Applying infectious disease forecasting to public health: a path forward using influenza forecasting examples.

BACKGROUND: Infectious disease forecasting aims to predict characteristics of both seasonal epidemics and future pandemics. Accurate and timely infectious disease forecasts could aid public health responses by informing key preparation and mitigation efforts. MAIN BODY: For forecasts to be fully integrated into public health decision-making, federal, state, and local officials must understand how forecasts were made, how to interpret forecasts, and how well the forecasts have performed in the past. Since the 2013-14 influenza season, the Influenza Division at the Centers for Disease Control and Prevention (CDC) has hosted collaborative challenges to forecast the timing, intensity, and short-term trajectory of influenza-like illness in the United States. Additional efforts to advance forecasting science have included influenza initiatives focused on state-level and hospitalization forecasts, as well as other infectious diseases. Using CDC influenza forecasting challenges as an example, this paper provides an overview of infectious disease forecasting; applications of forecasting to public health; and current work to develop best practices for forecast methodology, applications, and communication. CONCLUSIONS: These efforts, along with other infectious disease forecasting initiatives, can foster the continued advancement of forecasting science.

Effect of aliskiren and valsartan combination versus aliskiren monotherapy on hemostatic biomarkers in hypertensive diabetics: Aliskiren and Valsartan Impact in Diabetics pilot trial.

Valsartan is known to inhibit platelet activity in both in vitro and ex vivo clinical setting, whereas aliskiren in vitro modulates antithrombin-III in plasma. The authors tested how aliskiren and valsartan combination versus aliskiren monotherapy will affect hemostatic biomarkers in mild-to-moderate hypertensive diabetics in the frame of the Aliskiren and Valsartan Impact in Diabetics (AVID) trial. A total of 52 patients with type 2 diabetes and mild-to-moderate hypertension were equally randomized to aliskiren (150-300 mg/d) and valsartan (160 mg/d) versus aliskiren (150-300 mg/d) alone for 4 weeks. A total of 25 biomarkers were serially measured, of which 16 are related to platelet function, 6 to coagulation, and 3 to fibrinolysis. Aliskiren monotherapy has no significant impact on any of the assessed biomarkers. In contrast, valsartan on top of aliskiren provided significant inhibition of ADP-induced platelet aggregation (P=0.032), decreased shear-induced activation measured with PFA-100 analyzer (P=0.041), and diminished expression of GP IIb/IIIa activity (P=0.027) measured by PAC-1 antibody, GP Ib (CD42b, P=0.033), vitronectin receptor (CD51/61, P=0.046), P-selectin (CD62p, P=0.026), lysosome-associated membrane protein (CD107a, P=0.042), and CD40-ligand (CD154, P=0.048). In AVID trial, valsartan in combination with aliskiren mildly but significantly inhibited platelets, confirming previous observations. In contrast, aliskiren monotherapy does not enhance antithrombin activity, suggesting that previous data probably represent a laboratory artifact. Importantly, these randomized data were generated on top of low-dose daily aspirin, supporting extra benefit for combination use of angiotensin receptor blockers and renin inhibitors in high-risk diabetic population.

Fatal sepsis and systemic inflammatory response syndrome after off-label prasugrel: a case report.

Aggressive dual antiplatelet therapy is associated not only with more bleeding, impaired wound healing, and potentially more solid cancer rates but it also causes higher infection risks including sepsis, and systemic inflammatory response syndrome (SIRS). This may be especially true considering the alarming off-label use of prasugrel. A 65-year-old white male patient with a history of myocardial infarction treated with percutaneous coronary intervention and implantation of 2 bare metal stents, was treated with off-label clopidogrel for 4 years, including a double daily dose (150 mg) for the initial 13 months. Still on clopidogrel, the patient was hospitalized with suspected pneumonia. A diagnostic cardiac catheterization revealed a 60%-70% blockage of the mid left anterior descending, but there was no need for coronary intervention. At discharge, clopidogrel 75 mg/d was switched over to off-label prasugrel 10 mg/d on top of aspirin (81 mg/d). On day 3 after prasugrel was given, a football-sized bruise appeared on the patient's lower right abdomen, but computed tomography results were unremarkable. On day 6 after administration of prasugrel, the patient became dizzy, disoriented, confused, experienced difficulty breathing, severe headache, weakness, intensive petechial rash covering the entire body, and breathing difficulty requiring ventilation. Within 24 hours, the patient was unable to correctly identify his age; his eyes were pale in color to almost colorless and when hearing a sound he would turn his entire head toward the sound and he appeared to be blind. His lungs, liver, and kidneys began to show signs of failure over the next 5-9 days. Sixteen days after the administration of the first prasugrel dose, the patient died of sepsis complicated with SIRS. Aggressive off-label use of clopidogrel (double dose for 13 months, and >4 years overall duration), followed by off-label switchover to the highest daily dose (10 mg) prasugrel may trigger sepsis and fatal SIRS. The mechanism responsible for such harmful association is probably indirect, and involves the weakening of platelet-neutrophil-endothelial crosstalk necessary to combat infections, and/or keep inflammation from spreading.

