Assessment of new-onset heart failure prediction in a diabetic population using left ventricular global strain: a prospective cohort study based on UK Biobank.

Background: Impaired glucose utilization influences myocardial contractile function. However, the prognostic importance of left ventricular global radial strain (LV-GRS), left ventricular global circumferential strain (LV-GCS), and left ventricular global longitudinal strain (LV-GLS) in predicting new-onset heart failure (HF) in a population with diabetes is unclear. Methods: The study design is prospective cohort from the UK Biobank. Totally 37,899 participants had a complete data of cardiac magnetic resonance (CMR), of which 940 patients with diabetes were included, and all the participants completed follow-up. LV-GRS, LV-GCS, and LV-GLS were measured by completely automated CMR with tissue tagging. Cox proportional hazards regression analysis and C-index was performed to evaluate the association between the strain parameters and the new-onset HF in patients suffering from diabetes. Results: The average age of the 940 participants was 57.67 ± 6.97 years, with males comprising 66.4% of the overall population. With an average follow-up period of 166.82 ± 15.26 months, 35 (3.72%) patients reached the endpoint (emergence of new-onset HF). Significant associations were found for the three strain parameters and the new-onset HF (LV-GRS-hazard ratio [HR]: 0.946, 95% CI: 0.916-0.976; LV-GCS-HR: 1.162, 95% CI: 1.086-1.244; LV-GCS-HR: 1.181, 95% CI: 1.082-1.289). LV-GRS, LV-GCS, and LV-GLS were closely related to the related indicators to HF, and showed a high relationship to new-onset HF in individuals with diabetes at 5 and 10 years: LV-GRS: 0.75 (95% CI, 0.41-0.94) and 0.76 (95% CI, 0.44-0.98), respectively; LV-GCS: 0.80 (95% CI, 0.50-0.96) and 0.75 (95% CI, 0.41-0.98), respectively; LV-GLS: 0.72 (95% CI, 0.40-0.93) and 0.76 (95% CI, 0.48-0.97), respectively. In addition, age, sex, body mass index (BMI), and presence of hypertension or coronary artery disease (CAD) made no impacts on the association between the global strain parameters and the incidence of HF. Conclusion: LV-GRS, LV-GCS, and LV-GLS is significantly related to new-onset HF in patients with diabetes at 5 and 10 years.

Phantom study of a self-shielded X-ray bone age assessment instrument against scattered radiation in children.

Hand-wrist radiography is the most common and accurate method for evaluating children's bone age. To reduce the scattered radiation of radiosensitive organs in bone age assessment, we designed a small X-ray instrument with radioprotection function by adding metal enclosure for X-ray shielding. We used a phantom operator to compare the scattered radiation doses received by sensitive organs under three different protection scenarios (proposed instrument, radiation personal protective equipment, no protection). The proposed instrument showed greater reduction in the mean dose of a single exposure compared with radiation personal protective equipment especially on the left side which was proximal to the X-ray machine (≥80.0% in eye and thyroid, ≥99.9% in breast and gonad). The proposed instrument provides a new pathway towards more convenient and efficient radioprotection.

A versatile upconversion-based multimode lateral flow platform for rapid and ultrasensitive detection of microRNA towards health monitoring.

MicroRNAs are small single-stranded RNA molecules associated with gene expression and immune response, suggesting their potential as biomarkers for health monitoring. Herein, we designed a novel upconversion-based multimode lateral flow assay (LFA) system to detect microRNAs in body fluids by simultaneously producing three unique signals within a detection strip. The core-shell Au-DTNB@Ag nanoparticles act as both the Raman reporters and acceptors, quenching fluorescence from upconversion nanoparticles (UCNPs, NaYF4: Yb3+, Er3+) via the Förster resonance energy transfer mechanism. Using microRNA-21 as a representative analyte, the LFA system offers remarkable detection range from 2 nM to 1 fM, comparable to outcomes from signal amplification methods, due to the successful single-layer self-assembly of UCNPs on the NC membrane, which greatly enhances both the convenience and sensitivity of the LFA technique. Additionally, our proprietary fluorescence-Raman detection platform simplifies result acquisition by reducing procedural intricacies. The biosensor, when evaluated with diverse bodily fluids, showed remarkable selectivity and sustained stability. Importantly, our LFA biosensor effectively identified periodontitis and lung cancer patients from healthy subjects in genuine samples, indicating significant potential for disease prediction, early diagnosis, and progression tracking. This system holds promise as a multifunctional tool for various biomarker assays.

