COVID-19 Mortality and Progress Toward Vaccinating Older Adults - World Health Organization, Worldwide, 2020-2022.

After the emergence of SARS-CoV-2 in late 2019, transmission expanded globally, and on January 30, 2020, COVID-19 was declared a public health emergency of international concern.* Analysis of the early Wuhan, China outbreak (1), subsequently confirmed by multiple other studies (2,3), found that 80% of deaths occurred among persons aged ≥60 years. In anticipation of the time needed for the global vaccine supply to meet all needs, the World Health Organization (WHO) published the Strategic Advisory Group of Experts on Immunization (SAGE) Values Framework and a roadmap for prioritizing use of COVID-19 vaccines in late 2020 (4,5), followed by a strategy brief to outline urgent actions in October 2021.† WHO described the general principles, objectives, and priorities needed to support country planning of vaccine rollout to minimize severe disease and death. A July 2022 update to the strategy brief§ prioritized vaccination of populations at increased risk, including older adults,¶ with the goal of 100% coverage with a complete COVID-19 vaccination series** for at-risk populations. Using available public data on COVID-19 mortality (reported deaths and model estimates) for 2020 and 2021 and the most recent reported COVID-19 vaccination coverage data from WHO, investigators performed descriptive analyses to examine age-specific mortality and global vaccination rollout among older adults (as defined by each country), stratified by country World Bank income status. Data quality and COVID-19 death reporting frequency varied by data source; however, persons aged ≥60 years accounted for >80% of the overall COVID-19 mortality across all income groups, with upper- and lower-middle-income countries accounting for 80% of the overall estimated excess mortality. Effective COVID-19 vaccines were authorized for use in December 2020, with global supply scaled up sufficiently to meet country needs by late 2021 (6). COVID-19 vaccines are safe and highly effective in reducing severe COVID-19, hospitalizations, and mortality (7,8); nevertheless, country-reported median completed primary series coverage among adults aged ≥60 years only reached 76% by the end of 2022, substantially below the WHO goal, especially in middle- and low-income countries. Increased efforts are needed to increase primary series and booster dose coverage among all older adults as recommended by WHO and national health authorities.

Tonabersat Significantly Reduces Disease Progression in an Experimental Mouse Model of Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease marked by chronic neuroinflammation thought to be mediated by the inflammasome pathway. Connexin 43 (Cx43) hemichannels contribute to the activation of the inflammasome through the release of adenosine triphosphate (ATP) inflammasome activation signals. The objective of the study was to evaluate if the Cx43 hemichannel blocker, tonabersat, is effective in modulating the inflammatory response and reducing disability in the myelin oligodendrocyte glycoprotein 35-55-induced experimental autoimmune encephalomyelitis (MOG35-55 EAE) model of MS. Here, we show that the Cx43 hemichannel blocking drug, tonabersat, significantly reduced expression of neuroinflammatory markers for microglial activation (ionized calcium-binding adapter molecule 1 (Iba1)) and astrogliosis (glial fibrillary acidic protein (GFAP)) while preserving myelin basic protein (MBP) expression levels in the corpus callosum, motor cortex, and striatum regions of the brain in MOG35-55 EAE mice. Reduced NOD-like receptor protein 3 (NLRP3) inflammasome complex assembly and Caspase-1 activation confirmed the drug's mode of action. MOG35-55 EAE mice showed clinical signs of MS, but MOG35-55 EAE mice treated with tonabersat retained behavior closer to normal. These data suggest that clinical trial phase IIb-ready tonabersat may merit further investigation as a promising candidate for MS treatment.

The Transcription Factor Shox2 Shapes Neuron Firing Properties and Suppresses Seizures by Regulation of Key Ion Channels in Thalamocortical Neurons.