Incorporating endogenous human behavior in models of COVID-19 transmission: A systematic scoping review.

Background: During the COVID-19 pandemic there was a plethora of dynamical forecasting models created, but their ability to effectively describe future trajectories of disease was mixed. A major challenge in evaluating future case trends was forecasting the behavior of individuals. When behavior was incorporated into models, it was primarily incorporated exogenously (e.g., fitting to cellphone mobility data). Fewer models incorporated behavior endogenously (e.g., dynamically changing a model parameter throughout the simulation). Methods: This review aimed to qualitatively characterize models that included an adaptive (endogenous) behavioral element in the context of COVID-19 transmission. We categorized studies into three approaches: 1) feedback loops, 2) game theory/utility theory, and 3) information/opinion spread. Findings: Of the 92 included studies, 72% employed a feedback loop, 27% used game/utility theory, and 9% used a model if information/opinion spread. Among all studies, 89% used a compartmental model alone or in combination with other model types. Similarly, 15% used a network model, 11% used an agent-based model, 7% used a system dynamics model, and 1% used a Markov chain model. Descriptors of behavior change included mask-wearing, social distancing, vaccination, and others. Sixty-eight percent of studies calibrated their model to observed data and 25% compared simulated forecasts to observed data. Forty-one percent of studies compared versions of their model with and without endogenous behavior. Models with endogenous behavior tended to show a smaller and delayed initial peak with subsequent periodic waves. Interpretation: While many COVID-19 models incorporated behavior exogenously, these approaches may fail to capture future adaptations in human behavior, resulting in under- or overestimates of disease burden. By incorporating behavior endogenously, the next generation of infectious disease models could more effectively predict outcomes so that decision makers can better prepare for and respond to epidemics. Funding: This study was funded in-part by Centers for Disease Control and Prevention (CDC) MInD-Healthcare Program (1U01CK000536), the National Science Foundation (NSF) Modeling Dynamic Disease-Behavior Feedbacks for Improved Epidemic Prediction and Response grant (2229996), and the NSF PIPP Phase I: Evaluating the Effectiveness of Messaging and Modeling during Pandemics grant (2200256).

A novel therapeutic vaccine targeting the soluble TNFα receptor II to limit the progression of cardiovascular disease: AtheroVax™.

The burden of atherosclerotic cardiovascular disease contributes to a large proportion of morbidity and mortality, globally. Vaccination against atherosclerosis has been proposed for over 20 years targeting different mediators of atherothrombosis; however, these have not been adequately evaluated in human clinical trials to assess safety and efficacy. Inflammation is a driver of atherosclerosis, but inflammatory mediators are essential components of the immune response. Only pathogenic forms of sTNFR2 are acted upon while preserving the membrane-bound (wild-type) TNFR2 contributions to a non-pathogenic immune response. We hypothesize that the inhibition of sTNRF2 will be more specific and offer long-term treatment options. Here we describe pre-clinical findings of an sTNFR2-targeting peptide vaccine (AtheroVax™) in a mouse model. The multiple pathways to synthesis of the soluble TNFRII receptor (sTNFRII) were identified as sTNFRII(PC), sTNFRII(Δ7), and sTNFRII(Δ7,9). The sTNFRII(Δ7) peptide, NH2-DFALPVEKPLCLQR-COOH is specific to sTNFR2 based on an mRNA splice-variant in which exon 6 is joined to exon 8. The role of sTNFRII(Δ7) as a mediator of prolonged TNFα activity by preventing degradation and clearance was investigated. Inflammation is a critical driver of onset, progression and expansion of atherosclerosis. The TNFα ligand represents a driver of inflammation that is mediated by a splice variant of TNFR2, referred to as sTNFRII(Δ7). The multiple forms of TNFRII, both membrane bound and soluble, are associated with distinctly different phenotypes. sTNFRII(PC) and sTNFRII(Δ7) are not equivalent to etanercept because they lack a clearance mechanism. The unique peptide associated with sTNFRII(Δ7) contains a linear B-cell epitope with amino acids from both exon 6 and exon 8 supporting the vaccine design. Animal studies to evaluate the vaccine are ongoing, and results will be forthcoming. We describe a peptide vaccine targeting sTNFR2 in limiting the progression of atherosclerosis. A therapeutic vaccine limiting the progression of atherosclerosis will greatly contribute to the reduction in morbidity and mortality from cardiovascular disease. It is likely the vaccine will be used in combination with the current standards of care and lifestyle modifications.