Efficacy assessment of superficial temporal artery-middle cerebral artery bypass surgery in treating moyamoya disease from a hemodynamic perspective: a pilot study using computational modeling and perfusion imaging.

BACKGROUND: Superficial temporal artery-middle cerebral artery (STA-MCA) bypass is a common surgery in treating moyamoya disease (MMD) with occluded MCA. Computational fluid dynamics (CFD) simulation might provide a simple, non-invasive, and low-cost tool to evaluate the efficacy of STA-MCA surgery. AIM: We aim to quantitatively investigate the treatment efficacy of STA-MCA surgery in improving the blood flow of MMD patients using CFD simulation. METHODS: This retrospective study included 11 MMD patients with occlusion around proximal MCA who underwent STA-MCA bypass surgery. CFD simulation was performed using patient-specific blood pressure and postoperative artery geometry. The volumetric flow rates of STA and the bypass, average flow velocity in the proximal segment of transcranial bypass, transcranial pressure drop, and transcranial flow resistance were measured and compared with a postoperative increment of cerebral blood flow (CBF) in MCA territories derived from perfusion imaging. Per-branch pressure drop from model inlet to bypass branch outlet was calculated. RESULTS: The volumetric flow rates of STA and the bypass were 80.84 ± 14.54 mL/min and 46.03 ± 4.21 mL/min. Average flow velocity in proximal bypass, transcranial pressure drop, and transcranial flow resistance were 0.19 ± 0.07 m/s, 3.72 ± 3.10 mmHg, and 6.54 ± 5.65 10-8 Pa s m-3. Postoperative mean increment of CBF in MCA territories was 16.03 ± 11.72 mL·100 g-1·min-1. Per-branch pressure drop was 10.96 ± 5.59 mmHg and 7.26 ± 4.25 mmHg in branches with and without stenosis. CONCLUSIONS: CFD simulation results are consistent with CBF observation in verifying the efficacy of STA-MCA bypass, where postoperative stenosis may influence the hemodynamics.

Assessment of added activity of an antitumor agent.

An unprecedented number of novel oncology drugs are under preclinical and clinical development, and nearly all are developed in combinations. With an over-reliance on biological hypotheses, there is less effort to establish single agent activity before initiating late clinical development. This may be contributing to a decreased success rate going from phase 1 to approval in the immunotherapy era. Growing evidence in clinical trial data shows that the treatment benefit from most approved combination therapies can be explained by the independent drug action model. Using this working model, we develop a simple index to measure the added antitumor activity of a new drug based on mean response duration, an endpoint that naturally combines both response status and duration information for all patients, which is shown to be highly predictive of clinical benefit of FDA-approved anti-PD-(L)1 immunotherapies. This index sheds light on challenges and opportunities in contemporary oncology drug development and provides a practical tool to assist with decision-making in early clinical trials.

Genomic assessment of quarantine measures to prevent SARS-CoV-2 importation and transmission.

Mitigation of SARS-CoV-2 transmission from international travel is a priority. We evaluated the effectiveness of travellers being required to quarantine for 14-days on return to England in Summer 2020. We identified 4,207 travel-related SARS-CoV-2 cases and their contacts, and identified 827 associated SARS-CoV-2 genomes. Overall, quarantine was associated with a lower rate of contacts, and the impact of quarantine was greatest in the 16-20 age-group. 186 SARS-CoV-2 genomes were sufficiently unique to identify travel-related clusters. Fewer genomically-linked cases were observed for index cases who returned from countries with quarantine requirement compared to countries with no quarantine requirement. This difference was explained by fewer importation events per identified genome for these cases, as opposed to fewer onward contacts per case. Overall, our study demonstrates that a 14-day quarantine period reduces, but does not completely eliminate, the onward transmission of imported cases, mainly by dissuading travel to countries with a quarantine requirement.

Several explorations on how to construct an early warning system for local government debt risk in China.

