An Invasive Yet Potentially Diverse and Unexplored Genus: Typha L.

Aim: Typha genus belongs to the family Typhaceae and is comprising of about 13 known species distributed in the subtropical and tropical regions of North America, South America, Asia, Africa, Australia and Europe. Several species are considered as invasive weeds that colonize wetlands and marshes because they are highly productive by clonal growth, forming very large, persistent and often monospecific stands. This review offers detailed information on the aquatic species of the cosmopolitan genus Typha L. with specific focus on their distribution, identification, importance in bioremediation, usability and traditional uses along with chemical and biological diversity. Methodology: An extensive browsing in three electronic databases (Unbound Medline, PubMed and ScienceDirect) and internet search engines (Scifinder and Google Scholar) enabled us to connote the studies on Typha genus available till date. Results: Literature survey corroborated that some species of Typha are valuable as sources of traditional medicine in human health, while some are still widely used for non-pharmacological purposes. Numerous phytochemical investigations of plants of this genus confirmed the presence of alkaloids, glycosides, tannins, steroids, phenols, saponins, flavanoids, carbohydrates, proteins, oils and fats. Besides, various studies cited in this review article have demonstrated that the extracts or active substances that have been isolated from the species of Typha genus have multiple pharmacological activities. Conclusion: The review draws the attention of scientists towards the utility and important issues associated with the probable approaches that should be investigated to encourage people to take maximal benefit of the potentially useful species of Typha genus.

Measuring adherence to therapy in airways disease

Non-adherence to medication is one of the most significant issues in all airways disease and can have a major impact on disease control as well as on unscheduled healthcare utilisation. It is vital that clinicians can accurately determine a patient's level of adherence in order to ensure they are gaining the maximal benefit from their therapy and also to avoid any potential for unnecessary increases in therapy. It is essential that measurements of adherence are interpreted alongside biomarkers of mechanistic pathways to identify if improvements in medication adherence can influence disease control.In this review, the most common methods of measuring adherence are discussed. These include patient self-report, prescription record checks, canister weighing, dose counting, monitoring drug levels and electronic monitoring. We describe the uses and benefits of each method as well as potential shortcomings. The practical use of adherence measures with measurable markers of disease control is also discussed.Educational aimsTo understand the various methods available to measure adherence in airways disease.To learn how to apply these adherence measures in conjunction with clinical biomarkers in routine clinical care.

Real-time monitoring of the rollout of pneumococcal conjugate vaccines in rural India using a digital tracking platform

Background: In 2017, the pneumococcal conjugate vaccine (PCV) was introduced into the Indian immunization program as a priority. However, monitoring the implementation of this program has been a major challenge in rural India. Novel digital health platforms, used to track vaccine delivery, can address this issue. Methods: We analyzed data collected in a rural part of the Udaipur District of India, which recently introduced PCV13 into the routine immunization program. The data were collected by Khushi Baby, a novel technology platform which facilitates tracking the vaccination status of individual children. We assessed the percent of children receiving 1, 2, or 3 doses of the vaccine at different ages and time points, as well as geographic variations in uptake. Only doses received before 12 months of age were considered for this analysis. Results: More than 96% of children captured by the database received the first dose of PCV13. Uptake of the second dose ranged from 69% to 90% across the five regions, and 44% to 76% of children received the third (booster) dose within 3 months of the recommended date. Conclusions: These data provide early evidence that the primary doses of PCV13 are being administered at a high level in rural India; however, there is considerable variability between regions. Additionally, the receipt of the booster dose may be lower than desired. Given the importance of the booster dose in reducing pneumococcal transmission, its delivery is essential to ensure maximal benefit of the vaccine program.

A Middleware-Based Approach for Multi-Scale Mobility Simulation

Modeling and simulation play an important role in transportation networks analysis. In the literature, authors have proposed many traffic and mobility simulations, with different features and corresponding to different contexts and objectives. They notably consider different scales of simulations. The scales refer to the represented entities, as well as to the space and the time representation of the transportation environment. However, we often need to represent different scales in the same simulation, for instance to represent a neighborhood interacting with a wider region. In this paper, we advocate for the reuse of existing simulations to build a new multi-scale simulation. To do so, we propose a middleware model to couple independent mobility simulations, working at different scales. We consider all the necessary processing and workflow to allow for a coherent orchestration of these simulations. We also propose a prototype implementation of the middleware. The results show that such a middleware is capable of creating a new multi-scale mobility simulation from existing ones, while minimizing the incoherence between them. They also suggest that, to have a maximal benefit from the middleware, existing mobility simulation platforms should allow for an external control of the simulations, allowing for executing a time step several times if necessary.

