Mentha is a strongly scented herb genus of the Lamiaceae (formerly Labiatae) and includes 18 species, 31 subspecies or botanical varieties, and 11 recognized hybrid species (Tucker and Naczi, 2007; GRIN-Global, 2020). The mint family includes diverse additional aromatic genera, such as mountain mint (Pycnanthemum L.), lavender (Lavendula L.), sage (Salvia L.), rosemary (Rosmarinus L.), and oregano (Origanum L.), which are grown commercially for essential oils that are distilled from leaves and stems. Mint shoots and leaves are used for medicinal and aromatic purposes, such as dried organic extracts, distillates, condiments, and food flavorings. Likewise, Mentha includes many commercially valuable species, including peppermint (Mentha ×piperita), Scotch spearmint (M. ×gracilis), native spearmint (M. spicata), American wild mint (M. canadensis), and corn mint (M. arvensis), which are cultivated in different parts of the world for their culinary and medicinal properties. Plants in this genus are herbaceous, rhizomatous, perennial, and aromatic, with smooth, wide-spreading underground stems, which are square in cross-section. The leaves are arranged in opposite pairs, and the white, pink, or purple flowers are produced in clusters.

The name Mentha is derived from Classical Greek mythology, from Minthe, (Minthê), who was a beautiful Cocythian (river nymph) beloved by Hades (Pluto) god of the underworld. Minthe was metamorphosed into dust by Hades's wife, Demeter (Persephone) (Rosengarten, 1969), but Hades caused the fragrant mint plant to grow from the dust. The etymology of "mint" is from the old English minte (= mint plant), which is derived from Proto-Germanic, through Latin from the Ancient Greek, and is akin to old Norse.

At the base of Mt. Minthe, there was a temple dedicated to Hades and a grove for Demeter (Ovid Met. 10) Near Pylos, Greece, Mt. Minthe is thought to be a location of the origin of triploid sterile spearmint (2n = 3x = 36), which likely arose from the introgression of the conspecific endemic ancient amphidiploid Mentha spicata (2n = 4x = 48) and the diploid M. longifolia (2n = 2x = 24) (Kokkini, 1991; Lawrence, 1991).

Since the time of Linneaus, more than 3,000 specific epithets have been reported for Mentha (Tucker and Naczi, 2007). As a measure of mint species taxonomic diversity, the Global Biodiversity Information Facility (GBIF) network includes more than 740,000 locality data points from 454 Mentha taxa with occurrences throughout the world (GBIF, 2020). The plethora of names and occurrences of hybrid and naturalized mints have created confusion in the literature. Wild species of mint hybridize readily, and over evolutionary time, native hybrid-species swarms developed in conspecific regions. Subsequently, minor variances have achieved species rank.

The Plants of the World database (http://www.plantsofthe worldonline.org/) (Kew Science, 2020) describes 39 taxa including, 24 species and 15 hybrid species (Figure 1). Tucker and Naczi (2007) prepared a more conservative list of the number of mints, synonymizing many to recognize 18 species, 31 subspecies or botanical varieties, 11 hybrid species, and one excluded species. They chose to consider Mentha cunninghamii (Benth.) Benth., as Micromeria cunninghamii Benth. GRIN-Global (2020) taking a moderate course, includes 20 Mentha species.

For this manuscript, we applied the determination by Tucker and others (Tucker and Chambers, 2002; Tucker and

Naczi, 2007) for 18 recognized species, with one exception: For this review, we considered Mentha repens (J.D. Hook.) Briq. as M. pulegium L. subsp. repens.

### Species Distribution

Mentha L. has a cosmopolitan native range (Kew Science, 2020). The Mentha distribution map (Kew Science) included 163 countries, provinces, and regions for native distribution and 43 regions of introduction (Figure 1). Considering the tendency for species hybridization within this genus and the successful expansion strategies of mint around the globe, we used a conservative estimation to develop global richness maps. We considered only the taxa accepted by Tucker and Naczi (2007). We prepared global richness maps searching GBIF data for the 17 mint species (Figures 2 and 3).

