**Acknowledgements**

**5. Summary and conclusions**

186 Recent Developments in Tropical Cyclone Dynamics, Prediction, and Detection

basins, respectively.

for a long time.

and NRC cases.

tively.

An objective method is developed to categorize concentric eyewall structures in the western North Pacific (WNP) TCs using the NRL SSM/I and TMI satellite imagery database. For the WNP (ATL) basin, there are 91 (33) CE TCs and 113 (50) CE cases identified from 29,785 (19,001) satellite images between 1997 and 2014. Excluding the cases that are 200 km close to landfall and cases with temporal resolution higher than12 h, 83 (34) CE cases were studied for the

**1.** Three CE types are categorized: CE with an eyewall replacement cycle (ERC; 51 and 56% in the WNP and ATL), CE with no replacement cycle (NRC; 27 and 29% in the WNP and ATL), and CE that is maintained for an extended period of time (CEM; 23 and 15% in the WNP and ATL). The mean duration of CEM type is 32 and 27 h in the WNP and ATL

**2.** The CEM cases have relatively high intensity, large widths of both the moat and outer eyewall that last for a long duration time. The large widths of the moat and outer eyewall may reduce the barotropic instabilities of CE storms and thus maintain the CE structures

**3.** Most CEM cases in the WNP basin are located to the west of 140°E with the smallest northward translation speed of 2.2 m s−1. The average location of CEM cases in the ATL basin is farther west than that of ERC and NRC cases with the smallest northward translation speed of 1.4 m s−1. The NRC cases often have fast northward translation speeds and are located in higher latitudes of relative strong vertical shear and cold SST zones. The unfavorable environmental conditions thus act to weaken the convective activity for these cases. On the other hand, the CEM cases occur in favorable environment and tend to form in the warm episode of ENSO in the WNP basin. There are 12% (3%) of CE cases

**4.** The variabilities of intensity and structural changes in the WNP basin are larger than that in the ATL basin. For example, the moat size and outer eyewall width in the WNP (ATL) basin are approximately 20–50% (15–25%) larger in the CEM cases than that in the ERC

**5.** In the WNP basin, a very good relationship of 0.77 was found between the annual CE TC numbers and the NCEP Oceanic Niño Index (ONI). The probability of CE TCs formation is strongly influenced by the ENSO environmental factors. For example, there are 29 out of 69 (42%) TCs that possess CE structures in the warm episode. In contrast, there are only 16 out of 65 (25%) TCs that possess CE structures in the cold episode. The averaged CE formation frequencies are 0.8 and 0.3 per month in the warm and cold episodes, respec-

**6.** In the ATL basin, the correlation between ONI and CE formation frequency suggests that the ENSO may not influence the CE formation. It may be due to the average location of CE formation during warm episode farther south over the ATL in the relative warm SST

structural and intensity changes. The primary findings are as follows:

with more than 30 h long duration in the WNP (ATL) basin.

This work was supported by the Ministry of Science and Technology in Taiwan under grants MOST 104-2111-M-002-002-MY3 and MOST 104-2625-M-002-006, and the Naval Research Laboratory under grant N62909-15-1-2008.


**2.1. Chlorine Gas**

Chlorine is a greenish-yellow gas. By providing high pressure, the gas becomes liquid. It is toxic. Chlorine gas is mostly used as a water disinfectant. Introducing chlorine to water plays a very effective role for removing almost all pathogenic microorganisms. It can be used both as a primary and a secondary disinfectant. The gas is not applicable to be used in household system as it is very dangerous. It is lethal at concentrations as low as 0.1% air by volume [1].

*2.1.3. Process*

*2.1.4. Equipment*

*2.1.5. Chemical*

*2.2.1. Advantages*

Chlorine readily combines with all the water components, i.e., chemicals, small animals, microorganisms, plant material, odors, colors, and tastes. Sufficient quantity of chlorine is necessary to meet with the demand of chlorine in the water and provide residual disinfection. Residual (free) chlorine is termed as the one that does not combine with other water components. The point at which free chlorine is available for continuous disinfection is termed as the breakpoint. The system at which free chlorine is supplied at a concentration of 0.3–0.5 mg/l is an ideal system. Simple test kits, most commonly the DPD (N,N-diethyl-p-phenylenediamine) colorimetric test kits are available for testing breakpoint and chlorine residual in private sys-

Disinfection Methods

5

http://dx.doi.org/10.5772/intechopen.80999

This consists of 908 kg (2000 lb) or 68 kg (150 lb) containers, weigh scales, chlorinator, injectors, switchover modules, vacuum lines, booster pumps, solution lines, diffusers, and a flow meter. Safety requirements are passive ventilation, mechanical ventilation, warning alarms and devices, showers, panic hardware for doors, and eye washes. A separate air tight room for chlorination

Chlorine can be used as liquid or gas form. It is a very strong, oxidizing agent. Both the forms (liquid and gas) can be stored and used from gas cylinders under pressure. The chlorine cylinders can be 150 pounds. Small drinking water systems commonly use cylinders of 150 pounds. Hypochlorous and hypochlorite ions are formed when chlorine is mixed with water. The hypochlorous ion is a better disinfectant which is formed in greater concentration at low pH concentrations. The hypochlorite and hypochlorous ions will be present in equal concentrations at pH 7.3. At pH above 8.3, the hypochlorite ion predominates which is not a better disinfectant. So, better disinfection is achieved at low pH. To avoid the formation of trihalomethanes and haloacetic acids, chlorination should be applied after treatment [5] (**Figure 1**).

Sodium hypochlorite is used as a bleaching agent, mostly to bleach papers or textiles, and as a disinfectant in solution. The solution generally contains 10–15% of the available chlorine, but rapidly loses its force in storing process. Regular controlled environment is needed as the

• Both sodium hypochlorite and chlorine gas shows similar disinfection effectiveness.

solution is affected greatly by the pH, light, heat, and heavy metals [6].

• Sodium hypochlorite can also be used as a disinfectant.

equipment is mandatory. For disinfection process, 100% of chlorine gas is available [4].

tems. The kit must test the amount of free chlorine, not total chlorine [3].

**2.2. Chlorination (sodium hypochlorite solution)**


Preface

Although serotonin (5-HT) was discovered as a neurotransmitter less than 80 years ago, the successive decades have yielded a dramatic increase in our knowledge of serotonin, its receptors, enzymes, transporters and accessory proteins and its associated functions. Serotonin constitutes one of the oldest neurotransmitter systems in nature; it is estimated to have originated about 800 million years ago. This enormous time span enabled the serotonergic complex to evolve into a highly important system involved in many important biological processes in the body, particularly in the central nervous, gastro-intestinal, cardiovascular and immune systems. It is remarkable that the neurotransmitter itself has not evolved during evolution, but the molecules with which it interacts have shown an amazing diversity, variability and extent and seem to vary according to species, organ, cell, gender and disease state. The complexity of the involvement of serotonin is illustrated in the chapters contributing to this volume.

In Chapter 1 investigators from various countries and backgrounds have collaborated on mathematical modeling of neurotransmitter metabolism, focusing on 5-HT and histamine, applying various techniques and trying to connect their findings to neuropsychiatric disorders, notably depression. By eloquently combining various advanced methods and techniques they present a new serotonin model of 5-HT synthesis, release, reuptake and autoreceptor control and make an intriguing connection to neuro-inflammation as a causative factor in major depression.

Chapter 2 deals with the interconnection between serotonin, sleep and depression. The involvement of 5-HT neurotransmission in sleep and wakefulness has been known since the sixties, but many questions have not been resolved. In this chapter a new hypothesis is formulated involving 5-HT and excessive long pre-morning periods of REM-sleep, leading to a complete stop of monoamine release. It is suggested that fragmentation of this sleep phase may have antidepressant effects.

Chapter 3 describes the putative role of the serotonergic system in post-traumatic stress disorder (PTSD), a troublesome condition that is increasing in prevalence worldwide. This review shows the involvement of the serotonergic system in the regulation of sensitivity to highly stressful events and how to cope with them.

Chapter 4 deals with the use of small molecule drugs for the treatment of Alzheimer's Disease which is developed on the basis of a mechanistic understanding of the Serotonin Receptors 4 and 6.

Chapter 5 deals with serotonergic brain mechanisms of aggression and sexual behavior, focusing on 5-HT1A- and 5-HT1B-receptors, as there is evidence for (partly) overlapping in CNS circuitry for aggression and sexual behavior. As 5-HT1B-receptors seem particularly involved in aggression and 5-HT1A-receptors in sexual behavior, their precise interrelationship is not clear and far from understood. This information is badly needed to develop anti-aggressive (serenic) and prosexual drugs for human applications.

Chapter 6 describes new ligands for 5-HT4- and 5-HT6-receptors that might create new treatments in the modulation of cognition and amyloid pathology. The chapter nicely describes recent progress in understanding how to modulate underlying systems by medicinal chemistry methods of advanced pharmacophores. This will hopefully lead to new pharmacological approaches and drugs to treat Alzheimer's disease.

