent manner. Consistently, pharmacological inhibition or degradation of WDR5 impedes cellular translation rate and the clonogenic ability of breast cancer cells. Furthermore, combination of WDR5-targeting with mTOR inhibitors leads to potent suppression of translation and proliferation of breast cancer cells. These results reveal novel therapeutic strategies to treat metastatic breast cancer.</jats:p

The Impact of Physical Activity on the Prevention of Type 2 Diabetes: Evidence and Lessons Learned From the Diabetes Prevention Program, a Long-Standing Clinical Trial Incorporating Subjective and Objective Activity Measures

OBJECTIVE Across the Diabetes Prevention Program (DPP) follow-up, cumulative diabetes incidence remained lower in the lifestyle compared with the placebo and metformin randomized groups and could not be explained by weight. Collection of self-reported physical activity (PA) (yearly) with cross-sectional objective PA (in follow-up) allowed for examination of PA and its long-term impact on diabetes prevention. RESEARCH DESIGN AND METHODS Yearly self-reported PA and diabetes assessment and oral glucose tolerance test results (fasting glucose semiannually) were collected for 3,232 participants with one accelerometry assessment 11–13 years after randomization (n = 1,793). Mixed models determined PA differences across treatment groups. The association between PA and diabetes incidence was examined using Cox proportional hazards models. RESULTS There was a 6% decrease (Cox proportional hazard ratio 0.94 [95% CI 0.92, 0.96]; P &amp;lt; 0.001) in diabetes incidence per 6 MET-h/week increase in time-dependent PA for the entire cohort over an average of 12 years (controlled for age, sex, baseline PA, and weight). The effect of PA was greater (12% decrease) among participants less active at baseline (&amp;lt;7.5 MET-h/week) (n = 1,338) (0.88 [0.83, 0.93]; P &amp;lt; 0.0001), with stronger findings for lifestyle participants. Lifestyle had higher cumulative PA compared with metformin or placebo (P &amp;lt; 0.0001) and higher accelerometry total minutes per day measured during follow-up (P = 0.001 and 0.047). All associations remained significant with the addition of weight in the models. CONCLUSIONS PA was inversely related to incident diabetes in the entire cohort across the study, with cross-sectional accelerometry results supporting these findings. This highlights the importance of PA within lifestyle intervention efforts designed to prevent diabetes and urges health care providers to consider both PA and weight when counseling high-risk patients. </jats:sec