We separately examined world occurrences of point data within GBIF data for each of the 17 species. We filtered out the introduced, naturalized, and cultivated locality data, keeping only natural endemic occurrences. We used climatic and topographic predictors to model likely occurrence for the 17 individual species maps. The data for the separate species maps were merged to produce the global species richness maps (Figures 2 and 3). These

maps can be used for applied research or conservation planning and investigating the processes that have shaped these patterns.

While the highest diversity of present day species occurs in Western Europe (Figure 2), significant endemic mint species occur in Eastern and Western North America, Asia, Southern Australia, and Tasmania (Figure 3). In addition to this natural species diversity, hundreds of thousands of data points of introduced, naturalized, and cultivated mint occur throughout five continents (GBIF, 2020). The multitude of global mint occurrences (Figure 1) speak to the global success of this genus, starting from Centers of Diversity in Europe, Asia, North America, and Australia and spreading throughout the globe.

The ease of propagation by seeds and clonal propagules, such as rhizomes and cuttings, and the survivability of the plants during harsh and undesirable climactic conditions, allow for spread and diversification. The utilitarian application of mint for human pharmaceutical, food, and cosmetic needs encouraged domestication and cultivation throughout the world and across multiple cultures.

### Prehistory

Throughout human history, medicinal and aromatic plants have been used for flavor enrichment in culinary and medicinal purpose in folk medicine (Sonmezdag et al., 2017). Mentha has been of great importance considering its unique aroma and nutritional value (Naghibi et al., 2010). Archeological excavations showed that the usage of lavenders, sage, and mints occurred in prehistoric times, harvested locally from the wild (Nuńez and De Castro, 1992). In western traditions, mints have been cultivated in the dry, mild, and cold districts of Asia, Europe, and North Africa since antiquity (Jamzad et al., 2003). Native peoples in America have documented traditions of uses of mints as cold remedies (Chehalis, Cowlitz), treatments for gastrointestinal ailments (Kiowa), food (Kiowa, chewing leaves), and ceremonial medicine (Navaho) (Vestal and Schultes, 1939; Elmore, 1944; Gunther, 1973).

### Antiquity

Multiple mint species are referenced (Bostok, 1885) throughout Greek and Roman herbals (Aeschylus, Hippocrates, Krataeus, Dioscorides, and Galen; Romans: Cato, Ovid, and Pliny the Elder); Asian medicinal traditions, traditional Chinese medicine, and the Ayurvedic tradition of India.

The earliest published mint species images in existence can be found on gr. III fol. 129r and 132r of the Juliana Anicia Codex or Vindobonensis Codex (Janick and Hummer, 2012). The Juliana Anicia Codex is a magnificently illustrated manuscript with written information based on the Peri Ylis Iatrikis (De Materia Medica in Latin; Of Medical Matters of Dioscorides). This codex, one of the earliest books, was presented to the imperial Princess Juliana Anicia in Constantinople 512 CE (Collins, 2000). In the 15th century, it was purchased by the Emperor Maximilian for the Imperial Library and was moved to Vienna, where it now resides. The translation of the uses for mints as described in Byzantine Greek written in the background of the images was prepared by Lily Beck (Beck, 2005) and is presented (Table 1). These uses described in the Juliana Anicia Codex were reiterated, revised, and interpreted in many recensions of Dioscorides TABLE 1 | English translation of reference to species of Mentha in De Materia Medica of Dioscorides (Beck, 2005).

When drunk, it draws the menses, afterbirth, and embryos/fetuses. It brings up from the long phlegm when drunk with salt and honey and it helps people with spasms, and with sour wine mixed with water it relieves nausea and gnawing pains of the stomach. With wine, it drives down the bowel dark matter and helps those bitten by wild animals and when applied to the nostrils with vinegar, it revives those who fainted.