Setting the standard: multidisciplinary hallmarks for structural, equitable and tracked antibiotic policy

There is increasing concern globally about the enormity of the threats posed by antimicrobial resistance (AMR) to human, animal, plant and environmental health. A proliferation of international, national and institutional reports on the problems posed by AMR and the need for antibiotic stewardship have galvanised attention on the global stage. However, the AMR community increasingly laments a lack of action, often identified as an ‘implementation gap’. At a policy level, the design of internationally salient solutions that are able to address AMR’s interconnected biological and social (historical, political, economic and cultural) dimensions is not straightforward. This multidisciplinary paper responds by asking two basic questions: (A) Is a universal approach to AMR policy and antibiotic stewardship possible? (B) If yes, what hallmarks characterise ‘good’ antibiotic policy? Our multistage analysis revealed four central challenges facing current international antibiotic policy: metrics, prioritisation, implementation and inequality. In response to this diagnosis, we propose three hallmarks that can support robust international antibiotic policy. Emerging hallmarks for good antibiotic policies are: Structural, Equitable and Tracked. We describe these hallmarks and propose their consideration should aid the design and evaluation of international antibiotic policies with maximal benefit at both local and international scales.

Tumor organoids to study gastroesophageal cancer: a primer

Gastroesophageal cancers are leading causes of cancer death. Our attempts at adopting molecularly based treatment approaches have been slow and ineffective even though we begin to identify specific targetable gene mutations and pathways. It is clear that we should no longer treat all gastroesophageal cancers as a homogeneous disease, which is what we do when we use non-specific chemotherapy. However, we currently cannot monitor successful gene/pathway targeting, nor understand how/when tumors develop resistance, nor predict which patients will derive maximal benefit. To improve outcomes, we must precisely detail the heterogeneity of these tumors to then individualize cancer therapy as well as develop novel avenues to study and predict treatment effects in individual patients. To this end, patient-derived organoids, in which tumor cells from individual patients are grown in a Petri dish, are a new versatile system that allows for timely expandability, detailed molecular characterization, and genetic manipulation with the promise of enabling predictive assessment of treatment response. In this review, we will explore the development and basic techniques for organoid generation, and discuss the current and potential future applications of this exciting technology to study the basic science of carcinogenesis and to predict/guide cancer patient care in the clinics.

A PK/PD mathematical model to forecast severe toxicities in pancreatic cancer patients treated with FOLFIRINOX regimen.

e16774 Background: FOLFIRINOX regimen is the most efficient treatment in pancreatic adenocarcinoma. However, this triple-therapy causes significant and dose-limiting toxic effects leading to empirical dose-reduction, postponement of the forthcoming courses and sometimes treatment discontinuation. Dose-limiting toxicities with FOLFIRINOX are mostly oxaliplatin-induced peripheral neuropathy (OIPN) and irinotecan-induced diarrhoea (IID). The first aim of our study was to establish dose-concentration-toxicity relationships for these two main ordinal toxicities. Second, we aimed to perform in silico simulations to define the optimal FOLFIRINOX administration protocol (i.e., dosing, scheduling, sequencing) for a maximal benefit to risk ratio. Methods: We performed a retrospective pharmacometric analysis from clinical data collected in three French institutes. Patients had all confirmed diagnosis of PDAC treated with FOLFIRINOX as first line regimen. Demographic characteristics, toxicity data and dosage modifications were collected. Two mathematical models connecting dose – concentration – toxicity (PKPD Tox model) were developed using Monolix2019 to describe both OIPN and IID. Results: Data from 75 patients (36 females/39 males) treated with FOLFIRINOX regimen between 2015-2018 and representing 566 courses were collected. Median age was 65.4 years (range 29-78). The performance status at the start of treatment was 0-1 for 70% of patients. The most frequent location of the tumor was pancreatic head (50%). 91% of patients were subject to empirical dose reduction during their treatment. Oxaliplatin doses were decreased in 258 courses and stopped in 66 courses. Irinotecan doses were decreased in 257 courses and stopped in 33 courses. Overall, 130 IID and 198 OIPN events were observed. From these data, two different PKPD Tox models were developed. The individual concentrations of SN38 (active metabolite of irinotecan) and oxaliplatin were simulated with population PK models, either home-built or taken from the literature. Concentrations were translated into adequate exposure via an interface model developed by our group. Exposure was finally related to a pharmacodynamic model to predict probabilities assigned to each grade of IID or OIPN. Conclusions: These PKPD Tox models help to predict dose-limiting toxicities upon FOLFIRINOX and are useful to select the administration protocol of FOLFIRINOX minimizing the occurrence probabilities of treatment-related neuropathy and diarrhoea, while maintaining efficacy.