Chapter 7 discusses the role of serotonin in cerebral edema after traumatic brain injury. Traumatic brain injury leads to very complex processes where many different mechanisms play a role. Serotonin is clearly involved in early cytotoxic edema after traumatic brain injury. Maintaining low serotonin levels in the brain immediately after an injury has neuroprotective effects and may contribute to a better outcome for the patient.

Chapter 8 is a nice overview of the role of 5-HT pathways in neuro-immuno communication and their role in autoimmune and inflammatory pathology in CNS diseases, including multiple sclerosis, Alzheimer's disease and mood disorders. The chapter also outlines the important role of the 'brain-gut axis' and shows the involvement of brain-gut communication in the pathogenesis and pathophysiology of several brain disorders.

This book excellently illustrates the broadness of research and therapy in the serotonergic field. It also indicates that new developments continuously occur in a 'seemingly old' system. It is evident that we still are only at the beginning of understanding the role of serotonin in health and disease.

> **Dr. Berend Olivier** Professor, Professor Emeritus Pharmacology of the Central Nervous System, Faculty of Sciences, Department of Psychopharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands

> > Adjunct Professor, Department of Psychiatry, Yale University School of Medicine, New Haven, USA

## **Chapter 1**


REPEAT YOUR BLOCK (TRPD) # IN YOURSCANNERPET (8 detectores) # LYSO box is repeated around z axis /gate/LYSO/repeaters/insert ring /gate/LYSO/ring/enableAutoRotation /gate/LYSO/ring/setFirstAngle 270 deg # the above line sets the first detector at 12 hour /gate/LYSO/ring/setPoint1 0. 0. 0. mm /gate/LYSO/ring/setPoint2 0. 0. -1. mm /gate/LYSO/ring/setRepeatNumber 8

#trapezoid is repeated around x axis /gate/trapezoid/repeaters/insert ring /gate/trapezoid/ring/enableAutoRotation /gate/trapezoid/ring/setFirstAngle 270 deg # the above line sets the first detector at 12 hour /gate/trapezoid/ring/setPoint1 0. 0. 0. mm /gate/trapezoid/ring/setPoint2 1. 0. 0. mm /gate/trapezoid/ring/setRepeatNumber 8 /gate/trapezoid/repeaters/insert cubicArray /gate/trapezoid/cubicArray/setRepeatNumberX 3 /gate/trapezoid/cubicArray/setRepeatVector 54.4 0.0 0.0 mm /gate/PETscanner1/placement/setRotationAxis 0 1 0 /gate/PETscanner1/placement/setRotationAngle 90 deg


**7. Climate impact on vectors**

Grassland diseases are highly affected by the availability of the mode of transmission in the environment. The knowledge on entomology is required to understand the point of interference in the life cycle in order to have successful management strategies.

#### **7.1 Aphids**

Aphids belong to a superfamily of Aphidoidea, which belongs to the Hemipteran sternorrchyna with whiteflies, jumping plant lice, scale insects and mealybugs. This superfamily is then separated into two sub groups of primitive "aphids" and a group of new world aphids [19].

The studies on aphids' ability to transmit viruses have become more complex as they are capable of switching between sexual and parthenogenetic reproduction. Aphids are a vector of Ribonucleic Acid (RNA) grass pathogens and such viruses include barley and cereal yellow dwarf viruses. The severity of grassland diseases are dependent on the areas located. For instance, in California, United States of America (USA), the pathogen-mediated invasion in grasslands is the result of competition between native and exotic plants where aphids have higher fecundity on exotic plants compared to that of the natives [20]. This factor has potentially led to the increase in pathogens transmission rates throughout the community. The life cycle has then been studied closely to understand and in hopes to discover a point of interference which would break the reproduction rate.

A single host plant species is often observed to be utilised throughout the year. In response to the decreasing daylight, sexual morphs are produced in the fall. Genetically recombinant eggs that are reproduced by the male and his oviparae4 mate would overwinter on the host plant and often experience a high mortality rate. Fundatrix5 that emerges from the eggs in spring will proceed to reproduce to live births parthenogenetically. These nymphs would be viviparae6 and will continue the lifecycle in summer. The parthenogenetic mode of reproduction has ensured a rapid population build-up by ensuring that there are eggs available on the plant year round. The rapid increase in aphids population in a single host plant could quickly lead up to overcrowding. This would allow the future offspring of the aphids would be switched to those with wings to have efficient dispersal of feeding opportunity and ensures the genetic survival.

Aphids (49.4%) are transmitters for the majority of the mosaic virus and leafhoppers (6.7%) are transmitters for yellow-type viruses. There are many other insects of interest such as whiteflies (32.3%), thrips (4.0%), mealybugs, plant hoppers (4.5%), grasshoppers, scales and beetles.  They strive generally well in regions with cold winters. The use of their mouthparts include a needle-like stylet that assist aphids to have access and feed on the contents of plant cells. The insect's feeding habits will weaken the plant and cause metabolic imbalance. In addition, aphids secrete honeydew. This is an ideal medium for a variety of fungi to populate. As such, sunlight would be blocked out as the fungi populate, building a barrier for the plant to photosynthesize. During the process of feeding, their stylet has created a point of entry for the pathogens to enter the system of the plant host. The plant, if infected with secondary infection, would then be infected and display disease symptoms.

Aphids have been covered in a relatively large proportion in this chapter. This insect has eggs that are cold-hardy to survive winter. The efficacy to have population build-up is only possible when the temperature is optimum. Every species of aphids have different optimal temperatures. However, the minimum range is said to be at 4 degree Celsius. *Acrythosiphon pisum* is an aphid that reproduction is dependent on the temperature. The overall increase in global temperature by 2 degree Celsius would have an approximation of generations increased from 18 to 23 generations per year (based on a study in the United Kingdom). However, the generation time of a female differs between species and this could potentially be shorten by the decrease in temperature due to global warming. France has a mean temperature of 10 degree Celsius (in the north) and 15 degree Celsius (in the south)

4 Oviparity refers to female that produce eggs, not live young.

5 Fundatrix is a viviparous parthenogenetic winged or wingless female aphid produced on the primary host plant from an overwintering fertilised egg.

6 Viviparity meant that the female bringing forth live young which have developed inside the body of the parent.

which place the aphids in suboptimal temperature conditions. However, this is an alarming increase for entomologists to study aphids further. Apart from the temperature being favourable to the rate of reproduction. The temperature increase is also favouring the mobility of the aphids. The winged aphids have a threshold of 13 to 16 degree Celsius and an upper threshold of approximately 31 degree Celsius [18].

### **7.2 Soil dwelling organisms**

Apart from aphids that are attacking above ground, there are also vectors attacking below ground. Larvae of *Cerapteryx graminis*, a moth from the *Lepidoptera*, are soil-dwelling and the larvae can cause *Charaeas graminis* on grasses. Larvae of *Tholera decimalis* Poda (from *Lepidoptera*) are soil-dwelling and can cause disease to a plant by feeding on its roots. Other larvae that are soil-dwelling can cause large amounts of damage to the plant as the larvae mainly feed on the roots of the host plant and some adults may continue to dwell in the same plant causing more harm. Larvae feeding at the root system may invite secondary infection causing more complications. Nematodes and soil-dwelling borers are also a vector for infection in plants as they could create entry for bacteria to cause further complications to plant health.

These soil-dwelling organisms will be impacted by the decrease in moisture in soil (regions where desertification occurs). Increase in flooding will also be a concern to these organisms as they may not survive if the soil moisture increases too drastically. Their living conditions are also affected by the temperature. The adaptation to the changing climate is similar to that of other insects living aboveground.

### **7.3 Soil bacteria**

Bacteria can be transmitted naturally through exudation out of the host plant and when contact is made between injured plants, they can infect the plant through the wound site. Insects that come in contact with the exudates that infected host plants produce, they can also transmit to other plants as secondary infection. Insects are often attracted to the sugars in the bacterial exudates. During the process of consumption, the mouthparts of the insects will then carry the strains of bacteria. Upon travelling and feeding on other plant, they will create an entry for these bacteria they carry and the plant will now be infected.

Bacteria being microscopic organisms will be sensitive to the change in environment conditions. Depending on the types of bacteria, some may strive in the areas of higher temperature like the *Xanthomonas spp.* are at advantage but not for *Puccinia spp*. The virulence of the bacteria have been studied to have been affected by the change in temperature. *Agrobacterium* strains have their virulence gene amplified as temperature increases but they will have a loss of phosphorylation activity [21]. *Pseudomonas* have increased production of phytotoxins as there is an increase in temperature to maintain its virulence. Therefore, the change in climate will affect the physiological functions of the bacteria differently and ensure the continuum of bacteria in the environment. The effect of bacterial virulence of some effectors may become apparent under specific environment conditions such as humidity.

#### **7.4 Soil fungus**

Soil fungus has different roles in the soil which then serves different ecosystem services. They are also bioindicators of soil health. However, as mentioned earlier, crown rust is a genus of fungus (*Puccinia spp.*). Some of the *Puccinia spp.* are considered as parasites of plants. The presence of harmful plant pathogens indicates poor soil quality. The factors that cause changing soil fungal biodiversity are mainly due to the management practices, chemical fertilisation, application of herbicides and fungicides, biochemical amendments of the soil, soil degradation, soil contaminants and soil properties such as salinity and drought conditions.