Ground up dry and burned, it also strengths the gums; plastered on with barley groats, it soothes all inflammations; it is suitable to use all by itself on the gouty until the skin surfaces becomes irritated and when used with a cerate, it checks facial eruptions; it also helps patients with spleen disease when plastered on with salt. Its decoction used as a wash stops itching and is suitable in a sitz bath for uterine inflations, indurations, and twistings. Some people call it blechon because sheep that taste it when in bloom bleat continuously.

 Applied as a plaster with barley groats, it dissipates abscesses, placed on the forehead, it assuages headaches, and it abates distension and swelling of the breasts. With salt, it is a plaster for people bitten by dogs, and its juice with hydromel is suitable for earaches. Used by women as a pessary before sexual intercourse, it causes barrenness, and if rubbed on a rough tongue, it smothes it; it keeps milk from curdling when little sprays are stirred about in it, and it is through and through wholesome and spicy.

There is also a wild green mint which has thicker leaves, all told it is larger than bergamot mint which has thicker leaves, all told it is larger than bergamont mint, rather foul smelling, and less useful for health purposes.

works and in subsequent herbals for the next several millennia (Collins, 2000; Figures 4 and 5).

Dioscorides mentions about 500 plants (Singer, 1927). About 130 of these were referenced in the Hippocratic collection. Thus, many of these treatments, including peppermint, were utilized in the Greek world for more than four centuries before Dioscorides writings and have survived throughout the times to medicinal applications in the present day.

Mint is mentioned in the bible: Mathew 23:23, "For you tithe mint, dill, and cumin, and have neglected the weightier matters of the law: justice and mercy and faith. It is these you ought to have practiced without neglecting the others" and Luke 11:42, "Woe to you Pharisees, because you give God a tenth of your mint, rue and all other kinds of garden herbs, but you neglect justice and the love of God. You should have practiced the latter without leaving the former undone." Parry (1925) suggests that these quotations refer to Mentha longifolia, long leafed mint, native to North Africa. Robert Gunther (1934) prepared a translation of John Goodyear's 1655 version of Eduosmos agrios in Dioscorides as: "But ye wilde mint, which ye Romans call Mentastrum, is round in the leaves and altogether greater than Sisymbrium, but poisonous in smell, and lesse fitting for use in health."

Mentha in the traditional Galenic medicine in the Islamic period (Table 2) can be traced to the writings of Dioscorides and other Greek authors.

FIGURE 4 | M. pulegium, pennyroyal, Ḡleḵon, glήcοn Vienna Dioscorides, Juliana Anicia Codex, dating to 512 CE. This illustration is Book III, plate 31. The Arabic writing on the right is translated "type of thyme". The Arabic on the left is the translation of Ḡleḵon. The faded Byzantine Greek in the background is translated by L. Beck (Table 1).

### Egyptian

The Ebers Papyrus dating to 1550 BCE and purchased by Georg Ebers in Luxor in 1874, is one of the earliest surviving Egyptian medical papyri. It is kept in the library at the University of Lipzig, Germany. This 110-page scroll is about 20 m long, and the text is scribed in hieratic Egyptian, likely copied from earlier manuscripts. One treatment suggests that peppermint be mixed with flour, incense, wood of the waneb plant, a stag's horn, sycamore seeds, mason's plaster, seeds of zart, and water to create a curative paste for headaches supporting later Anglo-Saxon and Greek prescriptions for headache and migraine pain relief (Aboelsoud, 2010; Elansary and Ashmawy, 2013).

In the Hearst Papyrus, dated to approximately 2000 BCE, peppermint is recommended as a treatment for rhinitis, where a plaster is applied directly to the nose. In prescription 171, peppermint is mixed with wine and is used to treat what might be edema of the legs. After the mint and wine mixture is consumed, some sort of bloodletting is required, though the physician doesn't provide much in terms of specificity. Mint is still used to treat edema today, though most modern references

FIGURE 5 | Image of M. aquatica, labeled Eduosmos agrios, is from the Pierpont Morgan recession of Dioscorides De material medica. This book dates to about 1050 CE, and the plants are alphabetically arranged. Morgan Library New York.

TABLE 2 | Application of mint in Arabic traditional texts. (Iranian encyclopedia online, 2020).

