**2. Nivolumab in Clinical Trials**

The CheckMate 057 trial was designed for patients with non-squamous NSCLC. Eligible patients had primary CS IIIB/IV NSCLC or recurrent NSCLC after radiation therapy or surgical resection and documented disease progression during or after one platinum-based doublet chemotherapy regimen [3]. Patients with an acceptable general condition and adequate organ function without major comorbidities were included [3]. In all, 582 patients were randomized: 292 were assigned to receive nivolumab at a dose of 3 mg/kg every 2 weeks, and 290 to receive docetaxel at a dose of 75 mg/m2 every 3 weeks. OS was the primary endpoint. The key secondary endpoints were investigator-assessed confirmed objective response rate and progression-free survival (PFS). Tumor response was assessed with the use of the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), at week 9 and then every 6 weeks until disease progression. Safety was assessed with the Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.

The median OS was longer in the nivolumab group than in the docetaxel group (12.2 months, 95% confidence interval (CI) 9.7–15.0, versus 9.4 months, 95% CI 8.1–10.7; hazard ratio (HR) 0.73, 95% CI 0.59–0.89; *p* = 0.002). The objective response rate was 19% with nivolumab versus 12% with docetaxel (*p* = 0.02). Treatment-related adverse events (AEs) of any grade were reported in 69% of patients in the nivolumab group and in 88% in the docetaxel group, while grade 3–4 AEs occurred in 10% of the nivolumab group and in 54% of the docetaxel group [3]. The most important data from that study are presented in Table 1.

**Table 1.** Nivolumab for previously treated non-small-cell lung cancer—CheckMate 017/057 [2,3].

HR—hazard ratio, ORR—overall response rate, PFS—progression-free survival, OS—overall survival, AE—adverse event.

The CheckMate 017 trial was designed for patients with squamous NSCLC. Eligible patients had CS IIIB/IV NSCLC and documented disease progression after one platinum-based doublet chemotherapy [4]. The main inclusion or exclusion criteria and treatment outline were similar to those for the CheckMate 057 trial. In all, 272 patients underwent randomization: 135 patients were assigned to receive nivolumab and 137 to receive docetaxel [4].

The median OS was longer with nivolumab than with docetaxel (9.2 months, 95% CI 7.3–13.3, versus 6.0 months, 95% CI 5.1–7.3; HR 0.59, 95% CI 0.44–0.79; *p* < 0.001). The response rate was 20% with nivolumab versus 9% with docetaxel (*p* = 0.008). Treatment-related AEs of any grade occurred in 58% of patients in the nivolumab group and in 86% in the docetaxel group. Grade 3–4 AEs occurred in 7% of the nivolumab group and in 55% of the docetaxel group. The most important data from that study are presented in Table 1.

A pooled analysis of long-term outcomes confirmed the efficacy of nivolumab [4,5]. The 4-year OS rate was 14% in patients treated with nivolumab, compared with 5% in patients treated with docetaxel (14.9% for patients with non-squamous NSCLC and 9.4% for patients with squamous NSCLC in the nivolumab population); the 5-year OS rate was 13.4% with nivolumab versus 2.6% with docetaxel (HR 0.68, 95% CI 0.59–0.78) [4,5]. Patients in the nivolumab group who achieved an objective response had the best long-term results. Median OS in patients with an objective response was not reached in the nivolumab group (95% CI 25.6–not reached) versus 17.1 months (95% CI 11.1–28.7) in the docetaxel group. The 4-year OS rate in patients with an objective response was 58% with nivolumab and 12% with docetaxel [4].


**4. Conclusions**

**2.3. Calibration**

6 Metrology

**3. Data evaluation**

**Figure 1.** Hierarchy of calibration/traceability pyramid.

The purpose of calibration is to determine and document how much of the equipment is in error with the actual value. The correct value is obtained by considering the amount of error in the result. Calibration is the process of determining the relationship between the value read in a gauge and the gauge size. Calibration and control of measuring, inspection, and control equipments ensure the appropriateness of measurements made during manufacturing. The continuity of this safety is ensured by the regular and identifiable calibration of the equipment in question. Calibration is performed by comparison with a measurement of normality known to the measurement magnitude. To sum up, calibration is explained in the related standard: under specified conditions, the series of operations in which the relationship between the values indicated by a measuring instrument or device and the values indicated by a material measurement or reference material is established [3]. In order to supply traceability in measurements, calibration hierarchy in **Figure 1** should be followed up carefully.