Impact of population mask wearing on Covid-19 post lockdown

COVID-19, caused by SARS-CoV2 is a rapidly spreading global pandemic. Although precise transmission routes and dynamics are unknown, SARS-CoV2 is thought primarily to spread via contagious respiratory droplets. Unlike with SARS-CoV, maximal viral shedding occurs in the early phase of illness, and this is supported by models that suggest 40-80% of transmission events occur from pre- and asymptomatic individuals. One widely-discussed strategy to limit transmission of SARS-CoV2, particularly from presymptomatic individuals, has been population-level wearing of masks. Modelling for pandemic influenza suggests some benefit in reducing total numbers infected with even 50% mask-use. COVID-19 has a higher hospitalization and mortality rate than influenza, and the impacts on these parameters, and critically, at what point in the pandemic trajectory mask-use might exert maximal benefit are completely unknown.We derived a simplified SIR model to investigate the effects of near-universal mask-use on COVID-19 assuming 8 or 16% mask efficacy. We decided to model, in particular, the impact of masks on numbers of critically-ill patients and cumulative mortality, since these are parameters that are likely to have the most severe consequences in the COVID-19 pandemic. Whereas mask use had a relatively minor benefit on critical-care and mortality rates when transmissibility (Reff) was high, the reduction on deaths was dramatic as the effective R approached 1, as might be expected after aggressive social-distancing measures such as wide-spread lockdowns. One major concern with COVID-19 is its potential to overwhelm healthcare infrastructures, even in resource-rich settings, with one third of hospitalized patients requiring critical-care. We incorporated this into our model, increasing death rates for when critical-care resources have been exhausted. Our simple model shows that modest efficacy of masks could avert substantial mortality in this scenario. Importantly, the effects on mortality became hyper-sensitive to mask-wearing as the effective R approaches 1, i.e. near the tipping point of when the infection trajectory is expected to revert to exponential growth, as would be expected after effective lockdown. Our model suggests that mask-wearing might exert maximal benefit as nations plan their post-lockdown strategies and suggests that mask-wearing should be included in further more sophisticated models of the current pandemic.

Teaching an old drug new tricks: repositioning strategies for spinal muscular atrophy

Spinal muscular atrophy (SMA) is a childhood disorder caused by loss of the SMN gene. Pathological hallmarks are spinal cord motor neuron death, neuromuscular junction dysfunction and muscle atrophy. The first SMN genetic therapy was recently approved and other SMN-dependent treatments are not far behind. However, not all SMA patients will reap their maximal benefit due to limited accessibility, high costs and differential effects depending on timing of administration and disease severity. The repurposing of commercially available drugs is an interesting strategy to ensure more rapid and less expensive access to new treatments. In this mini-review, we will discuss the potential and relevance of repositioning drugs currently used for neurodegenerative, neuromuscular and muscle disorders for SMA.

Corticosteroids for Septic Shock: Another Chapter in the Saga

The use of corticosteroids in the management of septic shock has been a highly debated topic for quite some time. Corticosteroids have the ability to combat hyperinflammatory and exaggerated vasodilatory responses, as well as to sensitize adrenergic receptors to decrease the duration of shock. While helpful clinically, this has not translated to consistent mortality benefits. Conflicting results from 2 landmark trials published in 2002 and 2008 have led to varying clinical practices, and a clearly defined role of corticosteroids in septic shock is lacking. A decade later, an influx of new data derived from 2 more large trials continues to echo diverging viewpoints regarding patient mortality. In combination with fluctuating study designs (eg, adjunctive therapies and shock management) and patient populations (eg, illness severity), generalized conclusions are still difficult to draw. Despite these challenges, this review critically analyzes recently published data in the context of historical debate to provide an updated comment on the role of corticosteroids in septic shock. In summary, hydrocortisone therapy is likely to demonstrate maximal benefit when initiated on patients with septic shock and organ failure refractory to vasopressor therapy and should be used judiciously in other settings as it comes without a demonstrated benefit in mortality and increased potential for adverse effects.