Thalamocortical neurons (TCNs) play a critical role in the maintenance of thalamocortical oscillations, dysregulation of which can result in certain types of seizures. Precise control over firing rates of TCNs is foundational to these oscillations, yet the transcriptional mechanisms that constrain these firing rates remain elusive. We hypothesized that Shox2 is a transcriptional regulator of ion channels important for TCN function and that loss of Shox2 alters firing frequency and activity, ultimately perturbing thalamocortical oscillations into an epilepsy-prone state. In this study, we used RNA sequencing and quantitative PCR of control and Shox2 knockout mice to determine Shox2-affected genes and revealed a network of ion channel genes important for neuronal firing properties. Protein regulation was confirmed by Western blotting, and electrophysiological recordings showed that Shox2 KO impacted the firing properties of a subpopulation of TCNs. Computational modeling showed that disruption of these conductances in a manner similar to Shox2's effects modulated frequency of oscillations and could convert sleep spindles to near spike and wave activity, which are a hallmark for absence epilepsy. Finally, Shox2 KO mice were more susceptible to pilocarpine-induced seizures. Overall, these results reveal Shox2 as a transcription factor important for TCN function in adult mouse thalamus.

Dynamics of adrenergic signaling in cardiac myocytes and implications for pharmacological treatment.

Dense innervation of the heart by the sympathetic nervous system (SNS) allows cardiac output to respond appropriately to the needs of the body under varying conditions, but occasionally the abrupt onset of SNS activity can trigger cardiac arrhythmias. Sympathetic activity leads to the release of norepinephrine (NE) onto cardiomyocytes, activating ß1-adrenergic receptors (ß1-ARs) and leading to the production of the second messenger cyclic AMP (cAMP). Upon sudden activation of ß1-ARs in experiments, intracellular cAMP can transiently rise to a high concentration before converging to a steady state level. Although changes to cellular cAMP concentration are important in modulating the overall cardiovascular response to sympathetic tone, the underlying mechanisms of the cAMP transients and the parameters that control their magnitude are unclear. We reduce a detailed computational model of the ß1-adrenergic signaling cascade to a system of two differential equations by eliminating extraneous variables and applying quasi-steady state approximation. The structure of the reduced model reveals that the large cAMP transients associated with abrupt ß1-AR activation are generated by the interplay of production/degradation of cAMP and desensitization/resensitization of ß1-ARs. The reduced model is used to predict how the dynamics of intracellular cAMP depend on the concentrations of norepinephrine (NE), phosphodiesterases 3 and 4 (PDE3,4), G-protein coupled receptor kinase 2 (GRK2), and ß1-AR, in healthy conditions and a simple model of early stages of heart failure. The key findings of the study are as follows: 1) Applying a reduced model of the dynamics of cardiac sympathetic signaling we show that the concentrations of two variables, cAMP and non-desensitized ß1-AR, capture the overall dynamics of sympathetic signaling; 2) The key factors influencing cAMP production are AC activity and PDE3,4 activity, while those that directly impact ß1-AR phosphorylation are GRK2 and PKA1. Thus, disease states that affect sympathetic control of the heart can be thoroughly assessed by studying AC activity, PDE3,4, GRK2 and PKA activity, as these factors directly impact cAMP production/degradation and ß1-AR (de) phosphorylation and are therefore predicted to comprise the most effective pharmaceutical targets in diseases affecting cardiac ß1-adrenergic signaling.

Total and high-affinity corticosteroid-binding globulin depletion in septic shock is associated with mortality.