This paper aims to explore several ways to construct a scientific and comprehensive early warning system (EWS) for local government debt risk in China. In order to achieve this goal, this paper studies the local government debt risk from multiple perspectives, i.e., individual risk, contagion risk, static risk and dynamic risk. Firstly, taking China's 30 provinces over the period of 2010~ 2018 as a sample, this paper establishes early warning indicators for individual risk of local government debt, and uses the network model to establish early warning indicators for contagion risk of local government debt. Then, this paper applies the criteria importance though intercrieria correlation (CRITIC) method and coefficient of variation method to obtain the proxy variable Ⅰ, which combines the above two risks. Secondly, based on the proxy variable Ⅰ, both the Markov-switching autoregressive (MS-AR) model and coefficient of variation method are used to obtain the proxy variable Ⅱ, which comprehensively considers the individual risk, contagion risk, static risk and dynamic risk of local government debt. Finally, machine learning algorithms are adopted to generalize the EWS designed in this paper. The results show that: (1) From different perspectives of local government debt risk, the list of provinces that require early warning is different; (2) The support vector machines can well generalize our EWS.

Pollution characteristics and source analysis of microplastics in the Qiantang River in southeastern China.

Microplastic pollution resulting from industrialization and urbanization is increasingly serious. Hangzhou is a city with high industrial/urban growth in Southeast China. Focusing on the microplastic pollution in the Hangzhou section Qiantang River, six samples were collected and analyzed during different hydrological periods (normal, wet, and dry periods) and the relationship between microplastic pollution and economic development was investigated. Results showed that more microplastics were found during the dry period than that of the wet period (49.8 vs. 13.2%). Microplastic abundance was 1.5-9.4 items L-1, showing significant spatial differences in sampling sites. Among the collecting microplastics, debris and fibers accounted for 36.4 and 30.9%. Polyethylene terephthalate and polyvinyl chloride were the main polymers, accounting for 48.3 and 31.8%, respectively. Microplastics with size <1 mm accounted for 60% of the microplastics in surface water samples. Spatially, microplastic abundance was the highest in the middle of the river. Redundant analysis revealed that the per capita GDP (p = 0.002), high-end equipment industry (p = 0.028) and fashion manufacturing (p = 0.006) influenced microplastic abundance. Urbanization coupled with rapid economic development led to increase in local microplastic pollution. Our results provide insight into microplastic distribution patterns in urban river systems in China.

Urban-rural disparities in mild cognitive impairment and its functional subtypes among community-dwelling older residents in central China.

BACKGROUND: Substantial variations in the prevalence of mild cognitive impairment (MCI) and its subtypes have been reported, although mostly in geographically defined developed countries and regions. Less is known about MCI and its subtypes in rural areas of less developed central China. AIMS: The study aimed to compare the prevalence of MCI and its subtypes in residents aged 65 years or older in urban and rural areas of Hubei Province, China. METHODS: Participants aged 65 years or older were recruited between 2018 and 2019. Inperson structured interviews and clinical and neuropsychological assessments were performed at city health community centres and township hospitals. RESULTS: Among 2644 participants without dementia, 735 had MCI, resulting in a prevalence of 27.8% for total MCI, 20.9% for amnestic MCI (aMCI) and 6.9% for non-amnestic MCI (naMCI). The prevalence of MCI in urban and rural areas was 20.2% and 44.1%, respectively. After adjusting for demographic factors, the prevalence of total MCI, aMCI and naMCI differed significantly between rural and urban areas (adjusted odds ratio (OR) 2.10, 1.44 and 3.76, respectively). Subgroup analysis revealed an association between rural socioeconomic and lifestyle disadvantage and MCI and its subtypes. CONCLUSIONS: Our findings suggest that the prevalence of MCI among urban residents in central China is consistent with that in other metropolis areas, such as Shanghai, but the prevalence in rural areas is twice that in urban areas. Prospective studies and dementia prevention in China should focus on rural areas.

Patient-level and system-level barriers associated with treatment delays for ST elevation myocardial infarction in China.