\*Persian "sherbet", sekanjabin, a concoction of honey and vinegar flavored with mint extract.

deal with topical creams for livestock, particularly cattle (Aboelsoud, 2010).

### European Medieval and Renaissance 1400–1600

The majority of Medieval and Renaissance herbals elaborated the traditions described by ancient Greek and Roman text (Hummer and Janick, 2007). Mint species played a prominent role in many treatments. Adams et al. (2011) compared malaria treatments in Fuchs (1543) and Brunfels (1532), both of whom suggested the use of mints against this disease. Fuchs (1543) also recommended taking pennyroyal (M. pulegium) in vinegar against epilepsy. Essential oil extracted from pennyroyal was amongst the pro-convulsive essential oils discussed by Duke (1985), Burkhard et al. (1999), and Riddle and Estes (1992).

Nicholas Culpeper's work, the Complete Herbal (Culpeper, 1652) documents the use of several mint species. Unlike the Egyptian papyri, or Anglo-Saxon Leech books, Culpeper's work provides in-depth descriptions and growth habits of the plant entries. Culpeper discusses spearmint, which he refers to alternatively as "heartmint." The plant is labeled an "herb of Venus," which directly refers to Dioscorides' De Materia Medica, inferring that mint possesses healing, binding, and drying qualities. Much of the entry borrows directly from this text but has some additions. Culpeper includes treatments using mint for a sore and itchy scalp, pain of the ears, venomous bites, headache, indigestion, and flatulence. He also includes prescriptions for the resolution of bad breath and soreness of the gums and palate. Horse or wild mint are then referenced. Due to menthol's innate analgesic qualities, mint is described to be used against headaches, migraines, and general pain and swelling. Mint is also recommended as a digestive aid. Mint relaxes stomach muscles, allowing food and flatulence to pass more easily.

Mint was employed topically to treat dry, itchy skin, and insect and animal bites and lessen the appearance of scars, bruises and scabs, particularly on the scalp and face. Due to its antimicrobial and antifungal properties, mint was used for millennia to treat fungal infections, such as ringworm, and to treat parasites, such as roundworm. Mint is also a diuretic and, as such, can be used to stimulate urination and possibly even treat hypertension.

# INDUSTRIAL PRODUCTION OF MINT

Mint was significant to humans from early history, being collected from the wild and brought to the convents, monasteries, and kitchen gardens for direct use. Japan preceded western countries in the cultivation of mint and extraction of menthol from M. arvensis, begun before 0 CE (Flueckiger, 1891; Hayden, 1929). Tamba Yasudori (984 CE), in the oldest surviving Japanese medical text, stated that menthol was used in preparation of an aqueous eye medication. Japan began exporting menthol in 1873 (Gildemeister and Hoffman, 1913). In Japan, this oil was extracted from corn mint (Mentha arvensis L.).

Production of peppermint for menthol in large areas in the western world did not occur until 1750 in England (Parry, 1925). By 1796, about 40.5 ha (100 acres) of peppermint (M. ×piperita) were grown near Mitcham, England. The plant material was harvested, bundled, and sent to London for distilling. This early production of peppermint oil yielded 900–1360 kg (2,000–3,000 lb) (Parry, 1925). Over the next 20 years, the production area expanded to 10 townships surrounding Mitcham. By 1940, peppermint cultivation in the original Mitcham area ceased (Parry, 1925).

Peppermint plants were imported from England to the United States with early settlers. By 1812, peppermint was raised commercially near Ashfield, Massachusetts (Lawrence, 1991). Enterprising farmers and distillers, such as Archibald Burnett and Hiram G. Hotchkiss, brought mint westward to New York. By 1830, mint production was sufficient for nine distilleries. These stills also processed spearmint, tansy, wintergreen, spruce, and hemlock oils (Lawrence, 1991). Mint production began to move further west in the US. Both spearmint and peppermint were introduced in New York, Ohio, Michigan, and Indiana. In the western states, mint from Oregon and Washington spread into Idaho, Montana, California, Nevada, and Utah. Lawrence (1991) provides details of early mint production in the US.