Global warming can influence the host plant associations through alteration of interactions between plant and mycorrhizal fungi. This group of fungi have the role of having direct influence on individual plant function and the indirect impact processes such as plant dispersal and community interactions. However, to mediate and to survive, they have ways to mediate the current changes of climate. Such methods involve varying in hyphal exploration type liked to root density [5, 22]. Climate change does not seem all that bad when the essential fungus in the soil required are still able to survive.

The change in climate has created new environmental pressures that results in novel fungus diseases. The effect of climate change on the emergence and reemergence of fungal pathogens have raised concerns on food security, human and animal health, and wildlife extinction due to the report worldwide. There are new virulent fungal lineages with adaptations emerging and they have been suggested to have evolved alongside with the increased pressure of climate change. One such fungus is the *Puccinia striiformis*, commonly known as rust fungus (same genus to the current crown rust pathogen). Stripe rust has affected wheat crops worldwide. There were records that indicate the preference for cooler regions but has recently invaded to warmer regions. The ability to disperse to warmer regions has allowed the emergence of three novel strains. These strains have been described as being more aggressive with increased thermotolerant [23]. The spread of novel strains have been hypothesised for having the ability to replace older strains and expanding the spread of disease. Through microsatellite genotyping and virulence phenotyping on the novel strains, it has been demonstrated that the evolution can potentially be ongoing alongside with the change in climate.

Another fungal concern would be the emergence of *Fusarium* head blight in wheat and other cereal crops [14]. The infection can reduce crop yield and quality. Thus, threatening food security. Outbreaks have been reported specifically with years that experience warmer and humid weather. The economic loss during outbreaks could be up to 75 percent [4]. The shift in temperature due to climate change have allowed the fungi to be more aggressive and able to expand the spread of territory. The change of favourable weather has been observed in two species of the *Fusarium* genus. *Fusarium graminearum* and *Fusarium culmorum* are two of the species that display prominent change towards the shift in temperature over the regions. They have very contrasting weather preferences. Thus, these fungus can expand through larger areas that do not adapt. The increase in environmental stress due to the change in climate have also evidently shown some of the species to react by producing more mycotoxins. As such this has a rising concern not only to food security but also human and animal health.

Apart from the changes that the fungi have evolved to ensure the survival of its kind, the spread of spores have then been extensive through the rising disastrous events. Frequent flooding and strong winds causing dust storms are two such extensive transmission methods. Soil-borne fungal pathogens have been speculated to have increased frequency or range due to climate change [6]. They are found out of their normal range and at times can be challenging to have a first diagnosis [24].

### **8. Future perspective**

There might be results that the resistant plant type is achieving ideal suppression of damage done. However, all living things have the ability to change and adapt to

#### *Earth's Energy Budget Impact on Grassland Diseases DOI: http://dx.doi.org/10.5772/intechopen.99971*

the environment they live in. Plants that as antibiosis may achieve ideal results when planted in Region A. However, when planted in Region B and C, the result may vary. Assuming that the soil conditions in all three regions are the same. However, abiotic factors cannot be controlled and that may be the factor that causes the difference in results. Therefore, grassland management has to be very specific to a particular location and changes that occur through the years can be used to study closely to have a more effective management plan.

Disease in grassland have been affected by the Earth's energy imbalance due to the change in living environment and transmission mode. The change in climate have affected the population of the vectors. Having vectors in the environment is essential for transmission mode in the ecosystem. The reduced availability vectors in the population will ideally have a decreased in the extensiveness of the spread of disease. However, if the disease, in particular consideration to viroids, where to mutate, the mode of transmission could change to either, air-borne or even have a longer dormancy capability to ensure sustainability of its existence.

#### **8.1 Innovative management**

The different kinds of vectors will require different methods of surviving as the climate changes. The increase in certain greenhouse gases in the atmosphere makes it complex to understand the change that the vectors are going through. However, there are a few significant points that could be brought across in this chapter. Vectors such as insects have expanded their distribution to regions where it will be more habitable to them. This can be supported by the pink bollworm (*Pectinophora gossypiella*), an infamous cotton pest that has expanded towards the central of California and away from the South. Other vectors such as the Olive fly (*Bactrocera oleae*) have demonstrated migration behaviour. They would travel southwards during winter to experience summer in other areas. However, this would increase competition of insects for the availability of food for the population. This will potentially lead the insects to have a change in diet if available and adaptable.

Apart from migration behaviour, vectors that have remained have increased in overwintering survival. They will produce eggs that are more hardy to withstand the change in temperature and environmental damages. Insects have also adapted to migrate as mentioned earlier. Vectors that are freeze-tolerant have physiological adaptation to be diapause7 . They could be obligate or facultative. Regardless of which they are, the insects will be hormonally mediated to a state of having low metabolic activity. This will suppress development, suspend activities and increase resistance to adverse environmental factors change. Insects will also display aestivation or hibernation. The ability for the insect to synchronise with the changing environment will be the most ideal situation where the expansion and the spread of diseases are still highly plausible.

The change in ambient temperature have accelerated reproduction rates. This has caused an increase in population size. As such, it can lead to the number of species having dynamic equilibrium. To understand the phenological shifts caused by climate variability, it has been measured with growing degree days (GDD). The GDD will then aid in determining the minimum and maximum temperature threshold. Insects of multivoltine, such as aphids, are at the advantage of the rising temperature. Increase in 2 degree Celsius in temperature could have an estimate of additional five generations. Other insects demonstrated having earlier flight as the ambient temperature increases.

7 Diapause is an adaptive trait that plays an important function in the seasonal regulation of insect life cycles and is influenced by environmental factors.

The change in climate has also brought about the change in precipitation patterns. High rainfall will have insects such as aphids being washed off and will decrease the opportunity of the insect or pathogens overwintering. However, the insects can migrate further up the soil horizons or deep down. Soil-dwelling wireworms have adapted to the change in precipitation pattern by populating on the upper soil horizon and migrate as they grow as an adult.

#### **8.2 Potential limitations**

The cruciality of understanding vectors in plant diseases in relation to that of climate change is complex and underestimated. The importance of vectors' movement and traceability have yet to be identified clearly as they are showing signs of evolution with rapid reproduction rate. As such, plant diseases can be said to have spread as rapidly as the vectors expand their area of infection. Plant diseases cause secondary infections which are mainly facilitated by insects to allow entry to a pathogen by creating a wound site on the plant organ regardless of it being above or underground. Pathogens that are vectored by insects can also overcome survival to adverse environment factors through the maintenance of over-seasoning in the body of the insect.

There are different management methods innovated in order to suppress the damage incurred. Having a plant that is resistant to specific insects or pathogens is an innovative way or management. For example, antibiosis in host plant resistance is a primary mechanism that works against aphids [17]. The process occurs at the utilisation phase of the interaction between the plant and the insect. It is the result of action of plant-biochemicals in the biological processes of herbivorous insects. Antibiosis would then be expressed in terms of larval mortality, decreased larval and pupal weights, prolonged larval and pupal development, reduced fecundity, prolonged generation time and overall effect on insect survival and development.


CI 1.06–1.14) among lower-middle-income countries, and 1.03 (95% CI 0.96–1.14) among upper-middle-income countries.

**Figure 2.** *Cont*.

**Figure 2.** Latest situation of inequality in PAB coverage by World Bank income group (DHS/MICS, 2011–2020). (**a**) Wealth quintile; (**b**) maternal age; (**c**) maternal education; (**d**) place of residence.

The median difference between PAB coverage in children of mothers with secondary or higher education and mothers with no education was 11.6 percentage points (95% CI 8.4–15.7), and the ratio in coverage between these groups was 1.18 (95% CI 1.12–1.25). Differences in PAB coverage by maternal education were substantial across all country income groups. In low-income countries, the median difference between PAB coverage in children of mothers with secondary or higher education and mothers with no education was 15.6 percentage points (95% CI 4.3–25.2). Lower-middle-income countries had a gap of 13.1 percentage points (95% CI 10.0–25.9), while upper-middle-income countries had a gap of 7.3 percentage points (95% CI −3.3–9.5). The median ratio of coverage between the children of more and less educated mothers followed a similar pattern: 1.23 (95% CI 1.05–1.53) among low-income countries, 1.20 (95% CI 1.17–1.47) among lower-middle-income countries, and 1.11 (95% CI 0.96–1.15) among upper-middle-income countries.

The median difference between PAB coverage in urban areas compared to rural areas was 3.7 percentage points (95% CI 1.9–6.4), and the ratio in coverage between these groups was 1.05 (95% CI 1.03–1.10). In low-income countries, the median difference in coverage was 7.3 percentage points (95% CI 3.8–11.3). Lower-middle-income countries had a gap of 4.7 percentage points (95% CI 1.3–8.1), while upper-middle-income countries had a negligible gap of 0.2 percentage points (95% CI −1.7–2.9). The median ratio of coverage between the children in urban versus rural areas followed a similar pattern: 1.10 (95% CI 1.05–1.21) among low-income countries, 1.07 (95% CI 1.02–1.13) among lower-middle-income countries, and 1.00 (95% CI 0.94–1.05) among upper-middle-income countries.