OBJECTIVE: This study aims to understand the current ST elevated myocardial infarction (STEMI) treatment process in Guangdong Province and explore patient-level and system-level barriers associated with delay in STEMI treatment, so as to provide recommendations for improvement. METHODS: This is a qualitative study. Data were collected using semistructured, face-to-face individual interviews from April 2018 to January 2019. Participants included patients with STEMI, cardiologists and nurses from hospitals, emergency department doctors, primary healthcare providers, local health governors, and coordinators at the emergency medical system (EMS). An inductive thematic analysis was adopted to generate overarching themes and subthemes for potential causes of STEMI treatment delay. The WHO framework for people-centred integrated health services was used to frame recommendations for improving the health system. RESULTS: Thirty-two participants were interviewed. Patient-level barriers included poor knowledge in recognising STEMI symptoms and not calling EMS when symptoms occurred. Limited capacity of health professionals in hospitals below the tertiary level and lack of coordination between hospitals of different levels were identified as the main system-level barriers. Five recommendations were provided: (1) enhance public health education; (2) strengthen primary healthcare workforce; (3) increase EMS capacity; (4) establish an integrated care model; and (5) harness government's responsibilities. CONCLUSIONS: Barriers associated with delay in STEMI treatment were identified at both patient and system levels. The results of this study provide a useful evidence base for future intervention development to improve the quality of STEMI treatment and patient outcomes in China and other countries in a similar situation.

Oncology phase II proof-of-concept studies with multiple targets: Randomized controlled trial or single arm?

For oncology drug development, phase II proof-of-concept studies have played a key role in determining whether or not to advance to a confirmatory phase III trial. With the increasing number of immunotherapies, efficient design strategies are crucial in moving successful drugs quickly to market. Our research examines drug development decision making under the framework of maximizing resource investment, characterized by benefit cost ratios (BCRs). In general, benefit represents the likelihood that a drug is successful, and cost is characterized by the risk adjusted total sample size of the phases II and III studies. Phase III studies often include a futility interim analysis; this sequential component can also be incorporated into BCRs. Under this framework, multiple scenarios can be considered. For example, for a given drug and cancer indication, BCRs can yield insights into whether to use a randomized control trial or a single-arm study. Importantly, any uncertainty in historical control estimates that are used to benchmark single-arm studies can be explicitly incorporated into BCRs. More complex scenarios, such as restricted resources or multiple potential cancer indications, can also be examined. Overall, BCR analyses indicate that single-arm trials are favored for proof-of-concept trials when there is low uncertainty in historical control data and smaller phase III sample sizes. Otherwise, especially if the most likely to succeed tumor indication can be identified, randomized controlled trials may be a better option. While the findings are consistent with intuition, we provide a more objective approach.

Assessment of countermeasure effectiveness and informativeness in mitigating wrong-way entries onto limited-access facilities.

Wrong-way crashes are a major cause for safety concerns along freeways and limited-access facilities. Although wrong-way crashes account for a relatively small portion of total crashes, the impact between two cars crashing into each other at high speeds in opposite directions often results in severe injuries or fatalities compared to any other type of crash. To seek solutions for mitigating wrong-way driving (WWD), multiple field tests involving a number of countermeasures using Intelligent Transportation Systems (ITS) technologies have been conducted in Florida. This study was aimed to evaluate these WWD countermeasures in Florida and develop recommendations regarding the most effective and informing WWD countermeasures through (1) analysis of existing data and studies, (2) field WWD testing using focus groups, (3) a public opinion survey, and (4) capturing human factors elements using simulation via a driving simulator. The results proved that red Rectangular Rapid Flashing Beacons (RRFBs) are the top countermeasure for mitigating WWD at freeway off-ramps, with wigwag flashing beacons as the second best, and detection-triggered blank-out signs and detection-triggered LED lights around "WRONG WAY" signs (tie) as third best. Red flush-mount Internally Illuminated Raised Pavement Markers (IIRPMs) were found to be statistically significantly effective for possible consideration as a supplemental countermeasure for mitigating WWD at freeway off-ramps. The countermeasure of delineators along off-ramps was found to be the least effective and was not considered for recommendation for deterring WWD at freeway off-ramps. This study further confirms that the newly-developed signing and pavement marking standards in Florida are a positive countermeasure on arterials to mitigate wrong-way entries onto freeway off-ramps.

How many tumor indications should be initially screened in development of next generation immunotherapies?