CONTEXT: Corticosteroid-binding globulin (CBG) and albumin transport circulating cortisol. Cleavage of high-affinity CBG (haCBG) by neutrophil elastase at inflammatory sites causes cortisol release into tissues, facilitating immunomodulatory effects. OBJECTIVE: To determine whether depletion of haCBG is related to mortality in septic shock. DESIGN: A single-center prospective observational cohort study of patients recruited with critical illness or septic shock, using serum samples collected at 0, 8, 24, 48 and 72 hours. Serum total and haCBG, and total and free cortisol were assayed directly. Glucocorticoid treatment was an exclusion criterion. Mortality was assessed at 28 days from Intensive Care Unit admission. RESULTS: Thirty septic shock (SS) and 42 nonseptic critical illness (CI) patients provided 195 serum samples. SS/CI patients had lower total CBG, haCBG and low-affinity CBG (laCBG) than controls. Total CBG and haCBG were significantly lower in septic shock patients who died than in those that survived (P < 0.009, P = 0.021, respectively). Total and free cortisol were higher in septic than nonseptic individuals. Free/total cortisol fractions were higher in those with low haCBG as observed in septic shock. However, cortisol levels were not associated with mortality. Albumin levels fell in sepsis but were not related to mortality. CONCLUSIONS: Low circulating haCBG concentrations are associated with mortality in septic shock. These results are consistent with an important physiological role for haCBG in cortisol tissue delivery in septic shock.

Perioperative diabetic ketoacidosis associated with sodium-glucose co-transporter-2 inhibitors: a systematic review.

BACKGROUND: Perioperative diabetic ketoacidosis (DKA) with near-normal blood glucose concentrations, termed euglycaemic ketoacidosis (EDKA), is an adverse effect associated with sodium-glucose co-transporter-2 inhibitors (SGLT2i). Guidelines are still evolving concerning the perioperative management of patients on SGLT2i. We performed a systematic review of published reports of DKA from SGLT2i in the surgical setting to understand better the clinical presentation and characteristics of SGLT2i-associated DKA. METHODS: We searched PubMed, Embase, and ProQuest for reports of perioperative DKA involving SGLT2i up to January 2019. RESULTS: Forty-two reports of EDKA and five cases of hyperglycaemic diabetic ketoacidosis (HDKA) were identified from 33 publications. Canagliflozin was implicated in 26 cases. Presentation time varied from a few hours up to 6 weeks after operation. Precipitating factors may include diabetes medication changes, diet modifications, and intercurrent illnesses. There were 13 cases (12 EDKA and one HDKA) of bariatric surgery, 10 of them noted very-low-calorie diet regimes as a precipitating factor. No precise association between interruption of SGLT2i and the occurrence of DKA could be identified. Seven patients required mechanical ventilation, and acute kidney injury was noted in five. Five cases needed imaging to rule out anastomotic leak and pulmonary embolism, all of them revealed negative findings. Outcome data were available in 32 cases, all of them recovered completely. CONCLUSIONS: EDKA is likely to be under-recognised because of its atypical presentation and may delay the diagnosis. Understanding this clinical entity, vigilance towards monitoring plasma/capillary ketones helps in early identification and assists in the management.

Epithelial junctions maintain tissue architecture by directing planar spindle orientation.

During epithelial cell proliferation, planar alignment of the mitotic spindle coordinates the local process of symmetric cell cleavage with the global maintenance of polarized tissue architecture. Although the disruption of planar spindle alignment is proposed to cause epithelial to mesenchymal transition and cancer, the in vivo mechanisms regulating mitotic spindle orientation remain elusive. Here we demonstrate that the actomyosin cortex and the junction-localized neoplastic tumour suppressors Scribbled and Discs large 1 have essential roles in planar spindle alignment and thus the control of epithelial integrity in the Drosophila imaginal disc. We show that defective alignment of the mitotic spindle correlates with cell delamination and apoptotic death, and that blocking the death of misaligned cells is sufficient to drive the formation of basally localized tumour-like masses. These findings indicate a key role for junction-mediated spindle alignment in the maintenance of epithelial integrity, and also reveal a previously unknown cell-death-mediated tumour-suppressor function inherent in the polarized architecture of epithelia.

Vasculogenic hyperprolactinemia: severe prolactin excess in association with internal carotid artery aneurysms.