We analyzed both simple and complex measures of inequality in PAB coverage for each of the four examined dimensions of inequality. As simple and complex measures demonstrated similar patterns of results, we focus on reporting the simple measures of inequality (difference and ratio) here. Complex measure findings can be found in Interactive Supplemental Table S1.

### *3.3. Change in Inequality in PAB Coverage over Time*

We focus our change over time results on inequalities in household wealth; findings for other dimensions of inequality are available in Interactive Supplemental Table S2). The change over time analyses included 41 countries with data in both the periods 2001–2010 and 2011–2020.

Examining annual absolute change in national average PAB coverage (see Figure 3, x-axis; Interactive Supplemental Table S2), we find almost no annual change (median −0.04 percentage points, 95% CI −0.35–0.76) in overall PAB coverage across the examined countries from earlier (2001–2010) to more recent (2011–2020) time frames. There is substantial variation by country, however, ranging from an annual decrease in coverage of 2.0 percentage points in Suriname to an annual increase of 2.6 percentage points in Afghanistan. Twelve countries saw annual improvements in coverage of 1 percentage point or more (suggesting at least a 10-percentage point improvement in coverage over the examined 10-year time period), while three countries saw annual decreases in coverage of at least 1 percentage point (suggesting at least a 10-percentage point decrease in coverage over the examined time period). Of note, no countries with 80% or higher coverage at the earlier time period (*n* = 8) saw any improvements in national coverage.

Examining annual absolute excess change in the poorest compared to the richest wealth quintiles (Figure 3, y-axis; Interactive Supplemental Table S2), we find an annual excess change median value of 0.26 percentage points (95% CI 0.05–0.41), indicating slightly more favorable change over time for the poorest quintile over the examined time period. This measure also demonstrated heterogeneity by country, ranging from 2.4 percentage points annual excess change in Liberia to −1.9 percentage points annual excess change in Zambia. Ten countries had excess annual change of 1 percentage point or more (equivalent to 10 percentage points or more over the examined time period, favoring the poorest quintile), while six countries had excess annual change of −1 percentage point or less (equivalent to 10 percentage points or more over the examined time period, favoring the richest quintile).

Six of the examined countries had a substantial increase in national average of 15 percentage points over the 10-year time period (annual change of 1.5 percentage points increase or more)—Afghanistan, Cambodia, Namibia, Nepal, Senegal, and Togo. All six countries also had positive annual absolute excess change, indicating faster improvement among the poorest than the richest. Afghanistan and Cambodia saw the largest statistically significant annual excess change, equivalent to 23 percentage points excess improvement for the poorest relative to the richest in Afghanistan, and 13 percentage points excess improvement for the poorest relative to the richest in Cambodia over the examined 10-year time

period. The Gambia, Lesotho, Liberia, and Nigeria also indicated statistically significant excess change in favor of the poorest quintile, all four with excess change of 15 percentage points or more over the 10-year time period. Only three countries—the Democratic Republic of the Congo, Egypt, and Zambia—saw statistically significant excess change in favor of the richest quintile of 15 percentage points or more over the 10-year time period; all three countries saw decreases in their average national coverage over the same time period.

**Figure 3.** Change in national average and wealth-related inequality in PAB coverage (DHS/MICS, 2001–2010 and 2011–2020).

Examining the subset of 15 countries with data from the two most recent years of available data (2019–2020), we see substantial heterogeneity in change over time for coverage level and inequality by wealth quintile (see Figure 4). For example, Senegal had significant improvement in coverage levels for all wealth quintiles, but almost no changes in absolute inequality across levels of wealth. In contrast, Liberia had a negligible change in the national average coverage, but substantial reductions in inequality. Thus, while cross-national medians suggest little change for either coverage or inequality of PAB from 2001–2020, specific country patterns demonstrate meaningful changes over the time period.

**Figure 4.** Change in inequality in PAB coverage (DHS/MICS, 2001–2010 and 2011–2020), countries with latest survey in 2019 or later.

### *3.4. PAB Coverage in Countries by MNTE Achievement Status*

This study includes data from 10 of the 12 countries who have not achieved MNTE as of 2020: Afghanistan, Angola, Central African Republic, Guinea, Mali, Nigeria, Pakistan, Papua New Guinea, Sudan, and Yemen (Somalia and South Sudan have not met MNTE but did not have available data) [5]. All 10 countries demonstrated statistically significant inequality in PAB coverage across maternal education; nine had significant inequality in PAB across household wealth, nine had significant inequality in PAB across place of residence, and four had significant inequality in PAB across maternal age. Of the five countries for which we had data to examine change over time, three (Afghanistan, Nigeria, and Pakistan) demonstrated significant improvements in national average coverage over the examined time period, while two (Central African Republic and Mali) had stagnant coverage. Of these five, only Afghanistan and Nigeria had statistically significant excess change over time across any of the examined dimensions, indicating decreased inequality in PAB coverage by wealth in Afghanistan, and decreased inequality for all dimensions in Nigeria.

As a post hoc analysis, we also examined median inequality measures by MNTE achievement status (see Table 2, Supplemental Figure S1). We find that there is substantially larger inequality (as measured by difference and ratio) in household wealth, maternal education, and place of residence among countries which have not achieved MNTE compared to those which have achieved MNTE; no meaningful difference in inequality by MNTE status is observed for maternal age.

**Table1.**MediandifferenceandratioinPABcoverageacrossfourdimensionsofinequality,overallandbyWorldBankincomegroup(DHS/MICS,2011–2020).

**Table 2.** Median difference and ratio in PAB coverage across four dimensions of inequality, overall and by MNTE status (DHS/MICS,

 2011–2020).

#### **4. Discussion**

Findings from this study of 76 countries suggest that there is substantial inequality in maternal tetanus immunization coverage globally. In particular, we find substantial inequality in tetanus protection at birth coverage by household wealth quintile, maternal age, maternal education, and place of residence. Though previous studies have demonstrated inequalities in coverage in one or more of these inequality dimensions in single-country or single-continent contexts, this is the first study to examine inequalities in PAB coverage across all four of these dimensions utilizing a large, global sample of low-, lower-middle, and upper-middle income countries. As the burden of MNT is highest in the most vulnerable populations (including those with lower wealth, younger maternal age, lower maternal education, and rural residence) [1], the lower immunization coverage we observe in these groups is particularly concerning.

We find that greater maternal education and urban (compared to rural) residence are associated with greater PAB coverage, overall and for each country income grouping. This is consistent with prior research of other childhood vaccines, and with priority focus areas of major immunization initiatives, which include reducing gender-related barriers to immunization (such as maternal education) and reaching remote rural populations [12,27,38–42].

Older maternal age and higher household wealth are also associated with greater PAB coverage overall and for low- and lower-middle-income countries, similarly consistent with prior research and immunization targets. However, the upper-middle-income country group demonstrated approximately equitable coverage by maternal age and wealth. As MNTE has been achieved in all examined upper-middle-income countries, many for more than 20 years, tetanus toxoid vaccination efforts likely differ from those in low- or lowermiddle-income countries, possibly resulting in alternate patterns of coverage [43].

With regard to age, upper-middle-income countries generally have higher and more equitable childhood vaccination coverage and have for the past several decades [7] meaning more young mothers received the basic three doses of DTP vaccines and additional TTCV doses in childhood and adolescence, resulting in complete PAB coverage by the time of childbirth. We similarly expect inequalities in PAB coverage by maternal age to continue to narrow over time as childhood DTP3 and additional TTCV dose coverage increases. With regards to wealth, the fact that the lowest wealth quintile had the highest coverage was unexpected. Similarly, the observation of lower overall median PAB coverage across uppermiddle-income countries (65%) compared to low- and lower-middle income countries (both 71%) was counter to hypothesized patterns based on other childhood vaccine coverages. These findings provide further evidence of differences in tetanus immunization strategies across country income groupings. This includes substantial supplementary immunization activities (SIAs) or campaigns in countries with the highest burden of maternal and neonatal tetanus, which are largely low- and lower-middle-income countries, and relatively few such activities in upper-middle-income settings [44]. Additionally, as MNTE has been achieved in all upper-middle-income countries analyzed, the disease is often no longer considered a priority public health issue, and immunization may be considered less necessary as there is near universal access to clean birth environments and adequate umbilical cord management practices [43]. Nonetheless, the findings regarding equitable PAB coverage by wealth within upper-middle-income countries, and relatively lower PAB coverage overall in these settings, warrant further exploration within country-specific contexts.

Differential patterns of PAB coverage across dimensions of inequality and country income grouping highlight the importance of examining multiple dimensions of inequality. However, this study examines only four potential factors which may influence PAB coverage. Additional factors, such as conflict-affected areas and intensity [24,45], or subpopulations defined by double disaggregation, such as urban poor [46,47], have been shown to be associated with lower PAB coverage. Future work using multi-country samples should examine these and other potentially related factors to better understand determinants of coverage levels and inequalities, and consider multivariate analyses to understand the relative importance of co-existing factors. For analyses of smaller geographic scope, examining factors which are as relevant and as specific to the context as possible will best enable targeted efforts to improve TTCV coverage and eliminate MNT [5].

