Modeling patient access to therapeutic oxytocin in Zanzibar, Tanzania.

BACKGROUND: Our objective is to estimate the effects of therapeutic oxytocin supply chain factors and social determinants of health on patient access to oxytocin in low-income settings using system dynamics modeling. Postpartum hemorrhage (PPH), a major cause of maternal mortality disproportionately affects women in low and middle income countries (LMICs). The World Health Organization recommends therapeutic oxytocin as the frontline uterotonic for PPH management and prevention. However, lack of access to quality therapeutic oxytocin in Tanzania, and throughout Sub-Saharan Africa, continues to result in a high number of preventable maternal deaths. METHODS: We used publicly available data from Zanzibar and Sub-Saharan Africa, literature review, oxytocin degradation kinetics and previously developed systems dynamics models to understand the barriers in patient access to quality therapeutic oxytocin. RESULTS: The model makes four basic predictions. First, there is a major gap between therapeutic oxytocin procurement and availability. Second, it predicts that at current population increase rates, oxytocin supply will have to be doubled in the next 30 years. Third, supply and storage temperature until 30 °C has minimal effect on oxytocin quality and finally distance of 5 km or less to birthing facility has a small effect on overall access to oxytocin. CONCLUSIONS: The model provides a systems level approach to therapeutic oxytocin access, incorporating supply and procurement, socio-economic factors, as well as storage conditions to understand how women's access to oxytocin over time can be sustained for better health outcomes.

Timing of Decompressive Hemicraniectomy for Stroke: A Nationwide Inpatient Sample Analysis.

BACKGROUND AND PURPOSE: Previous clinical trials were not designed to discern the optimal timing of decompressive craniectomy for stroke, and the ideal surgical timing in patients with space-occupying infarction who do not exhibit deterioration within 48 hours is debated. METHODS: Patients undergoing decompressive craniectomy for stroke were extracted from the Nationwide Inpatient Sample (2002-2011). Multivariable logistic regression evaluated the association of surgical timing with mortality, discharge to institutional care, and poor outcome (a composite end point including death, tracheostomy and gastrostomy, or discharge to institutional care). Covariates included patient demographics, comorbidities, year of admission, and hospital characteristics. However, standard stroke severity scales and infarct volume were not available. RESULTS: Among 1301 admissions, 55.8% (n=726) underwent surgery within 48 hours. Teaching hospital admission was associated with earlier surgery (P=0.02). The timing of intervention was not associated with in-hospital mortality. However, when evaluated continuously, later surgery was associated with increased odds of discharge to institutional care (odds ratio, 1.17; 95% confidence interval, 1.05-1.31, P=0.005) and of a poor outcome (odds ratio, 1.12; 95% confidence interval, 1.02-1.23; P=0.02). When evaluated dichotomously, the odds of discharge to institutional care and of a poor outcome did not differ at 48 hours after hospital admission, but increased when surgery was pursued after 72 hours. Subgroup analyses found no association of surgical timing with outcomes among patients who had not sustained herniation. CONCLUSION: s-In this nationwide analysis, early decompressive craniectomy was associated with superior outcomes. However, performing decompression before herniation may be the most important temporal consideration.

Modeling Supply and Demand Dynamics of Vaccines against Epidemic-Prone Pathogens: Case Study of Ebola Virus Disease.

Health emergencies caused by epidemic-prone pathogens (EPPs) have increased exponentially in recent decades. Although vaccines have proven beneficial, they are unavailable for many pathogens. Furthermore, achieving timely and equitable access to vaccines against EPPs is not trivial. It requires decision-makers to capture numerous interrelated factors across temporal and spatial scales, with significant uncertainties, variability, delays, and feedback loops that give rise to dynamic and unexpected behavior. Therefore, despite progress in filling R&D gaps, the path to licensure and the long-term viability of vaccines against EPPs continues to be unclear. This paper presents a quantitative system dynamics modeling framework to evaluate the long-term sustainability of vaccine supply under different vaccination strategies. Data from both literature and 50 expert interviews are used to model the supply and demand of a prototypical Ebolavirus Zaire (EBOV) vaccine. Specifically, the case study evaluates dynamics associated with proactive vaccination ahead of an outbreak of similar magnitude as the 2018-2020 epidemic in North Kivu, Democratic Republic of the Congo. The scenarios presented demonstrate how uncertainties (e.g., duration of vaccine-induced protection) and design criteria (e.g., priority geographies and groups, target coverage, frequency of boosters) lead to important tradeoffs across policy aims, public health outcomes, and feasibility (e.g., technical, operational, financial). With sufficient context and data, the framework provides a foundation to apply the model to a broad range of additional geographies and priority pathogens. Furthermore, the ability to identify leverage points for long-term preparedness offers directions for further research.