PURPOSE: Internal carotid artery (ICA) aneurysms have rarely been found in association with marked hyperprolactinemia in the absence of prolactinoma; the cause of hyperprolactinemia has never been investigated. We aimed to determine if the observed hyperprolactinemia is due to a vascular-derived or known prolactin secretagogue from the injured ICA, analogous to pregnancy-associated hyperprolactinemia putatively due to placental factors. METHODS: We conducted a case series and literature review of individuals with severe hyperprolactinemia in association with ICA aneurysms. In two affected patients at our institutions, we performed RT-PCR and ELISA of prolactin secretagogues that are produced by vascular tissue and/or upregulated in pregnancy: AGT (encoding angiotensinogen), TAC1 (encoding substance P), HDC (encoding the enzyme responsible for conversion of histidine to histamine), and prolactin-releasing hormone (PRLH). Patient blood samples were compared to pregnancy blood samples (positive controls) and middle-aged male blood samples (negative controls). RESULTS: Two men presented with serum prolactin >100-fold normal associated with cavernous ICA aneurysms and no pituitary adenoma. Aneurysm stenting in one man more than halved his serum prolactin. In both men, dopamine agonist therapy markedly reduced serum prolactin. RT-PCR and ELISA showed no differences between patients and controls in AGT, TAC1 or HDC expression or PRLH titre, respectively. Literature review revealed 11 similar cases. CONCLUSIONS: We propose the term 'vasculogenic hyperprolactinemia' to encompass the hyperprolactinemia associated with ICA aneurysms. This may be mediated by an endothelial factor capable of paracrine stimulation of lactotrophs; however, angiotensin II, substance P, histamine and PRLH appear unlikely to be causative.

Feedback regulation of Drosophila BMP signaling by the novel extracellular protein larval translucida.

The cellular response to the Drosophila BMP 2/4-like ligand Decapentaplegic (DPP) serves as one of the best-studied models for understanding the long-range control of tissue growth and pattern formation during animal development. Nevertheless, fundamental questions remain unanswered regarding extracellular regulation of the ligand itself, as well as the nature of the downstream transcriptional response to BMP pathway activation. Here, we report the identification of larval translucida (ltl), a novel target of BMP activity in Drosophila. Both gain- and loss-of-function analyses implicate LTL, a leucine-rich repeat protein, in the regulation of wing growth and vein patterning. At the molecular level, we demonstrate that LTL is a secreted protein that antagonizes BMP-dependent MAD phosphorylation, indicating that it regulates DPP/BMP signaling at or above the level of ligand-receptor interactions. Furthermore, based on genetic interactions with the DPP-binding protein Crossveinless 2 and biochemical interactions with the glypican Dally-like, we propose that LTL acts in the extracellular space where it completes a novel auto-regulatory loop that modulates BMP activity.

On the origins of the mitotic shift in proliferating cell layers.

BACKGROUND: During plant and animal development, monolayer cell sheets display a stereotyped distribution of polygonal cell shapes. In interphase cells these shapes range from quadrilaterals to decagons, with a robust average of six sides per cell. In contrast, the subset of cells in mitosis exhibits a distinct distribution with an average of seven sides. It remains unclear whether this 'mitotic shift' reflects a causal relationship between increased polygonal sidedness and increased division likelihood, or alternatively, a passive effect of local proliferation on cell shape. METHODS: We use a combination of probabilistic analysis and mathematical modeling to predict the geometry of mitotic polygonal cells in a proliferating cell layer. To test these predictions experimentally, we use Flp-Out stochastic labeling in the Drosophila wing disc to induce single cell clones, and confocal imaging to quantify the polygonal topologies of these clones as a function of cellular age. For a more generic test in an idealized cell layer, we model epithelial sheet proliferation in a finite element framework, which yields a computationally robust, emergent prediction of the mitotic cell shape distribution. RESULTS: Using both mathematical and experimental approaches, we show that the mitotic shift derives primarily from passive, non-autonomous effects of mitoses in neighboring cells on each cell's geometry over the course of the cell cycle. Computationally, we predict that interphase cells should passively gain sides over time, such that cells at more advanced stages of the cell cycle will tend to have a larger number of neighbors than those at earlier stages. Validating this prediction, experimental analysis of randomly labeled epithelial cells in the Drosophila wing disc demonstrates that labeled cells exhibit an age-dependent increase in polygonal sidedness. Reinforcing these data, finite element simulations of epithelial sheet proliferation demonstrate in a generic framework that passive side-gaining is sufficient to generate a mitotic shift. CONCLUSIONS: Taken together, our results strongly suggest that the mitotic shift reflects a time-dependent accumulation of shared cellular interfaces over the course of the cell cycle. These results uncover fundamental constraints on the relationship between cell shape and cell division that should be general in adherent, polarized cell layers.