Metrology and inspection together serve as the control function of the quality of conformance. Inspection helps to evaluate the degree of conformance or nonconformance to specifications, provides for reporting of deficiencies early in the production process, and helps to assure that desired quality requirements have been met. The field of knowledge concerned with measurement. Metrology includes all aspects of both theoretical and practical with reference to measurements, whatever their level of accuracy, and in whatever fields of science or technology they occur. Since quality performance decisions are based on inspection and measurement, undesirable consequences may result if these tasks are not performed properly. Not only incorrect measurements lead to wrong decisions, which can have serious consequences, but also improper data evaluations can cause undesirable consequences. Since Statistical Process Control is the utilization of statistiMetrology is a crucial science including its standards, systems of units, instruments, calibration procedures, uncertainties, inspection, and quality control topics in many industries such as automotive, aerospace, mechanical engineering, surface engineering, etc. and in many sciences like natural and applied sciences in different sizes like micro and nanometrology serving for sustainable improvements. Like being in today, there will always be valuable researches in the field of metrology, with the help of technological developments to support the scientific researches in the future. Care taken in the reliability of measurements and their traceability will always be crucial. Metrology is such useful for humanity if it is conducted according to its rules and international standards.


**5. Conclusion**

Currently fresh, chilled and frozen-thawed semen are used extensively for AI in animal breeding and production throughout the world. Dairy herd size has increased with increas‐ ing pressure to maximize milk yield, whilst at the same time reducing production costs is necessary. Accurate oestrus detection crucial for timed and successful AI and early detection of the success or otherwise of insemination can meaningfully reduce the time delay before repeated insemination if this is necessary. For these reasons it is very important to have a reliable method to accurately detect the occurrence of oestrus. Errors in efficiency and accu‐ racy of heat detection result in high semen cost and an increase in the interval from calving to conception, reducing cow production and net returns. The use of ultrasonography prior to AI for determining the ovarian status can significantly improve the success of AI.

Conversely, reproductive management is currently a major factor affecting profitability in the dairy industry. Early identification of non-pregnant dairy cows and heifers post AI can im‐ prove reproductive efficiency and pregnancy rate by decreasing the interval between AI serv‐ ices and increasing AI service rate. Thus, imaging technologies such as ultrasound to identify non-pregnant dairy cows and heifers early after AI may play a key role in management strat‐ egies to improve reproductive efficiency and increase profitability on commercial and small holder dairy farms. Early detection of non-pregnancy will lead to earlier intervention and de‐ cision that will shorten the calving interval, which has economic effect on the diary farm. Transrectal ultrasonography has also been used to determine foetus viability and hence can improve the outcome of AI by allowing knowledge based decision on problem cows.


**5. Conclusions**

UAVs offer an opportunity to make flexible, efficient radiation measurements at many locations and scales. Here, we validated a method of measuring albedo by UAV while minimizing payload and technical requirements. We found that UAVs provided stable albedo measurements across multiple flights over a mixed hardwood forest, with results that were well within the range of tower-estimated albedo at similar forested sites. Simultaneous albedo estimates by UAV and a fixed tower at the same site showed that the two methods produced near identical results. Finally, we demonstrated that in-situ albedo measurements (tower and UAV) capture more site-to-site variation in albedo than satellite measurements. Overall, we show that UAVs produce reliable, consistent albedo measurements that can capture crucial surface heterogeneity, clearly distinguishing between different land uses.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/2072-4292/10/8/1303/ s1, Table S1: Dates, times, and locations of described UAV flights, Table S2: Latitude and longitude of UAV satellite pixels Table S3: Latitude and longitude of tower satellite pixels, Table S4: Blue sky albedo estimates for sites in Tully, NY. Table S5: Current FAA requirements for UAV research within the United States.