Large-scale cultured meat production: Trends, challenges and promising biomanufacturing technologies.

Food systems of the future will need to face an increasingly clear reality - that a protein-rich diet is essential for good health, but traditional meat products will not suffice to ensure safety, sustainability, and equity of food supply chains at a global scale. This paper provides an in-depth analysis of bioprocess technologies needed for cell-based meat production and challenges in reaching commercial scale. Specifically, it reviews state-of-the-art bioprocess technologies, current limitations, and opportunities for research across four domains: cell line development, cell culture media, scaffolding, and bioreactors. This also includes exploring innovations to make cultured meat a viable protein alternative across numerous key performance indicators and for specific applications where traditional livestock is not an option (e.g., local production, space exploration). The paper explores tradeoffs between production scale, product quality, production cost, and footprint over different time horizons. Finally, a discussion explores various factors that may impact the ability to successfully scale and market cultured meat products: social acceptance, environmental tradeoffs, regulatory guidance, and public health benefits. While the exact nature of the transition from traditional livestock to alternative protein products is uncertain, it has already started and will likely continue to build momentum in the next decade.

Models to inform neutralizing antibody therapy strategies during pandemics: the case of SARS-CoV-2.

BACKGROUND: Neutralizing antibodies (nAbs) against SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) can play an important role in reducing impacts of the COVID-19 pandemic, complementing ongoing public health efforts such as diagnostics and vaccination. Rapidly designing, manufacturing and distributing nAbs requires significant planning across the product value chain and an understanding of the opportunities, challenges and risks throughout. METHODS: A systems framework comprised of four critical components is presented to aid in developing effective end-to-end nAbs strategies in the context of a pandemic: (1) product design and optimization, (2) epidemiology, (3) demand and (4) supply. Quantitative models are used to estimate product demand using available epidemiological data, simulate biomanufacturing operations from typical bioprocess parameters and calculate antibody production costs to meet clinical needs under various realistic scenarios. RESULTS: In a US-based case study during the 9-month period from March 15 to December 15, 2020, the projected number of SARS-CoV-2 infections was 15.73 million. The estimated product volume needed to meet therapeutic demand for the maximum number of clinically eligible patients ranged between 6.3 and 31.5 tons for 0.5 and 2.5 g dose sizes, respectively. The relative production scale and cost needed to meet demand are calculated for different centralized and distributed manufacturing scenarios. CONCLUSIONS: Meeting demand for anti-SARS-CoV-2 nAbs requires significant manufacturing capacity and planning for appropriate administration in clinical settings. MIT Center for Biomedical Innovation's data-driven tools presented can help inform time-critical decisions by providing insight into important operational and policy considerations for making nAbs broadly accessible, while considering time and resource constraints.

Cyberbiosecurity in Advanced Manufacturing Models.

Cybersecurity for the production of safe and effective biopharmaceuticals requires the attention of multiple stakeholders, including industry, governments, and healthcare providers. Cyberbiosecurity breaches could directly impact patients, from compromised data privacy to disruptions in production that jeopardize global pandemic response. Maintaining cybersecurity in the modern economy, where advanced manufacturing technologies and digital strategies are becoming the norm, is a significant challenge. Here, we highlight vulnerabilities in present and future biomanufacturing paradigms given the dependence of this industry sector on proprietary intellectual property, cyber-physical systems, and government-regulated production environments, as well as movement toward advanced manufacturing models. Specifically, we (1) present an analysis of digital information flow in a typical biopharmaceutical manufacturing value chain; (2) consider the potential cyberbiosecurity risks that might emerge from advanced manufacturing models such as continuous and distributed systems; and (3) provide recommendations for risk mitigation. While advanced manufacturing models hold the potential for reducing costs and increasing access to more personalized therapies, the evolving landscape of the biopharmaceutical enterprise has led to growing concerns over potential cyber attacks. Gaining better foresight on potential risks is key for implementing proactive defensive principles, framing new developments, and establishing a permanent security culture that adapts to new challenges while maintaining the transparency required for regulated production of safe and effective medicines.

Non-scaling regulation of AMPA receptors in homeostatic synaptic plasticity.