Approach the Patient With Obstructive Sleep Apnea and Obesity.

Obstructive sleep apnea (OSA) and obesity are highly prevalent and bidirectionally associated. OSA is underrecognized, however, particularly in women. By mechanisms that overlap with those of obesity, OSA increases the risk of developing, or having poor outcomes from, comorbid chronic disorders and impairs quality of life. Using 2 illustrative cases, we discuss the relationships between OSA and obesity with type 2 diabetes, dyslipidemia, cardiovascular disease, cognitive disturbance, mood disorders, lower urinary tract symptoms, sexual function, and reproductive disorders. The differences in OSA between men and women, the phenotypic variability of OSA, and comorbid sleep disorders are highlighted. When the probability of OSA is high due to consistent symptoms, comorbidities, or both, a diagnostic sleep study is advisable. Continuous positive airway pressure or mandibular advancement splints improve symptoms. Benefits for comorbidities are variable depending on nightly duration of use. By contrast, weight loss and optimization of lifestyle behaviors are consistently beneficial.

Cortisol, Stress, and Disease-Bidirectional Associations; Role for Corticosteroid-Binding Globulin?

Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic, and immunomodulation mechanisms, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis, and limbic structures are implicated in many chronic diseases by establishing an altered homeostatic state, allostasis. Consequent "primary stress system disorders" were popularly accepted, with phenotypes based on conditions such as Cushing syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolemic etiology, contrasting the "hypocortisolemic symptom triad" of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress etiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR) variants have been associated with metabolic/neuropsychological states. The SERPINA6 gene encoding corticosteroid-binding globulin (CBG), was the sole genetic factor in a single-nucleotide variation-genome-wide association study linkage study of morning plasma cortisol, a risk factor for cardiovascular disease, with alterations in tissue-specific GR-related gene expression. Studies showed genetically predicted high cortisol concentrations are associated with hypertension and anxiety, and low CBG concentrations/binding affinity, with the hypocortisolemic triad. Acquired CBG deficiency in septic shock results in 3-fold higher mortality when hydrocortisone administration produces equivocal results, consistent with CBG's role in spatiotemporal cortisol delivery. We propose some stress system disorders result from constitutional stress system variants rather than stressors themselves. Altered CBG:cortisol buffering may influence interstitial cortisol ultradian surges leading to pathological tissue effects, an example of stress system variants contributing to stress-related disorders.

Paramedic attitudes regarding prehospital analgesia.