**Author Contributions:** Conceptualization, C.R.L.; UAV and Satellite Dataset, C.R.L.; Harvard and Bartlett Forest Dataset, A.D.R.; Durham Forest Dataset, E.B.; Validation and Analysis, C.R.L.; Writing-Original Draft Preparation, C.R.L.; Writing-Review & Editing, C.R.L., E.B., and A.D.R.

**Funding:** This research was funded by the David R Atkinson Center for a Sustainable Future, through the Academic Venture Fund program. Harvard and Bartlett Forest measurements were funded by the National Science Foundation through the LTER program, which has supported research at Harvard Forest (DEB-1237491) and Bartlett Experimental Forest (DEB-1114804).

**Acknowledgments:** Timothy Fahey was the primary investigator on this grant, and is particularly thanked for his support. The authors would also like to extend sincere thanks and appreciation to Martin LaChance of UAV Imaging Systems for his expertise and hard work in realizing this project.

**Conflicts of Interest:** The authors declare no conflict of interest.


*4.2. Constellation Visibility*

The average number of visible satellites, the average PDOP value, and the satellite elevation distribution of the three tracking networks were analyzed with numerical comparison and statistical study. The number of visible satellites and their statistical property is shown in Figures 4 and 5, respectively.

**Figure 4.** The average number of visible satellites of GPS, GLONASS, and GPS+GLONASS in the high (red), middle (green), and low (blue) latitude networks.

From Figure 5, during the 8 days test period, both constellations have the largest average number of visible satellites in the high latitude network among the three networks. The average visible number of GPS in high latitude regions is significantly larger than in the middle and low latitude regions. The average number of visible satellites of GLONASS in the high and the middle latitude regions is similar but significantly larger than that of the low latitude region.

From the statistical point of view, the GLONASS visible satellites have the smallest standard deviation in the high and middle latitude networks. The percentages of most observed 9 and 8 GLONASS satellites in the high latitude network are 52.37% and 27.63%, respectively. The percentages of most observed 9 and 8 GLONASS satellites in the middle latitude network are 34.20% and 33.64%, respectively. However, the number of GLONASS visible satellites reduces significantly, and the standard deviation increases significantly in the low latitude network. Moreover, the standard deviation of GPS+GLONASS is relatively larger than GPS or GLONASS, and the average number of visible satellites is also larger than those of GPS and GLONASS. The probability of observing satellites less than 12

in three networks of combined GPS and GLONASS is almost zeros, indicating that the combined constellations provide more than 12 visible satellites in most cases.

**Figure 5.** The histogram of visible satellites in the high (red), middle (green), and low (blue) latitude networks. The position of the dashed line and the value x− indicate the average number of visible satellites. The σ2 represents the variance of the visible satellites' distribution. Please note that the horizontal axis of GPS and GLONASS visible satellites differs from that of GPS+GLONASS.

The histogram of the elevation distribution related to GLONASS, GPS, and GLONASS+GPS is also presented in Figure 6 to further evaluate the quality of the observed satellites.

From Figure 6, GLONASS has a much better elevation distribution than GPS in the high latitude network. The most observed GLONASS satellites' elevation angles in the high latitude network are between 13–33 degrees, while those of GPS are between 6–26 degrees, which are obviously lower than that of GLONASS. In addition, the mean elevation angle of GLONASS is 35.01◦, which is 3.97◦ higher than that of GPS. In the middle latitude network, the elevation angle distribution and average elevation angle between GPS and GLONASS have inconspicuous disparity. In the low latitude network, the percentage peak of GLONASS corresponds to an obviously lower elevation angle than GPS. The elevation distribution of GPS+GLONASS lies between GPS and GLONASS.

The PDOP of GPS, GLONASS, and GPS+GLONASS during the testing period is illustrated in Figure 7.

**Figure 6.** The histogram of elevation distribution of the high (red), middle (green), and low (blue) latitude networks, the position of the dashed line and the value x− indicate the mean elevation.