Despite large strides in MNTE efforts over the examined time period, and success in achieving MNTE in 47 of 59 countries with MNT as of 2020, there has been little change in maternal tetanus immunization levels and inequalities over the study time period on aggregate. However, this hides significant heterogeneity in coverage levels and inequality across countries. We see significant improvements in PAB coverage of 15 percentage points or more over 10 years for six countries, all of which also demonstrated reductions in wealthrelated inequality in PAB coverage over the same time period. Though we cannot determine the direction of this relationship in current analyses, efforts to improve coverage should simultaneously be oriented towards reducing inequality. Importantly, we see evidence of inequalities in PAB coverage for all ten examined countries which have not achieved MNTE, and only see improvements in coverage and inequality for two of these target countries. We also observe substantially greater inequalities in PAB coverage among countries which have not achieved MNTE compared to countries which have been successful in achieving MNTE for three of the four examined dimensions (wealth, maternal education, and place of residence) in the most recent data. Reductions in these inequalities in coverage will be crucial to achieve MNTE.

Efforts to improve PAB coverage and equity should thus remain a key aim of MNTE initiatives, including quality targeted supplementary immunization activities, increases in uptake by LMICs of TTCV booster doses along the life-course, improved antenatal care visit access and TTCV administration during antenatal care, and increased institutional deliveries and clean delivery practices [48–51]. Additionally, persistent inequalities in PAB coverage in those countries which have achieved MNTE suggest the need for ongoing efforts to ensure MNTE sustainability, such as periodic neonatal tetanus risk analyses and corrective measures to close immunity gaps [43]. Assessments of inequality such as this one may help inform the groups to be targeted in these MNTE sustainability efforts. Global initiatives, such as the Immunization Agenda 2030 (IA2030), also present opportunities to catalyze action to address inequalities in PAB [27]. Positioning maternal and neonatal tetanus as a tracer of inequality in health care provision will enable more visibility and enhanced resource mobilization for the global initiative to eliminate MNT.

This study relies largely on maternal vaccination self-report, which is subject to recall bias, particularly as childhood doses may have been received 20+ years prior [52]. No recent review has explored the reliability of recall for immunization coverage, but prior research suggests that it can be problematic for childhood vaccines [53]. In particular, older women and women with more children may be more susceptible to underreport prior doses, and maternal recall likely underestimates TTCV coverage generally [54]. However, TTCV immunization protocols indicate that women who do not remember if they received a dose—or who report that they have not received a dose—should be immunized; thus, successful TTCV immunization efforts should negate this bias. Increasing use of home-based records and digitalized personal health records will likely also lead to decreased recall bias, reduction in unnecessary doses, and improved coverage over time [55]. The complex nature of PAB definition requires surveyors to correctly and comprehensively collect information about past tetanus immunization, leading to potential underreporting of coverage if information is only partially collected. We do not have reason to think that such bias would differ by the dimensions of inequality examined, however. In particular, women with multiple prior pregnancies may have underreporting or inaccurate reporting of prior doses; limiting these analyses to first births only would help mitigate this potential bias. Though such analyses were outside of the scope of this manuscript, future work should consider examination of first births (single parity mothers) only. Despite limiting analyses to the most recent data available, we include surveys from 2011 to 2020, and the current situation in a country may have changed substantially in the time since. This is particularly a concern in light of the COVID-19 pandemic, which interrupted immunization efforts and healthcare access in many places. Conclusions from these analyses about specific country situations

should therefore be interpreted with caution. Finally, the nature of this cross-sectional, aggregate analysis does not allow for conclusions about the relative importance of the examined dimension of inequality, a causal relationship between inequality and coverage levels, subnational inequalities in coverage, the relative contributions of immunization prior to versus during the most recent pregnancy, nor the most effective potential solutions for improving coverage and reducing inequalities. All of these areas would benefit from examination in future research.

Despite these limitations, findings from this work can be used to inform future research, policy, and clinical practice and to benchmark progress. The occurrence of maternal and neonatal tetanus is a marker of inequities as this disease affects the most vulnerable populations, thus, MNTE efforts should continue considering equity a priority to ensure sustained results. This includes regular data collection of PAB coverage along with sociodemographic data to be able to regularly perform disaggregated data monitoring and analysis. Findings from this routine monitoring then can and should be used to inform subpopulations which can be the targets of interventions to improve coverage including SIAs, additional ANC-based screening and vaccination opportunities, improved immunization documentation efforts, and tetanus awareness and education activities. These analyses also provide an initial set of potential priority groups (the lowest wealth quintile, lower maternal education, and rural populations) for vaccinations efforts, and provide a potential framework for identifying additional subpopulations of interest.


**1. Introduction**

Sporadic cerebral amyloid angiopathy (CAA) is characterized by the progressive deposition of amyloid-β (Aβ) protein in the walls of small- to medium-sized arteries, arterioles, and capillaries in the cerebral cortex and overlying leptomeninges [1,2]. CAA is a common age-related cerebral small vessel disease (SVD) in the elderly [2,3] (especially those with Alzheimer's disease [4]), but it is most often recognized clinically by symptomatic intracerebral hemorrhage (ICH) restricted to the lobar areas of the brain [5,6]. Long-term antiplatelet therapy, which is widely used for the secondary prevention of cerebral infarction, myocardial infarction, and peripheral artery diseases, could increase the incidence of ICH. In consideration of the high incidence of cerebral bleeding in patients with

CAA and/or Alzheimer's disease, especially in antiplatelet drug users [7,8], the safety of antiplatelet therapies for those patients should be explored.

Cyclic nucleotide phosphodiesterases (PDEs) play critical roles in regulating intracellular cyclic nucleotides (cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate), which are important secondary messengers involved in intracellular signal transduction in all tissues. PDE III is the major cAMP-hydrolyzing PDE (a negative regulator of cAMP) uniquely expressed in vascular smooth muscle cells. A selective inhibitor of PDE III, cilostazol, has multiple effects on the vasculature including vasodilatation, antioxidation, anti-inflammation, the regulation of smooth muscle cell, and an increase in cerebral hemodynamics, pulse duration time, and arterial elasticity with the maintenance of microvascular integrity [9]. Cilostazol is known as a unique antiplatelet drug, which is superior to aspirin in terms of safety for reducing ICH after an ischemic stroke [10]. Cilostazol ameliorates collagenase-induced cerebral hemorrhage by protecting the blood–brain barrier in mice [11]. In a CAA mice model (Tg-SwDI mice), cilostazol improved cognitive performance, which may be associated with reduced Aβ deposition by cilostazol (0.3% cilostazol) [12]. However, it is unknown whether the safety and efficacy of cilostazol could be replicated in different settings (i.e., drug dose or experimental transgenic mice). Thus, we sought to determine whether lower-dose cilostazol could reduce the incidence of cerebral (micro-)hemorrhages or cerebrovascular Aβ depositions using different transgenic mice as a CAA model.

#### **2. Results**

#### *2.1. Survival Rate, Feed Consumption, and Drug Intake*

Sixty Tg2576 mice aged 3 months initially received the vehicle, but 10 mice died due to unknown reasons before 14 months. Thus, 50 mice aged 14 months were divided into three groups: control group (*n* = 14), aspirin group (*n* = 18), and cilostazol group (*n* = 18) (Figure 1). Within a month after the grouping, two mice died due to unknown reasons (control group, *n* = 1; cilostazol group, *n* = 1). Of the 48 survivors aged 15 months, 14 mice (control group, *n* = 4; aspirin group, *n* = 5; cilostazol group, *n* = 5) were randomly selected for the first evaluation (i.e., the first specimen). Among the remaining mice (*n*= 34), four mice died due to unknown reasons (control group, *n* = 1; cilostazol group, *n* = 3). Finally, 30 surviving Tg2576 mice aged 21–23 months were evaluated as the second specimens. There was no significant difference in the survival rate after the grouping among the three groups when the 14 mice evaluated for the first specimen were excluded from the analyses (*p* = 0.109, log-rank test: Figure A1: please see appendix). Even in the two group comparisons, no differences were seen in the survival rate between the control group and the aspirin or cilostazol group (*p* = 0.098 and *p* = 0.550, log-rank test). Table 1 shows estimated individual food consumption and drug intake (per mouse) of the three groups. There was no significant difference in food consumption between the control group (mean, standard deviation [SD]: 3.57 ± 0.40 g/day) and the aspirin group (3.67 ± 0.47 g/day) or the cilostazol group (3.67 ± 0.44 g/day) (*p* = 0.289 and *p* = 0.543, Mann–Whitney *U* test). Individual daily drug intake in the aspirin group (14.7 ± 1.9 mg/kg/day) was similar to that in the cilostazol group (14.7 ± 1.8 mg/kg/day).

**Figure 1.** The flow diagram of study schedule and grouping.

a *p* = 0.289 vs. control; b *p* = 0.324 vs. control (Mann–Whitney *U* test); NA = not applicable; SD = standard deviation.

#### *2.2. Confirmation of Age-Related Cerebrovascular Amyloid Burden and Smooth Muscle Cell Loss*

Confocal microscopic observation of double-immunolabeled vessels in different Tg2576 mice (15 months old, and 23 months old) fed with standard pelleted chow (i.e., control group) confirmed the age-related progression of amyloid burden and loss of smooth muscle cells (Figure 2a–d). The findings of the negative controls for Aβ show only a faint background stain in the vessel walls (Figure 2e–h).