INTRODUCTION: Although pain is a major reason why patients summon emergency medical services (EMS), prehospital medical providers administer analgesic agents at inappropriately low rates. One possible reason is the role of EMS provider attitudes. OBJECTIVE: This study was conducted to elicit attitudes that may act as impediments or deterrents to administering analgesia in the prehospital environment. METHODS: A qualitative methodology was employed. We recruited experienced paramedics, with at least one year of full-time fieldwork, from a variety of agencies in New England. We sought to include a balance of rural and urban as well as both private and hospital-based agencies. Participants at each site were selected through purposive sampling. A semistructured discussion guide was designed to elicit the paramedics' past experiences with administering analgesia, as well as reflections on their role in the care of patients in pain. Both interviews and focus groups were conducted. These sessions were recorded and transcribed verbatim. The transcripts were topic-analyzed and iteratively coded by two independent investigators utilizing the constant comparative method of Glaser and Strauss' Grounded Theory; coding ambiguities were resolved by consensus. Through a series of conceptual mapping and iterative code refinement, themes and domains were generated. RESULTS: Fifteen paramedics from five EMS agencies in three New England states were recruited. Major themes were: 1) a reluctance to administer opioids to patients without significant objective signs (e.g., deformity, hypertension); 2) a preoccupation with potential malingering; 3) ambivalence about the degree of pain control to target or to expect (e.g., aiming to "take the edge off"); 4) a fear of masking diagnostic symptoms; and 5) an aversion to aggressive dosing of opioids (e.g., initial doses of morphine did not exceed 5 mg). CONCLUSIONS: A number of potentially modifiable attitudinal barriers to appropriate pain management were revealed.

Additional challenges in reaching hepatitis C elimination goals in Germany due to the COVID-19 pandemic - descriptive analysis of drug prescription data from January 2018 to June 2021.

Effectively treating hepatitis C viral (HCV) infections prevents sequelae and onward transmission. In Germany, HCV drug prescriptions have declined since 2015. During the COVID-19 pandemic, lockdowns impacted the access to HCV care services and HCV treatment. We assessed if the COVID-19 pandemic further decreased treatment prescriptions in Germany. We built log-linear models with monthly HCV drug prescription data from pharmacies from January 2018 - February 2020 (pre-pandemic) to calculate expected prescriptions for March 2020-June 2021 and different pandemic phases. We calculated monthly prescription trends per pandemic phase using log-linear models. Further, we scanned all data for breakpoints. We stratified all data by geographic region and clinical settings. The number of DAA prescriptions in 2020 (n = 16,496, -21%) fell below those of 2019 (n = 20,864) and 2018 (n = 24,947), continuing the declining trend from previous years. The drop in prescriptions was stronger from 2019 to 2020 (-21%) than from 2018 to 2020 (-16%). Observed prescriptions met predictions from March 2020 to June 2021, but not during the first COVID-19 wave (March 2020-May 2020). Prescriptions increased during summer 2020 (June 2020-September 2020) and fell below the pre-pandemic numbers during the following pandemic waves (October 2020 - February 2021 and March 2021 - June 2021). Breakpoints during the first wave indicate that prescriptions plummeted overall, in all clinical settings and in four of six geographic regions. Both, outpatient clinics and private practices prescribed overall as predicted. However, outpatient hospital clinics prescribed 17-39% less than predicted during the first pandemic wave. HCV treatment prescriptions declined but stayed within the lower realms of predicted counts. The strongest decline during the first pandemic wave indicates a temporary HCV treatment gap. Later, prescriptions matched predictions despite of pronounced decreases during the second and third waves. In future pandemics, clinics and private practices need to adapt more rapidly to maintain a continuous access to care. In addition, political strategies should focus more on continuously providing essential medical care during periods of restricted access due to infectious disease outbreaks. The observed decrease in HCV treatment may challenge reaching the HCV elimination goals in Germany by 2030.

Corticosteroid-binding globulin (CBG): spatiotemporal distribution of cortisol in sepsis.

Corticosteroid-binding globulin (CBG) is a 50-60 kDa circulating glycoprotein with high affinity for cortisol. CBG is adapted for sepsis; its cortisol binding is reduced reversibly by pyrexia and acidaemia, and reduced irreversibly by neutrophil elastase (NE) cleavage, converting high cortisol-binding affinity CBG to a low affinity form. These characteristics allow for the targeted delivery of immunomodulatory cortisol to tissues at the time and body site where cortisol is required in sepsis and septic shock. In addition, high titer inflammatory cytokines in sepsis suppress CBG hepatic synthesis, increasing the serum free cortisol fraction. Recent clinical studies have highlighted the importance of CBG in septic shock, with CBG deficiency independently associated with mortality.