**Figure 7.** The PDOP of GPS, GLONASS, and GPS+GLONASS in the high (red), middle (green), and low (blue) latitude networks (The GLONASS PDOP for the low latitude network exceed the coordinate threshold, and the small picture in the upper right corner with the rose thread shows the full view of the PDOP).

Figure 7 shows that the PDOP values of GPS are less than 3.0 in all three regions, and the most stable PDOP values appear in middle latitude regions, indicating that the observation geometry of GPS in that region is the best among the three regions. Moreover, the PDOP values of GPS exist daily period in all three regions. GLONASS has the most stable PDOP in high latitude regions, which is more stable than GPS in the same region. However, the PDOP values of GLONASS increase obviously as the latitude decreases. In addition, the PDOP values of GLONASS at low latitude regions show some abnormally large values, up to 92.68, as shown in the upper right corner of the subfigure for low latitude GLONASS PDOP. The PDOP values of GPS+GLONASS exhibit better performance than both GLONASS and GPS stand-alone systems. Although some periods exist in high latitude regions where the PDOP of GPS is up to 2.80, the PDOP values of GPS+GLONASS are quite stable and less than 1.55. Although the PDOP of GPS is up to 2.75 in some periods in low latitudes and the PDOP of GLONASS is very large at certain epochs, the PDOP of GPS+GLONASS remains stable and below 1.44. The combined GPS and GLONASS constellations have the most obvious improvement in observation geometry at low latitudes.


*Review* **Antithrombotic Therapy in Peripheral Artery Disease: Current Evidence and Future Directions**

**Mario Enrico Canonico 1,2,\*, Raffaele Piccolo 2, Marisa Avvedimento 2,3, Attilio Leone 2, Salvatore Esposito 2, Anna Franzone 2, Giuseppe Giugliano 2, Giuseppe Gargiulo 2, Connie N. Hess 1, Scott D. Berkowitz 1, Judith Hsia 1, Plinio Cirillo 2, Giovanni Esposito 2 and Marc P. Bonaca 1**

1 CPC Clinical Research, Department of Medicine, University of Colorado, Aurora, CO 80045, USA

2 Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy

3 Quebec Heart and Lung Institute, Laval University, Quebec City, QC G1V0A6, Canada

**\*** Correspondence<EMAIL_ADDRESS>Tel.: +1-(303)-860-9900

**Abstract:** Patients with peripheral artery disease (PAD) are at an increased risk of major adverse cardiovascular events, and those with disease in the lower extremities are at risk of major adverse limb events primarily driven by atherothrombosis. Traditionally, PAD refers to diseases of the arteries outside of the coronary circulation, including carotid, visceral and lower extremity peripheral artery disease, and the heterogeneity of PAD patients is represented by different atherothrombotic pathophysiology, clinical features and related antithrombotic strategies. The risk in this diverse population includes systemic risk of cardiovascular events as well as risk related to the diseased territory (e.g., artery to artery embolic stroke for patients with carotid disease, lower extremity artery to artery embolism and atherothrombosis in patients with lower extremity disease). Moreover, until the last decade, clinical data on antithrombotic management of PAD patients have been drawn from subanalyses of randomized clinical trials addressing patients affected by coronary artery disease. The high prevalence and related poor prognosis in PAD patients highlight the pivotal role of tailored antithrombotic therapy in patients affected by cerebrovascular, aortic and lower extremity peripheral artery disease. Thus, the proper assessment of thrombotic and hemorrhagic risk in patients with PAD represents a key clinical challenge that must be met to permit the optimal antithrombotic prescription for the various clinical settings in daily practice. The aim of this updated review is to analyze different features of atherothrombotic disease as well as current evidence of antithrombotic management in asymptomatic and secondary prevention in PAD patients according to each arterial bed.

**Keywords:** peripheral artery disease (PAD); antithrombotic therapy; dual pathway inhibition (DPI); major adverse cardiovascular events (MACE); major adverse limb events (MALE)