An experimental oncology immunotherapy may have the potential to be effective in a large number of tumor indications. We have considered a staggered approach for efficacy screening in subjects with an unmet medical need. A cohort of tumor indications is selected for the first wave investigation and the second wave investigation in a different cohort of tumor indications is initiated only after the drug has been demonstrated to be effective in the first wave. The effectiveness of an experimental immunotherapy is unknown at the planning stage, and the assumptions at the planning stage are subject to revision later on. How many tumor indications should be investigated in the first wave for the development program to be cost-effective amid the uncertainties? We attempt to answer this question by maximizing a benefit-cost ratio, defined to be the expected number of effective tumor indications correctly identified in the two waves (benefit) divided by the expected total sample size in the two waves and the subsequent trials for more definitive testing triggered by those with a positive outcome in the first wave (cost). It is found from the benefit-cost ratio analyses that, depending on resource availability, three to five tumor indications may be initiated in the first wave to properly balance the risk and benefit, and adequate investment is important to maintain the quality of statistical design.

Economic burden and its associated factors of hospitalized patients infected with A (H7N9) virus: a retrospective study in Eastern China, 2013-2014.

BACKGROUND: H7N9 continues to cause human infections and remains a pandemic concern. Understanding the economic impacts of this novel disease is important for making decisions on health resource allocation, including infectious disease prevention and control investment. However, there are limited data on such impacts. METHODS: Hospitalized laboratory-confirmed H7N9 patients or their families in Jiangsu Province of China were interviewed. Patients' direct medical costs of hospitalization were derived from their hospital bills. A generalized linear model was employed to estimate the mean direct medical costs of patients with different characteristics. RESULTS: The mean direct cost of hospitalization for H7N9 was estimated to be ¥ 71 060 (95 % CI, 48 180-104 820), i.e., US$ 10 996 (95 % CI, 7 455-16 220), and was ¥12 060 (US$ 1 861), ¥136 120 (US$ 21 001) and ¥218 610 (US$ 33 728) for those who had mild or severe symptoms or who died, respectively. The principal components of the total fees differed among patients with different disease severity, although medication fees were always the largest contributors. Disease severity, proportion of reimbursement and family member monthly average income were identified as the key factors that contributed to a patient's direct medical cost of hospitalization. CONCLUSIONS: The direct medical costs of hospitalized patients with H7N9 are significant, and far surpass the annual per capita income of Jiangsu Province, China. The influencing factors identified should be taken into account when developing related health insurance policies and making health resource allocation. TRIAL REGISTRATION: Not applicable. This is a survey study with no health care intervention implemented on human participants.

Maximizing return on socioeconomic investment in phase II proof-of-concept trials.

Phase II proof-of-concept (POC) trials play a key role in oncology drug development, determining which therapeutic hypotheses will undergo definitive phase III testing according to predefined Go-No Go (GNG) criteria. The number of possible POC hypotheses likely far exceeds available public or private resources. We propose a design strategy for maximizing return on socioeconomic investment in phase II trials that obtains the greatest knowledge with the minimum patient exposure. We compare efficiency using the benefit-cost ratio, defined to be the risk-adjusted number of truly active drugs correctly identified for phase III development divided by the risk-adjusted total sample size in phase II and III development, for different POC trial sizes, powering schemes, and associated GNG criteria. It is most cost-effective to conduct small POC trials and set the corresponding GNG bars high, so that more POC trials can be conducted under socioeconomic constraints. If δ is the minimum treatment effect size of clinical interest in phase II, the study design with the highest benefit-cost ratio has approximately 5% type I error rate and approximately 20% type II error rate (80% power) for detecting an effect size of approximately 1.5δ. A Go decision to phase III is made when the observed effect size is close to δ. With the phenomenal expansion of our knowledge in molecular biology leading to an unprecedented number of new oncology drug targets, conducting more small POC trials and setting high GNG bars maximize the return on socioeconomic investment in phase II POC trials.

Profiling the dynamics of abscisic acid and ABA-glucose ester after using the glucosyltransferase UGT71C5 to mediate abscisic acid homeostasis in Arabidopsis thaliana by HPLC-ESI-MS/MS.

The HPLC-MS/MS method was developed to profile the dynamics of abscisic acid (ABA) and ABA-glucose ester (ABA-GE) after cloning glycosyltransferase enzyme family gene AtUGT71C5 into Arabidopsis thaliana. By constructing over-expression lines (OE) and down-expression lines (DN), we acquired mutant strains to analyze the function of AtUGT71C5. The multiple-reaction monitoring (MRM) was used for quantitative determination in negative mode. The transition was m/z 263.1→153.0 for ABA ([M-H]+), m/z 425.1→263.0 for ABA-GE ([M-H]+), and m/z 321.0→152.0 for chloramphenicol. The linear range was 0.8684-217.1 ng/mL for ABA and 0.3920-196.0 ng/mL for ABA-GE. The accuracy was 88.0-109.0% for ABA and 86.6-113.0% for ABA-GE; the inter-day and intra-day precisions were less than 5.4% for ABA and 8.9% for ABA-GE, respectively. This method is simple and sensitive enough for determination of ABA and ABA-GE in A. thaliana leaves. All the evidence confirmed the speculation that AtUGT71C5 can mediate abscisic acid homeostasis.