In 1853, Albert M. Todd imported 'Black Mitcham' roots from England and began production in St. Joseph County, Michigan. 'White Mitcham,' the original introduction, had become known as 'American peppermint.' Todd found 'Black Mitcham' to be superior to 'White Mitcham' for production in Michigan. Todd's production and distillery in Kalamazoo became a major mint producer. By 1915, Todd began several hundred acres of Scotch spearmint (M. x gracilis Sole), because of its productivity over the native spearmint (M. spicata).

The main mint crops produced in the US are peppermint and spearmint, the latter including Scotch and native spearmints. 'Black Mitcham' peppermint has been the most widely grown peppermint cultivar since at least the mid-20th century (Lawrence, 1991).

The US does not report peppermint production to the Food and Agriculture Organization of the United Nations (FAOSTAT, 2018). In 2018, the countries reporting the largest peppermint production included Morocco, Argentina, Mexico, Bulgaria, and Spain. Oil distilled in China, India, and Japan is M. arvensis var piperescens and is not counted in the FAO peppermint database. In 2018, the FAO reported world mint oil production at 106,728 MT.

The annual farm gate value of peppermint production in the US has been between \$100 and \$150 million, while that of spearmint has ranged between \$45 to \$50 million during the past decade (NASS, 2020).

Recent US mint oil production was highest in 2011, at about 7 million pounds (3,175 MT) of peppermint oil and 2.2 million pounds (998 MT) of spearmint oil. Since then, US production has dropped to under 6 million pounds (2,721 MT), as production of (-)-menthol from oils of M. arvensis has been increasing in China and India. The demand for mint oil by Southeast Asian countries has been driving the expansion of the market in recent years (Liu and Lawrence, 2006).

# PROTECTING MENTHA GENETIC RESOURCES

The FAO manages a list of world genebanks or botanical gardens and the crops that they preserve. This information is publically available in two global databases: Genesys PGR2 and CATIE. We queried both of these databases on 14 April 2020 and totaled entries for Mentha and combined results. This query determined that 65 genebanks in 42 countries as preserving Mentha genetic resources. The largest mint collections are held in the US, Ukraine, Germany, Japan, Portugal, and the United Kingdom (Supplemental Table 1).

### USDA NATIONAL CLONAL GERMPLASM REPOSITORY AT CORVALLIS, OREGON

The Mentha collection of the USDA, NCGR in Corvallis, Oregon, includes representatives of approximately 450 accessions of 13 species and 10 hybrid species plus cultivated types (Table 3). This working genebank maintains the primary collections as plants in containers in greenhouse or lath house environments (Hummer et al., 2020). Most of these plants represent diverse wild species collections from 57 countries.

Most mints in this collection were originally donated to the USDA from Dr. Merrit J. Murray, breeder at A.M. Todd Company, Kalamazoo, Michigan, dating back to the 1970s. At that time, the Todd Company decided to discontinue their mint breeding program and donated the collection to Dr. Chester Ellsworth Horner, USDA researcher in Corvallis, Oregon. Dr. Al Haunold assumed responsibility upon Dr. Horner's retirement and subsequently donated the collection to the NCGR in the mid-1980s.

At present, 216 mint accessions at the NCGR are species or advanced breeder selections originally donated from M. J. Murray. Other representatives of diverse mint taxa including wild accessions have since been obtained from breeders and taxonomic collaborators in the US, Australia, New Zealand, Europe, and Vietnam.

Besides maintaining diverse species representatives, the NCGR collection includes advanced breeder lines, cultivar and germplasm releases, and what are referred to as "donor-named selections," where the NCGR has kept the names provided by donors. In addition, virologists have donated 16 pathogen-positive mints for virus identification studies and certification programs.