Homeostatic synaptic plasticity (HSP) as an activity-dependent negative feedback regulation of synaptic strength plays important roles in the maintenance of neuronal and neural circuitry stability. A primary cellular substrate for HSP expression is alterations in synaptic accumulation of glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR). It is widely believed that during HSP, AMPAR accumulation changes with the same proportion at each synapse of a neuron, a process known as synaptic scaling. However, direct evidence on AMPAR synaptic scaling remains largely lacking. Here we report a direct examination of inactivity-induced homeostatic scaling of AMPAR at individual synapse by live-imaging. Surprisingly, instead of uniform up-scaling, a scattered pattern of changes in synaptic AMPAR was observed in cultured rat hippocampal neurons. While the majority of synapses showed up-regulation after activity inhibition, a reduction of AMPAR could be detected in certain synapses. More importantly, among the up-regulated synapses, a wide range of AMPAR changes was observed in synapses of the same neuron. We also found that synapses with higher levels of pre-existing AMPAR tend to be up-regulated by lesser extents, whereas the locations of synapses relative to the soma seem not affecting AMPAR scaling strengths. In addition, we observed strong competition between neighboring synapses during HSP. These results reveal that synaptic AMPAR may not be scaled during HSP, suggesting novel molecular mechanisms for information processing and storage at synapses.

The impact of aspirin and anticoagulant usage on outcomes after aneurysmal subarachnoid hemorrhage: a Nationwide Inpatient Sample analysis.

OBJECTIVE Although aspirin usage may be associated with a decreased risk of rupture of cerebral aneurysms, any potential therapeutic benefit from aspirin must be weighed against the theoretical risk of greater hemorrhage volume if subarachnoid hemorrhage (SAH) occurs. However, few studies have evaluated the association between prehemorrhage aspirin use and outcomes. This is the first nationwide analysis to evaluate the impact of long-term aspirin and anticoagulant use on outcomes after SAH. METHODS Data from the Nationwide Inpatient Sample (NIS; 2006-2011) were extracted. Patients with a primary diagnosis of SAH who underwent microsurgical or endovascular aneurysm repair were included; those with a diagnosis of an arteriovenous malformation were excluded. Multivariable logistic regression was performed to calculate the adjusted odds of in-hospital mortality, a nonroutine discharge (any discharge other than to home), or a poor outcome (death, discharge to institutional care, tracheostomy, or gastrostomy) for patients with long-term aspirin or anticoagulant use. Multivariable linear regression was used to evaluate length of hospital stay. Covariates included patient age, sex, comorbidities, primary payer, NIS-SAH severity scale, intracerebral hemorrhage, cerebral edema, herniation, modality of aneurysm repair, hospital bed size, and whether the hospital was a teaching hospital. Subgroup analyses exclusively evaluated patients treated surgically or endovascularly. RESULTS The study examined 11,549 hospital admissions. Both aspirin (2.1%, n = 245) and anticoagulant users (0.9%, n = 108) were significantly older and had a greater burden of comorbid disease (p < 0.001); severity of SAH was slightly lower in those with long-term aspirin use (p = 0.03). Neither in-hospital mortality (13.5% vs 12.6%) nor total complication rates (79.6% vs 80.0%) differed significantly by long-term aspirin use. Additionally, aspirin use was associated with decreased odds of a cardiac complication (OR 0.57, 95% CI 0.36%-0.91%, p = 0.02) or of venous thromboembolic events (OR 0.53, 95% CI 0.30%-0.94%, p = 0.03). Length of stay was significantly shorter (15 days vs 17 days [12.73%], 95% CI 5.22%-20.24%, p = 0.001), and the odds of a nonroutine discharge were lower (OR 0.63, 95% CI 0.48%-0.83%, p = 0.001) for aspirin users. In subgroup analyses, the benefits of aspirin were primarily noted in patients who underwent coil embolization; likewise, among patients treated endovascularly, the adjusted odds of a poor outcome were lower among long-term aspirin users (31.8% vs 37.4%, OR 0.63, 95% CI 0.42%-0.94%, p = 0.03). Although the crude rates of in-hospital mortality (19.4% vs 12.6%) and poor outcome (53.6% vs 37.6%) were higher for long-term anticoagulant users, in multivariable logistic regression models these variations were not significantly different (mortality: OR 1.36, 95% CI 0.89%-2.07%, p = 0.16; poor outcome: OR 1.09, 95% CI 0.69%-1.73%, p = 0.72). CONCLUSIONS In this nationwide study, neither long-term aspirin nor anticoagulant use were associated with differential mortality or complication rates after SAH. Aspirin use was associated with a shorter hospital stay and lower rates of nonroutine discharge, with these benefits primarily observed in patients treated endovascularly.

The impact of body habitus on outcomes after aneurysmal subarachnoid hemorrhage: a Nationwide Inpatient Sample analysis.