Evaluation of early efficacy endpoints for proof-of-concept trials.

A Phase II proof-of-concept (POC) trial usually uses an early efficacy endpoint other than a clinical endpoint as the primary endpoint. Because of the advancement in bioscience and technology, which has yielded a number of new surrogate biomarkers, drug developers often have more candidate endpoints to choose from than they can handle. As a result, selection of endpoint and its effect size as well as choice of type I/II error rates are often at the center of heated debates in design of POC trials. While optimization of the trade-off between benefit and cost is the implicit objective in such a decision-making process, it is seldom explicitly accounted for in practice. In this research note, motivated by real examples from the oncology field, we provide practical measures for evaluation of early efficacy endpoints (E4) for POC trials. We further provide optimal design strategies for POC trials that include optimal Go-No Go decision criteria for initiation of Phase III and optimal resource allocation strategies for conducting multiple POC trials in a portfolio under fixed resources. Although oncology is used for illustration purpose, the same idea developed in this research note also applies to similar situations in other therapeutic areas or in early-stage drug development in that a Go-No Go decision has to rely on limited data from an early efficacy endpoint and cost-effectiveness is the main concern.

[Analysis on layout of traditional Chinese medicine industry based on location quotient].

To observe the layout and evolution of the traditional Chinese medicine (TCM) medical industry, classify the industry by region and conduct a preliminary study on its professional advantages, competitiveness and possible cause by using the theory of location quotient in regional economics, in order to provide suggestions for the layout of the TCM medical industry.

[Genetic variation and association of prostaglandin F2alpha receptor (PTGFR) gene with sow maternal behaviors in a White Duroc x Erhualian resource population].

Maternal behaviors of sows around parturition are important for survival of newborn offspring. Failure to establish normal maternal bonds such as maternal infanticide and crushing often occurs in some individuals. It causes both significant economic losses to the pig industry and severe problems of piglet welfare. Prostaglandin F2-alpha not only can stimulate the nest-building behavior of sows before parturition but also plays an important role in reproductive process and maternal behavior through protein FP encoded by the prostaglandin F receptor gene (PTGFR) as its receptor. In this study, genetic variation and association study of PTGFR gene with nest-building behavior, maternal infanticide, and crushing behavior was carried out in a White Duroc x Erhualian resource population. As a result, five synonymous mutations were identified on exon 1 and exon 2. Exon 1 g .250 A>G, Exon 1 g.619 G>A and Exon 2 g.483 T>C were chosen for genotyping in individuals of F0, F1 and 289 F2 sows. Family-based transmission disequilibrium test (TDT) demonstrated that there were no significant associations of 3 SNPs and haplotypes of PTGFR gene with sow nest-building, maternal infanticide and crushing behavior (P > 0.05). Therefore, it can be concluded that PTGFR gene is not the causative candidate gene for sow maternal behaviors.

Optimal cost-effective designs of Phase II proof of concept trials and associated go-no go decisions.

This manuscript discusses optimal cost-effective designs for Phase II proof of concept (PoC) trials. Unlike a confirmatory registration trial, a PoC trial is exploratory in nature, and sponsors of such trials have the liberty to choose the type I error rate and the power. The decision is largely driven by the perceived probability of having a truly active treatment per patient exposure (a surrogate measure to development cost), which is naturally captured in an efficiency score to be defined in this manuscript. Optimization of the score function leads to type I error rate and power (and therefore sample size) for the trial that is most cost-effective. This in turn leads to cost-effective go-no go criteria for development decisions. The idea is applied to derive optimal trial-level, program-level, and franchise-level design strategies. The study is not meant to provide any general conclusion because the settings used are largely simplified for illustrative purposes. However, through the examples provided herein, a reader should be able to gain useful insight into these design problems and apply them to the design of their own PoC trials.