**Figure 2.** Upper line (**a**–**d**): Serial confocal microscopic changes of double-immunolabeled vessels (green, smooth muscle actin; red, amyloid). Lower line (**e**–**h**): Confocal microscopic findings represent negative controls without primary antibody for Aβ. a, b, Leptomeningeal vessel in a 15-month-old mouse shows small amyloid deposition and focal loss of smooth muscle cells at the site of cerebrovascular amyloid; c, d, In a 23-month-old mouse, smooth muscle cells are lost, and a thick sheet of amyloid covers the wall of a leptomeningeal vessel. e–f, Photos of the negative controls for Aβ (each section adjacent to a, b, c, d, respectively) show only a faint background stain in the vessel walls. Scale bar: 50 μm.


**2.1 Soil erosion definition**

"The dirt on top of a field is naturally eroded by forces such as wind and water. This occurrence is known as soil erosion" [16]. It leads to a constant loss of topsoil, ecological deterioration, soil collapse, etc. Soil erosion is a continuous process that can occur either slowly or quickly. Soil erosion (**Figure 1**) is caused by the loosening or washing away of dirt particles in ravines, seas, waterways, or distant lands [9].


**1.2 The mechanism of action of contraceptive implants**

The progestin-containing implantable contraceptives inhibit ovulation and restrict sperm penetration through sticky cervical mucus. This is done as a result of the antiestrogenic actions of the progestins, which affect the cervical mucus by making it sticky or glutinous, scanty, and impassable to sperm therefore preventing or hindering fertilisation of the ovum. High doses of progestins also prevent gonadotropin secretion, thereby halting the maturation of the follicles and ovulation. This double effect allows the efficacy and effectiveness of implantable contraceptives to be maintained though ovulation is not consistently altered in etonorgestrel implantable contraceptive users towards the end of the 3-year period of use. Oocytes are not fertilised even if the follicles grow while using progestin implantable contraceptives. Even if the follicle ruptures, the abnormalities of the ovulatory cycle or phases prevent the release of a viable ovum or egg. Although progestin suppresses endometrial activity, this is often not a contraceptively significant effect since the most mechanisms of action prevent fertilisation. There has never been any signs of embryonic development found among contraceptive implant users, showing that progestin implants are not medication or substances that cause pregnancy to terminate prematurely. Implants are simpler, easier and safer to use than other contraceptive methods because they do not require regular action by the user [8].


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imaging. *Clin Cancer Res.* 14: 7497-7503

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27(9):974-978.

48(10), 1614–1619.

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detected by magnetic resonance imaging: improvement of clinical target volume

does magnetic resonance imaging influence staging according to AJCC staging system for nasopharyngeal carcinoma compared with computed tomography? *Int J*

PET/CT in diagnosis and staging of nasopharyngeal carcinoma. *Ai Zheng*.

primary M staging of nonkeratinizing nasopharyngeal carcinoma. *J. Nucl. Med*.

for nasopharyngeal carcinoma and proposed improvement. *Int. J. Radiat. Oncol.*

local residual or recurrent nasopharyngeal carcinoma, which one is best? A

retropharyngeal lymph node metastasis in nasopharyngeal carcinoma: patterns of

(2008). The N staging system in nasopharyngeal carcinoma with radiation therapy oncology group guidelines for lymph node levels based on magnetic resonance

nasopharyngeal carcinoma and proposed improvement based on magnetic

Comprehensive imaging of residual/recurrent nasopharyngeal carcinoma using whole-body MRI at 3 T compared with FDG-PET-CT. *Eur Radiol*. 20:2229-2240. Ng S, Chan S, Yen T, Chang JT, Liao C, Ko S, Liu F, Chin S, Fan K, Hsu C (2009). Staging of

untreated nasopharyngeal carcinoma with PET/CT: comparison with conventional

metastases of nasopharyngeal carcinoma: patterns of disease on MRI and FDG PET.

Yousem DM, Som PM, Hackney DB, Schwaibold F, Hendrix RA (1992). Central nodal necrosis and extracapsular spread in cervical lymph nodes: MR imaging versus CT. *Radiology*. 182:753-759.

**7**

*China*

**MRI-Detected Cranial Nerve Involvement**

The incidence of cranial nerve (CN) palsy is not uncommon in patients with untreated nasopharyngeal cancer (NPC). In the 7th edition of the American Joint Committee on Cancer (AJCC) Staging Manual, the AJCC recommended that CN involvement be assessed by neurological evaluation rather than by cross-sectional imaging (computed tomography [CT] and magnetic resonance imaging [MRI]), because CN involvement is considered a poor

However, evaluation of CN palsy by clinical symptoms and physical examination has limitations. First, the accuracy of the neurological examination depends on the expertise of the examiner and the subjective report of the patient. Second, because CN involvement may be asymptomatic, it is difficult to diagnose CN palsy at an early stage by clinical neurological evaluation. In addition, neurological evaluation is not an optimal diagnostic method for assessing lesion localization and extension, which are critical factors in planning

With the excellent soft tissue contrast resolution and multiplanar imaging capability of MRI, direct visualization of smaller nerves and nerve branches is possible, making MRI a valuable tool in detecting and defining the extent of CN involvement in NPC. The difference and relationship between MRI findings of CN involvement and the symptoms and signs of CN

The goal of this study was to detect the difference and relationship between MRI findings suggestive of CN involvement and the symptoms and signs of CN dysfunction, and to evaluate the prognostic value of MRI-detected CN involvement in a large sample of consecutive patients. These information may contribute to understanding the patterns of spread and biological nature of NPC, and may also prove references in tumor staging and

**Patients:** From January 2003 to December 2004, 924 consecutive patients with newly diagnosed untreated NPC were included in our study. There were 685 male patients and 239 female patients, with a male-female ratio of 2.9:1, and the median age was 45 years (range, 11-78 years). All patients had a pretreatment evaluation that consisted of a

prognostic indicator in NPC patients, those with CN involvement are staged as T4.

treatment, particularly in delineation of target volume.

dysfunction have not been fully addressed.

treatment planning.

**2. Patients and methods**

**1. Introduction**

**in Nasopharyngeal Carcinoma**

Li Li, Wenxin Yuan, Lizhi Liu and Chunyan Cui

*Cancer Center, Sun Yat-Sen University*


*2.4.1. Domain*

**2. Occupational therapy**

4 Occupational Therapy - Therapeutic and Creative Use of Activity

**2.2. Occupational therapy**

to one's own health and well-being [3].

through engagement in occupation(s) [1].

**2.3. Occupation**

Occupational therapists are part of the rehabilitation team for persons with injury, illness,

Occupational therapy has been described as the art and science of helping people do the dayto-day activities that are important and meaningful to their health and well-being through engagement in valued occupations [1]. Occupational therapy draws on the centrality of occupations to daily life. It is concerned with helping clients engage in all the activities that occupy their time, enable them to construct identity through doing, and provide meaning throughout their lives [2]. As a part of the therapy provided, the client, group or population is expected to engage in meaningful occupation(s). Occupational engagement is the capacity to contribute

Ultimately, OT professionals (occupational therapists and occupational therapy assistants) help people of all ages participate in the things they want and need to do through the therapeutic use of everyday activities (occupations). Unlike other professions, occupational therapy helps people function in all of their environments (e.g., home, work, school, community, virtual) and addresses the physical, psychological, and cognitive aspects of their well-being

In exploring occupational therapy (OT) and its role in the treatment of individuals with an ASD, time must be spent defining the term occupation. Historically, the term *occupation* was defined as the way in which people use or occupy their time [4]. Yerxa, one of the founders of occupational science, more recently defined occupation as the "specific chunks of activity within an ongoing stream of behavior which are named in the lexicon of the culture…. These daily pursuits are self-initiated, goal directed (purposeful) and socially sanctioned" ([5], p. 5). Other occupational therapy scholars have described occupation as everything people do to occupy themselves, including looking after themselves (self-care), enjoying life (leisure) and

contributing to the social and economic fabric of their communities (productivity) [6].

Occupations occur throughout the lifespan, in context, and are influenced by the interplay among client factors (capacities characteristics and beliefs of the person), performance skills (goal directed actions), and performance patterns (habits, routines, and roles). Occupations occur over time; have purpose, meaning, and perceived utility to the individual; and can be observed by others (e.g. writing one's name) or known only to the person involved (e.g. morning grooming routine). Occupations can involve the execution of multiple activities for completion and result in various outcomes. The broad range of occupations are categorized by the American Occupational Therapy Association (AOTA) into activities of daily living

and/or disability. The primary goal of OT is to promote functional independence.

**2.1. Introduction**

The domain of occupational therapy practice is heavily influenced by AOTA's Occupational Therapy Practice Framework [1] and the World Health Organization's International Classification of Functioning [8]. The domain of occupational therapy includes the areas of occupation: activities of daily living, instrumental activities of daily living, rest and sleep, education, work, play, leisure, and social participation. The domain also encompasses aspects of functioning that impact occupational performance. According to AOTA, these aspects include performance skills (motor skills, process skills, and social interaction skills), performance patterns (habits, routines, rituals, and roles) and context/environment (cultural, personal, physical, social, temporal, and virtual) [1].