The impact of delayed access to COVID-19 vaccines in low- and lower-middle-income countries.

Introduction: A majority of low-income (LIC) and lower-middle-income countries (LMIC) were unable to achieve at least 10% population coverage during initial vaccine rollouts, despite the rapid development of the coronavirus disease 2019 (COVID-19) vaccines. Nearly three years into this pandemic, evaluating the impact of inequities in vaccine access, uptake, and availability is long overdue. We hypothesized that a delay in receiving COVID-19 vaccines was associated with an increased toll on cumulative cases and mortality. Furthermore, this relationship was modified by the size of a country's economy. Methods: We performed an ecological study assessing these relationships, in which a country's economic standing was assessed by world bank income classification, gross domestic product based on the purchasing power parity (GDP PPP) per capita category, and crude GDP PPP. Results: Countries with the smallest economies reported first vaccination much later than larger economies on all three rankings, as much as 100 days longer. Among low-income countries, a one-day increase until the first vaccination was associated with a 1.92% (95% CI: 0.100, 3.87) increase in cumulative cases when compared to high-income countries (p = 0.0395) when adjusting for population size, median age, and testing data availability. Similarly, among the lowest GDP PPP countries a one-day increase until the first vaccination was associated with a 2.73% (95% CI: 0.100, 5.44) increase in cumulative cases when compared to the highest GDP PPP countries (p = 0.0415). When modeling cumulative mortality, effects in the same direction and magnitude were observed, albeit statistically non-significant. Conclusion: Economic standing modified the effects of delayed access to COVID-19 vaccination on cumulative cases and mortality, in which LMICs tended to fare worse in outcomes than high-income countries despite the eventual rollout of vaccines. These findings highlight the importance of prioritizing equitable and timely access to COVID-19 vaccines across all countries, irrespective of economic size. Future studies should examine the impacts that vaccine inequities had on local transmission dynamics.

Human Placental Mesenchymal Stem Cells for the Treatment of ARDS in Rat.

The acute respiratory distress syndrome (ARDS) is one of the main causes of high mortality in patients with coronavirus (COVID-19). In recent years, due to the coronavirus pandemic, the number of patients with ARDS has increased significantly. Unfortunately, until now, there are no effective treatments for ARDS caused by COVID-19. Many drugs are either ineffective or have a low effect. Currently, there have been reports of efficient use of mesenchymal stem cells (MSCs) for the treatment of ARDS caused by COVID-19. We investigated the influence of freeze-dried human placenta-derived mesenchymal stem cells (HPMSCs) in ARDS rat model. All animals have received intratracheal injection of 6 mg/kg of lipopolysaccharide (LPS). The rats were randomly divided into five groups: I: LPS, II: LPS+dexamethasone, III: LPS+HPMSCs, IV: HPMSC, and V: saline. ARDS observation time was short-term and amounted to 168 hours. The study has shown that HPMSCs are able to migrate and attach to damaged lung tissue, contributing to the resolution of pathology, restoration of function, and tissue repair in the alveolar space. Studies have also shown that the administration of HPMSCs in animals with ARDS model significantly reduced the levels of key cytokines such as IL-1ß, IL-6, and TNF-α. Freeze-dried placental stem cell is a very promising biomaterial for the treatment of ARDS. The human placenta can be easily obtained because it is considered as a medical waste. At the same time, a huge number of MSCs can be obtained from the placental tissue, and there is no ethical controversy around their use. The freeze-dried MSCs from human placental tissue can be stored sterile at room temperature for a long time before use.

Targeted, Site-Specific, Delivery Vehicles of Therapeutics for COVID-19 Patients. Brief Review.

Definitive pharmacological therapies for COVID-19 have yet to be identified. Several hundred trials are ongoing globally in the hope of a solution. However, nearly all treatments rely on systemic delivery but COVID-19 damages the lungs preferentially. The use of a targeted delivery approach is reviewed where engineered products are able to reach damaged lung tissue directly, which includes catheter-based and aerosol-based approaches. In this review we have outlined various target directed approaches which include microbubbles, extracellular vesicles including exosomes, adenosine nanoparticles, novel bio-objects, direct aerosol targeted pulmonary delivery and catheter-based drug delivery with reference to their relative effectiveness for the specific lesions. Currently several trials are ongoing to determine the effectiveness of such delivery systems alone and in conjunction with systemic therapies. Such approaches may prove to be very effective in the controlled and localized COVID-19 viral lesions in the lungs and potential sites. Moreover, localized delivery offered a safer delivery mode for such drugs which may have systemic adverse effects.