OBJECTIVE Although the prevalence of obesity is increasing rapidly both nationally and internationally, few studies have analyzed outcomes among obese patients undergoing cranial neurosurgery. The goal of this study, which used a nationwide data set, was to evaluate the association of both obesity and morbid obesity with treatment outcomes among patients with aneurysmal subarachnoid hemorrhage (SAH); in addition, the authors sought to analyze how postoperative complications for obese patients with SAH differ by the treatment modality used for aneurysm repair. METHODS Clinical data for adult patients with SAH who underwent microsurgical or endovascular aneurysm repair were extracted from the Nationwide Inpatient Sample (NIS). The body habitus of patients was classified as nonobese (body mass index [BMI] < 30 kg/m2), obese (BMI ≥ 30 kg/m2 and ≤ 40 kg/m2), or morbidly obese (BMI > 40 kg/m2). Multivariable logistic regression analyzed the association of body habitus with in-hospital mortality rate, complications, discharge disposition, and poor outcome as defined by the composite NIS-SAH outcome measure. Covariates included patient demographics, comorbidities (including hypertension and diabetes), health insurance status, the NIS-SAH severity scale, treatment modality used for aneurysm repair, and hospital characteristics. RESULTS In total, data from 18,281 patients were included in this study; the prevalence of morbid obesity increased from 0.8% in 2002 to 3.5% in 2011. Obese and morbidly obese patients were significantly younger and had a greater number of comorbidities than nonobese patients (p < 0.001). Mortality rates for obese (11.5%) and morbidly obese patients (10.5%) did not significantly differ from those for nonobese patients (13.5%); likewise, no differences in neurological complications or poor outcome were observed among these 3 groups. Morbid obesity was associated with significantly increased odds of several medical complications, including venous thromboembolic (OR 1.52, 95% CI 1.01-2.30, p = 0.046) and renal (OR 1.64, 95% CI: 1.11-2.43, p = 0.01) complications and infections (OR 1.34, 95% CI 1.08-1.67, p = 0.009, attributable to greater odds of urinary tract and surgical site infections). Moreover, morbidly obese patients had higher odds of a nonroutine hospital discharge (OR 1.33, 95% CI 1.03-1.71, p = 0.03). Patients with milder obesity had decreased odds of some medical complications, including cardiac, pulmonary, and infectious complications, primarily among patients who had undergone coil embolization. CONCLUSIONS In this study involving a nationwide administrative database, milder obesity was not significantly associated with increased mortality rates, neurological complications, or poor outcomes after SAH. Morbid obesity, however, was associated with increased odds of venous thromboembolic, renal, and infectious complications, as well as of a nonroutine hospital discharge. Notably, milder obesity was associated with decreased odds of some medical complications, primarily in patients treated with coiling.

Hospital-Acquired Infections after Aneurysmal Subarachnoid Hemorrhage: A Nationwide Analysis.

BACKGROUND: This is the first nationwide study to evaluate the factors associated with developing hospital-acquired infections (HAIs) after aneurysmal subarachnoid hemorrhage (SAH) and analyze their impact on the efficiency of hospital care. METHODS: Data from patients with SAH who underwent aneurysm repair were extracted from the Nationwide Inpatient Sample (2008-2011). Urinary tract infections, pneumonia, central venous catheter (CVC)-associated blood stream infection, and meningitis/ventriculitis were evaluated. Independent predictors of HAIs used in multivariable logistic regression modeling were chosen using forward selection; hierarchical multivariable linear regression assessed length of stay and charges. RESULTS: Seven thousand five hundred sixteen admissions were included. Independent predictors in the logistic regression for developing a urinary tract infection (23.9%) included older age, female sex, noninfectious complications (P < 0.001), intracerebral hemorrhage (P = 0.009), and diabetes with complications (P = 0.04). Pneumonia (23.0%) was associated with older age (P = 0.003), congestive heart failure, severity of SAH, and noninfectious complications (P < 0.001). Severity of SAH and noninfectious complications were predictors of meningitis/ventriculitis (4.4%; P ≤ 0.02), whereas intracerebral hemorrhage and noninfectious complications were predictors of CVC-associated infections (1.0%; P ≤ 0.02). All HAIs were associated with significantly longer hospitalizations and higher charges. Pneumonia (odds ratio [OR], 2.85; 95% confidence interval (CI), 2.44-3.34) and CVC-associated infections (OR, 2.42; 95% CI, 1.26-4.66) were also independently associated with greater odds of poor outcome (death or institutional care). CONCLUSION: In this nationwide analysis, urinary tract infections and pneumonia were the most common hospital-acquired infections after SAH. Although all infections were associated with significantly longer hospitalizations and greater charges, pneumonia and CVC-associated infections were also associated with increased likelihood of a poor outcome.