### *2.4.2. Process*

The occupational therapy process involves the actions and reasoning of practitioners which are used to provide services that focus on the client's participation and performance in daily occupations. The occupational therapy process is designed to be holistic in nature capturing the client as the individual, his or her family, and other supports, while at the same time taking into consideration the individual's interaction with the physical, social and attitudinal contexts of function [1]. The process may be direct 1:1, group, and/or consultative in delivery, with the aim to create opportunities for optimal health, well-being, and lifelong engagement in occupations [1].

The evaluation aspect of the process includes gathering, interpreting and synthesizing information that is relevant to the client's past and current engagement and performance in meaningful occupations (ADLs, IADLs, play, etc.), in addition to his or her desired goals and priorities for the short and long term future [1]. Furthermore, the evaluating therapist assesses the barriers and supports that impact the client's health, well-being, and participation.


*2.2.3 Ethanol yield results analysis*

**Table 7** shows the statistical treatment of the ethanol yield from the experimental tests performed.

#### **Figure 5.**

*AR consumption, biomass, and ethanol concentrations during the alcoholic fermentation process of test 8.*

#### **Table 5.**

*Statistical treatment of AR consumption of the 12 experimental tests carried out at different temperatures, pH, and DAP concentrations.*

In **Table 7** of inter-subject effects, a significant value of 0.000 ˂ 0.05 is observed. Therefore, Ha is accepted. This value indicates that there is a significant difference between the groups (Test and time).

In **Figure 8** of estimated marginal means, it is shown that trial 8 has the highest yield of ethanol.

#### **2.3 Discussion**

About 20 or more species of maguey are found in all the states of the Republic of Mexico, except in Tabasco and the Yucatan peninsula. A large part of the harvested

*Evaluation of Ethanol Production Process by the Fermentation of Blue Cabuya Juice… DOI: http://dx.doi.org/10.5772/intechopen.111855*

**Figure 6.** *Estimated marginal means from the 12 experimental tests performed on the consumption of reducing sugars.*

#### **Table 6.**

*Statistical treatment of the biomass yield of the 12 experimental tests carried out at different conditions of temperature, pH, and DAP concentration.*

area corresponds to the species of the Americana group, mostly used to produce alcoholic beverages, mainly tequila, which has a denomination of origin [24].

Among the few varieties of cabuya existing in Peru, only two grow in large areas of rural land: the blue cabuya (*Agave americana L*.), which is distinguished by the bluish-green color of its leaves, and the other variety is the lineño (green cabuya), which belongs to the *A. angustifolia* Haw complex that is generally used in rural areas for the manufacturing of ropes, while in Mexico it is used to produce a distilled beverage that belongs to the mezcal family [25].

**Figure 7.** *Estimated marginal means from the 12 experimental tests performed on biomass yield.*

#### **Table 7.**

*Statistical treatment of the ethanol yield from the 12 experimental tests performed at different temperatures, pH, and DAP concentration.*

Even though blue cabuya grows wild in large tracts of land in the inter-Andean valleys of Peru with temperate climates (Cajamarca and Huánuco Regions), this resource is not used. In the southern regions of the country such as Huancavelica, Ayacucho, and Apurímac, blue cabuya is used for the artisanal production of chancaca (a solid sugar concentrate) and the sale of the juice as a drink. While in Mexico, some 120,000 hectares of blue agave [26] are intensively cultivated with an average of 2500 to 2800 plants per hectare. In 2018, according to the Tequila Regulatory Council (CRT), 1,138,800 tons of tequilana cabuya were used to produce 309.1 million liters of tequila at 40% alcohol volume.

*Evaluation of Ethanol Production Process by the Fermentation of Blue Cabuya Juice… DOI: http://dx.doi.org/10.5772/intechopen.111855*

**Figure 8.** *Estimated marginal means from the 12 experimental tests performed on ethanol yield.*

Due to climatic differences, land composition, and geographical location in which the blue cabuya grows in Peru; its physicochemical, physiological, metabolic, and morphological properties differ from the Mexican plants. One of the main differences is the maturation time of the plant. In our country, it takes 5 to 10 years but matures in less time in the inter-Andean valleys with temperate and rainy climates, which are between 1500 to 2200 meters above sea level. In Mexico, the plant matures in an average of 8 years [27]. Therefore, this shorter maturation time is an advantage for agro-industrial exploitation in Peru.

In Mexico, the cabuya tequilana is exploited on a large scale. Therefore, the pineapple plant is generally treated in ovens for the hydrolysis of the polysaccharides present in the juice [28]. Then, add water for the extraction of the juice in the milling at the ratio of 1 to 2.5 L per kg of pineapple pulp to obtain about 120 L of juice per pineapple. However, obtaining blue cabuya juice in Peru is done by hand. The juice is extracted about three times a day in an average of 3 L for each collection for two to three months depending on the plant size. Thus, an average of 270 L of juice is collected per month per plant. This constitutes an advantage for its exploitation on a small scale to produce the liquor-type tequila.

The industries that produce alcoholic beverages are based on the fact that, under proper fermentation conditions, sugar is transformed into alcohol. The organoleptic characteristic of the finished product depends on the raw material that provides the sugar and the conditions for transforming the sugar into alcohol. In the investigation, the factors that affect the alcoholic fermentation process of the blue cabuya juice were examined to obtain the highest ethanol yield, which was: substrate concentration of 60 g/L; temperature 24, 28, and 32 C; pH 3.5 and 4.5; and DAP nutrient concentration 1 and 2 g/L, during 26 h of the process, with an air supply with a flow of 1 vvm, during the first 8 h of the process, these results being very satisfactory. and they agree with the results obtained by other researchers who have worked in similar conditions but with different substrates.

The must was inoculated with *saccharomyces cerevisiae* yeast strains, genus D 47–Lalvin, at a concentration of 1,15 g/L (4,3 x 107 cells/mL). This genus of yeast was used for its property of fermenting white and red musts, in addition to having a good performance at low and high fermentation temperatures, which has been demonstrated with the statistical analysis, see **Figure 8** of estimated marginal means that shows that trial 8 has the highest yield of ethanol.

From the experimental results obtained, 12 tests, it is observed that test 8 is the one that gave the highest yield of biomass Y(x/s) = 0.1606 and ethanol Y(p/s) = 0.4739 at the conditions of substrate concentration, AR of 60 g/L; temperature 28 C; pH 3.5; and nutrient concentration DAP 2 g/L. The ethanol yield obtained represents approximately 93% of the theoretical maximum yield of alcoholic fermentation, which is 51.0% [29].


**3. Molecular regulations in prostate cancer**

The inappropriate expression of the growth inhibitory factors appears to contribute to prostate cancer progression. Epidermal growth factor (EGF) promotes chemo-migration of metastatic prostate cancer cells to lymph node and medullary bone sites [18]. In insulin signaling pathway, the ligand insulin binds to its receptor followed by tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase. Several studies suggested that alteration in the IGF signaling axis is associated with an increased risk of prostate cancer [19]. Signal transduction proteins interact with IRS including GRB2. GRB2 is a part of the cascade including SOS, RAS, RAF, and MEK that leads to activation of MAPK and mitogenic response in the form of gene transcription.

In AKT signaling pathway, PTEN is a regulator which is down regulated to protect the cell from tumor growth. The phosphatase activity on phosphatidylinositol 3,4,5-triphosphate allows dephosphorylation of PIP3 to PIP2. The PIP2 inhibits the P13K which is the membrane bound domain. When the phosphatase activity is lost, P13K transfers its phosphate group to PDK1 and PDK2 which in turn causes phosphorylation of AKT protein and regulatory amino acids Ser473 and Thr308. This leads to activation of MDM2, P21, CASP9, mTOR genes leading to apoptosis inhibition, tumor growth, etc. Smad3 gene plays a key role in prostate cancer serving as an essential mediator of most Smad-dependent TGF-beta responses, including control of gene expression, cell growth, apoptosis, and tumor suppression. Deregulated/ enhanced expression and activation of AR in prostate carcinomas may intercept the tumor suppressor function of TGF-β through transcriptional suppression of Smad3.

*Male Reproductive Health*

tufting, micropapillary, cribriform, and flat [5].

istered based on the stage of cancer progression.

**2. Androgen-dependent and androgen-independent prostate cancer**

receptor (AR), a nuclear transcription factor that controls expression of genes

involved in growth, differentiation, homeostatsis, and apoptosis. Receptor for steroid and thyroid hormones are mostly cytoplasmic/nuclear receptors and hormonereceptor complex binding to the promoter regions of responsive genes and stimulate or inhibit transcription from those genes. Nuclear receptors are ligand-inducible transcription factors that mediate the signals of a broad variety of fat-soluble hormones, including the steroid and vitamin D3 hormones, thyroid hormones retinoids.