Viral Coagulopathy in Patients With COVID-19: Treatment and Care.

COVID-19 has proven to be particularly challenging given the complex pathogenesis of SARS-CoV-2. Early data have demonstrated how the host response to this novel coronavirus leads to the proliferation of pro-inflammatory cytokines, massive endothelial damage, and generalized vascular manifestations. While SARS-CoV-2 primarily targets the upper and lower respiratory tract, other organ systems are also affected. SARS-CoV-2 relies on 2 host cell receptors for successful attachment: angiotensin-converting enzyme 2 and transmembrane protease serine 2. Clinicopathologic reports have demonstrated associations between severe COVID-19 and viral coagulopathy, resulting in pulmonary embolism; venous, arterial, and microvascular thrombosis; lung endothelial injury; and associated thrombotic complications leading to acute respiratory distress syndrome. Viral coagulopathy is not novel given similar observations with SARS classic, including the consumption of platelets, generation of thrombin, and increased fibrin degradation product exhibiting overt disseminated intravascular coagulation-like syndrome. The specific mechanism(s) behind the thrombotic complications in COVID-19 patients has yet to be fully understood. Parenteral anticoagulants, such as heparin and low-molecular-weights heparins, are widely used in the management of COVID-19 patients. Beyond the primary (anticoagulant) effects of these agents, they may exhibit antiviral, anti-inflammatory, and cytoprotective effects. Direct oral anticoagulants and antiplatelet agents are also useful in the management of these patients. Tissue plasminogen activator and other fibrinolytic modalities may also be helpful in the overall management. Catheter-directed thrombolysis can be used in patients developing pulmonary embolism. Further investigations are required to understand the molecular and cellular mechanisms involved in the pathogenesis of COVID-19-associated thrombotic complications.

Transcatheter Bariatric Embolotherapy for Weight Reduction in Obesity.

BACKGROUND: Obesity is well-appreciated to result in poor cardiovascular and metabolic outcomes. Dietary and medical weight loss strategies are frequently unsuccessful and unsustainable. Bariatric surgery is quite effective, but is reserved for the most obese patients because of the associated intraoperative/post-operative risks. In preclinical and early clinical case series, a novel therapy, transcatheter bariatric embolotherapy (TBE) of the left gastric artery, has been reported to promote weight loss by reducing ghrelin, an appetite-stimulating hormone secreted from the gastric fundus. OBJECTIVES: The purpose of this study was to examine TBE in a single-blind, sham procedure randomized trial. METHODS: Obese subjects (body mass index 35 to 55 kg/m2) were randomized 1:1 to either sham or TBE targeting the left gastric artery using an occlusion balloon microcatheter to administer 300- to 500-µm embolic beads. All patients entered a lifestyle counseling program. Patients and physicians performing follow-up were blind to the allocated therapy. Endoscopy was performed at baseline and 1-week post-procedure. The primary endpoint was 6-month total body weight loss (TBWL). RESULTS: Eligible subjects (n = 44; age 45.5 ± 9.4 years; 8 men/36 women; body mass index 39.6 ± 3.8 kg/m2) were randomized to undergo the sham or TBE procedure with no device-related complications and 1 vascular complication. Patients reported mild nausea and vomiting, and endoscopy revealed only minor self-limiting ulcers in 5 patients. At 6 months, in both the intention-to-treat and per-protocol populations, the TBWL was greater with TBE (7.4 kg/6.4% and 9.4 kg/8.3% loss, respectively) than sham (3.0 kg/2.8% and 1.9 kg/1.8%, respectively; p = 0.034/0.052 and p = 0.0002/0.0011, respectively). The TBWL was maintained with TBE at 12 months (intention-to-treat 7.8 kg/6.5% loss, per-protocol 9.3 kg/9.3% loss; p = 0.0011/0.0008, p = 0.0005/0.0005, respectively). CONCLUSIONS: In this randomized pilot trial, we have established the proof-of-principle that transcatheter bariatric embolotherapy of the left gastric artery is well-tolerated and promotes clinically significant weight loss over a sham procedure.(The Lowering Weight in Severe Obesity by Embolization of the Gastric Artery Trial [LOSEIT]; NCT03185949).

First-in-Human Percutaneous Circumferential Annuloplasty for Secondary Tricuspid Regurgitation.

Transcatheter therapies to treat tricuspid regurgitation are being developed, but few have attempted the gold standard of surgical repair: ring annuloplasty. We describe the first-ever fully percutaneous implantation of a circumferential, semirigid annuloplasty ring to treat massive secondary tricuspid regurgitation. (Level of Difficulty: Advanced.).

The Republic of Georgia High Blood Pressure Control Program.

INTRODUCTION: 52% of adults have uncontrolled hypertension in the Republic of Georgia. We incorporated a blood pressure control program into an existing primary healthcare system in an attempt to improve the rate of blood pressure control. METHODS: We conducted standardized trainings of rural primary care providers--doctors and nurses--in accurate measurement of blood pressure according to the Shared Care Method of Training and Certification. Our attention was focused especially on patient management based on Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) guidelines. Antihypertensive treatment was implemented by a stepped-care approach; hydrochlorothiazide and atenolol were given to patients at follow-up visits at no cost. The treatment goal was < 140/ 90 mm Hg based on the office blood pressure. RESULTS: A total of 251 patients with uncontrolled hypertension were enrolled in the program; 32% had stage I hypertension, 41% had stage II hypertension, and 27% had stage III, as defined by JNC VI. During the first 30 months of followup, blood pressure decreased gradually from 170/95 to 140/ 82 mm Hg. The rate of high blood pressure control increased progressively up to 59%. CONCLUSIONS: We conclude that hypertension control can be improved in all groups of patients, even in a healthcare system with limited resources. We emphasize that Georgia or any other healthcare system should not wait for universal health care to improve high blood pressure control. It can be incorporated into whatever system exists today.

A Novel Endoscopic Bariatric Procedure: Results of an Experimental Study.

BACKGROUND: Surgical treatment of obesity is characterized by both early and late complications, and thus, there is a need to develop safe and non-invasive techniques. Ghrelin is an orexigenic hormone produced by the fundus of the stomach, which may represent a novel target for obesity management. Unfortunately, numerous attempts to alter ghrelin levels have failed to present significant clinical results. We describe a novel procedure that involves modifying arterial blood flow to the gastric fundus for limiting plasma ghrelin levels. METHODS: A gastroscope was advanced into the gastric fundus of 13 healthy Yorkshire swine, and the fundus was clipped under direct visualization to restrict left gastric artery blood flow. Body weights and ghrelin levels were recorded before and once a week for 4 weeks after the procedure. RESULTS: Compared to controls, gastroscopic clipping of the fundus decreased plasma ghrelin levels and prevented further weight gain in the 4 weeks of follow-up. Immunohistochemistry and histomorphometry revealed reduced numbers of ghrelin-positive cells in the fundus of experimental animals. We also observed thrombosis in submucosal arteries and submucosal fibrosis. Histological studies demonstrated minimal gastric mucosal injury. CONCLUSION: Gastroscopic clipping of the fundus in an experimental porcine model resulted in sustained weight loss and a reduction in plasma ghrelin levels at 1 month post-procedure, with no adverse events. Further experimental studies in human patients are needed to examine the clinical utility of this procedure and to optimize a technique, which can facilitate adequate weight loss while minimizing the risk of mucosal injury.

Phase 1 Trial of Autologous Bone Marrow Stem Cell Transplantation in Patients with Spinal Cord Injury.

Introduction. A total of 18 patients, with complete motor deficits and paraplegia caused by thoracic and lumbar spine trauma without muscle atrophy or psychiatric problems, were included into this study. Materials and Methods. The bone marrow was aspirated from the anterior iliac crest under local anesthesia and the mononuclear fraction was isolated by density gradient method. At least 750 million mononuclear-enriched cells, suspended in 2 mL of saline, were infused intrathecally. Results and Discussion. The study reports demonstrated improvement of motor and sensory functions of various degrees observed in 9 of the 18 (50%) cases after bone marrow stem cell transplantation. Measured by the American Spinal Injury Association (ASIA) scale, 7 (78%) out of the 9 patients observed an improvement by one grade, while two cases (22%) saw an improvement by two grades. However, there were no cases in which the condition was improved by three grades. Conclusions. Analysis of subsequent treatment results indicated that the transplantation of mononuclear-enriched autologous BMSCs is a feasible and safe technique. However, successful application of the BMSCs in the clinical practice is associated with the necessity of executing more detailed examinations to evaluate the effect of BMSCs on the patients with spinal cord injury.