Human prostate is a walnut shaped, fibromuscular organ located beneath the urinary bladder and is made-up of several glandular and non-glandular components that are tightly fused together within a common capsule [9]. It is an exocrine gland functioning in secretion of complex proteolytic solution into the urethra during ejaculation which is important for sperm motility and nourishment. The growth and function of the prostate are regulated by androgens. The growth and development of normal prostate requires functioning androgen signaling pathway, which is regulated by hypothalamic-pituitary gonadal axis. Androgens (includes testosterone and DHT) are responsible for the male secondary sexual characteristics. Testosterone is synthesized in the testes and released into the circulation in response to specific hormonal signals regulated by GnRH, FSH, and LH. Testosterone is transported by steroid hormone binding globulin (SHBG) to the prostate, where it is converted by 5α-reductase to its active metabolite 5α-dihydrotestosterone (DHT). In the prostate, androgens mediate their effects *via* high affinity to the androgen

and veins causing lower body edema. The development of high-grade prostatic intraepithelial neoplasia (HGPIN) is identified as an intermediate stage between benign epithelium and the invasive malignant carcinoma at the outset of prostate cancer. Four main patterns of high-grade PIN (HGPIN) have been described as

Prostate specific antigen (PSA), major constituent in prostatic secretion and is used for screening prostatism. PSA testing is primarily associated with benign prostatic hyperplasia (BPH), however there is only rare connectivity of patients having BPH to develop prostate cancer. With conditions like BPH, inflammation, and disruption of prostate basal membrane increases the permeability and releases PSA into the circulation. Prostate cancer antigen 3 (PCA3) is more specific than PSA which is an important biomarker in personalized medicine. Also analysis of urinary protein markers, such as TMPRSS2-ERG and PCA3 are helpful in early diagnosis of the disease. The other tumors markers reported as prostatic acid phosphatase (PAP), cytoskeletal proteins, and annexin I are downregulated in PIN whereas C-erbB-2 (HER-2/neu) and C-erbB-3 oncoproteins, c-met protooncogene, Bcl-2 oncoprotein, several growth factors, nitric oxide synthase, alpha-methylacyl-CoA racemase, glycoprotein A-80, and apolipoprotein D, are upregulated in PIN. The histological grading system of prostate cancer is obtained from the Gleason score [6] which provides information that score 1–5 indicates low-grade prostate cancer and score 8–10 indicates high-grade prostate cancer. Digital rectal examination (DRE), examination of PSA levels, prostate ultrasound, and prostate biopsy are the current diagnostic methods in examining the primary and metastatic stages for prostate cancer [7, 8]. Prostate cancer stages are generally classified into three categories—T category, N category, and M category. T represents the primary tumor, N represents the cancer that has spread to regional (nearby) lymph nodes and M represents the distant metastasis cancer. The treatment strategies are admin-

**164**

TNFRs are activated by TNF in order to exhibit cellular response. TNF triggers the transcription of apoptotic proteins through NF-κB thereby achieving cell survival. Activation of TRAFs, such as TRAF2, TRAF5, and TRAF6 results in transduction of cellular response by TNFRs. In TNFRs pathway, TRAF3 acts as a repressor. APRL, BAFF, BAFF-R, BCMA, and TACI belong to the TNF superfamilies and play vital roles in immunity through B cells and T cells. BAFF binds to BAFF-R, BCMA, and TACI, while APRIL bands to two of them—BCMA and TACI only. In this pathway nuclear factors (NF-κB) are activated in signaling cascades. This activation process can be triggered by canonical and non-canonical pathways. The latter is activated by activation of BCMA, TCAI, and BAFF-R by BAFF. This counter activates TRAF2 and TRAF5 that signals NIK, a mitogen activated protein kinase. Once NIK is activated, phosphorylation of IKK-alpha that restrain processing NK-κB2 into NF-κB2 onsets. Along with RelB, NF-κB2 activates Bcl2 or Bcl-XL or both. Upon this activation cell survival is promoted. BAFF transcription is activated by NF-κB2 resulting in a positive feedback. I-kB is phosphorylated by IKK alpha, beta, and gamma which is activated by TRAF2 by canonical pathway. I-kB is disintegrated and ubiquitylated inside proteosome 26S. This process discharges NF-κB2 and RelA which are swiftly repositioned from cytoplasm to nucleus. Following which anti-apoptotic components, such as Bcl-2, Bcl-XL, and BFL1 are activated by transcription by NF-κB transfactors.

In non-canonical pathway, IKK alpha is activated by its phosphorylation once NIK kinase is promoted by TRAF. NF-κB2 is processed from p100 to p52 by IKK alpha which is adhered to RelB. The dimer (RelB-p52-NF-κB) engages in affecting gene transcription once it shifts to the nucleus. This pathway does not involve IKK beta and gamma. IKK, RelB, and NIK are mediated by TNF-R1 signal or TNF-R2 signal as well. NF-κB promoted cell growth and proliferation in prostate cancer cells by regulating expression of genes, such as c-myc, cyclin D1, and IL-6. Furthermore, NF-κB-mediated expression of genes involved in angiogenesis (IL-8, VEGF), and invasion and metastasis (MMP 9, uPA, and uPA receptor) may further contribute to the progression of androgen depleted prostate cancer [20].

Apoptosis is programmed cell death involving sequential events of elimination of cells without releasing harmful substances into the surrounding area. Apoptosis plays a crucial role in developing and maintaining the health of the body by eliminating old cells, unnecessary cells, and unhealthy cells. The two classes of regulatory molecules play vital role in the cell cycle progression and apoptosis processes are protein kinases, such as cyclin dependent kinases (CDKs), and cyclins. Disturbances in the cell cycle regulation due to uncontrolled cell growth and divisions through and escaping of the cell cycle checkpoints occur in the mutated cells. The cell cycle events are facilitated through the activated cyclin D-CDK4/6 complexes phosphorylating the retinoblastoma protein (pRb) bound with E2F transcriptional factors. This in turn inactivates pRb and weakening its affinity for E2F which then becomes free to enter the nucleus and transcription of cell cycle progression genes. The hypophosphorylated pRb impounds the transcription factor E2F in the cytosol, thus blocking the cell cycle at G1 phase.

Similarly B-cell lymphoma (Bcl-2) family genes are involved in the apoptosis pathway, including prostate, breast, and ovarian cancers. The Bcl-2 family proteins had the anti-apoptotic subgroup, such as, Bcl-extra-large (Bcl-xL), Bcl2-like 2 (Bcl-W), myeloid cell leukemia (Mcl-1) that interacted with another subgroup of proteins called the pro-apoptotic proteins (Bcl2-associated X protein (Bax) and Bcl2 antagonist/killer (Bak)). In the signal transduction cascade of apoptosis the pro-apoptotic proteins began induction of apoptosis *via* mitochondrial outermembrane permeabilization, followed by the release of cytochrome c, and finally the activation of cysteine aspartyl proteases (caspases). Second is the intrinsic pathway, with the release of cyt-c into the cytosol from mitochondria, a multiprotein

**167**

*Combinatorial Drug Therapy with Phytochemicals as Adjuvants in Prostate Cancer Management*

caspase-activating complex, called "apoptosome" binds procaspase-9 and cyt-c with its central component Apaf1, and activates apoptosis. Thus there should be a balance in the levels of anti-apoptotic and pro-apoptotic proteins for the proper

*Molecular pathways involved in prostate cancer progression (developed by pathway construction tool—PathVisio).*

**4. Phytomedicine: promoting synergistic actions in prostate cancer**

The history of ayurvedic and traditional systems of medicine showed that the medicinal plants have global importance in treating human diseases and disorders [21]. The references of ancient literature, a Sumerian clay slab from Nagpur, approximately 5000 years old suggested that people were depended on drugs from the nature [22]. Theophrast (371-287 BC) in his scientific book titled "De Causis Plantarium" has referred and classified nearly 500 medicinal plants. About 700 plant species including pomegranate, castor oil plant, aloe, senna, garlic, onion, fig, willow, coriander, juniper, common centaury, etc. [23] were reported having medicinal properties. The World Health Organization (WHO) estimated that trades of plantderived pharmaceutical drugs would account for five trillion US dollars by 2050. The survey reports on these medicinally valued plants and their preparations as tinctures, teas, poultices, powders, and other herbal formulations [24] served as the basis for novel drug discovery wherein a large number of synthetic drugs are developed on the small-molecule natural chemical entities and has been introduced as potential drugs worldwide [25]. Even our natural food intake relays on the medicinal aspects followed in our tradition thus have a strong impact on determining health at different stages/phases of life. In addition many food-based nutrients contribute to the prevention and management of deadly diseases like cancer. Wholesome diet including vegetables, fruit, and vitamins lowers the risk up to 80%

*DOI: http://dx.doi.org/10.5772/intechopen.86157*

progression of apoptosis (**Figure 1**).

of cancers of the large bowel, breast, and prostate.

**management**

**Figure 1.**

*Combinatorial Drug Therapy with Phytochemicals as Adjuvants in Prostate Cancer Management DOI: http://dx.doi.org/10.5772/intechopen.86157*

**Figure 1.** *Molecular pathways involved in prostate cancer progression (developed by pathway construction tool—PathVisio).*

caspase-activating complex, called "apoptosome" binds procaspase-9 and cyt-c with its central component Apaf1, and activates apoptosis. Thus there should be a balance in the levels of anti-apoptotic and pro-apoptotic proteins for the proper progression of apoptosis (**Figure 1**).