### DISTRIBUTION FROM THE NCGR MINT GENE BANK

The NCGR was dedicated in 1981. Since that time, the NCGR has distributed > 9,700 mints as plants, cuttings, rhizomes, tissue cultures, or seed lots for 1,277 orders. About 31% of the orders were sent to US researchers (including government agencies, universities, and non-profit organizations), 33% to US individuals and private companies, and 36% were shipped to foreign requestors. Additional plant and tissue culture shipments were made for secure remote backup of the collection at the USDA National Laboratory for Genetic Resource Preservation in Ft. Collins, Colorado, the designated base germplasm collection within the US National Plant Germplasm System (NPGS).Some

### TABLE 3 | Mentha L. species, distribution, habitat, and number of accessions in the USDA ARS National Clonal Germplasm Repository-Corvallis.

(Continued)

### TABLE 3 | Continued

of the most requested cultivars included M. × piperita 'Chocolate,' 'Pineapple,' 'Black Mitcham,' 'f. lavanduliodora,' 'Todd's Mitcham,' M. aquatica var. citrata 'Eau de Cologne,' M. × gracilis 'Scotch Spearmint,' and M. spicata 'Kentucky Colonel' (Table 4).

Many researchers noted that their purpose for requesting the germplasm was to seek diverse essential oil profiles or to perform genetic analyses. Many universities and companies requested propagules from the entire mint collection for this use. Private company results are unpublished and not publically available. Other scientists were interested in the taxonomy of specific accessions and systematic determinations (Tucker and Chambers, 2002). Others requested germplasm to seek disease resistance (Vining et al., 2005).

The policy of the US NPGS is to distribute plant genetic resources freely for crop improvement. The quarantine importation regulations on international shipment of Mentha are relatively minor compared to those for shipment of fruit, nut, and other more restricted horticultural crops. Fewer importation requirements facilitate the ease of transfer of germplasm for foreign requests.

# GERMPLASM EVALUATION AND CHARACTERIZATION

The primary objectives of a plant genebank includes the acquisition, maintenance, distribution, evaluation, and characterization of the assigned genetic resources (Chambers and Hummer, 1992). During the past 35 years, staff at the NCGR, working in collaboration with scientists at other institutions, have examined the cytology, essential oil content, disease resistance, and the development and use of molecular markers for identity confirmation and diversity determination. Data from these studies have been added as descriptors to the GRIN-Global database.

TABLE 4 | The 50 most distributed Mentha accessions from 1980 through 2020 from the USDA ARS National Clonal Germplasm Repository-Corvallis.

# CYTOLOGY

Harley and Brighton (1977) defined five sections within the genus Mentha (Mentha sect. Audibertia, sect. Eriodontes, sect. Mentha, sect. Preslia, and sect. Pulegium) including 19 species and 13 named hybrids. They also listed chromosome counts for sect. Mentha including most of the mint taxa recognized today. Chambers and Hummer (1994) summarized other documentation of chromosome counts and surveyed 73 Mentha accessions from the NCGR collection.

Many mint species have a monoploid (base) number of x = 12, though diverse species can have monoploid numbers of x = 9, x = 10, x = 18, or x = 25. In addition, ploidy series of several species are reported as diploid, tetraploid, hexaploid, octoploid, enneaploid, decaploid, or aneuploid.

Chambers and Hummer (1994) reported that ploidy determinations were obtained by cytological counts of dividing pollen mother cells in flower buds or meristematic cells in root tips. Unusual species counts included M. requenii with 2n = 2x = 18; M. pulegium with diploid (2n = 2x = 20), triploid (2n = 3x = 30), and tetraploid (2n = 4x = 40); and M. japonica with 2n = 2x = 50. This survey included chromosome counts for M. australis (two accessions), M. japonica, M. diemenica, and M. cunninghamii. For the majority of mint species with x = 12, diploid, triploid, tetraploid, hexaploid, octoploid, and decaploid members were observed (Chambers and Hummer, 1994). Vining et al. (2019) recently reported several unusual ploidy counts, finding diploid and triploid clones in M. suaveolens and octoploid and enneaploid clones of M. aquatica in the NCGR mint collection.

### ESSENTIAL OILS

The Lamiaceae, and particularly Mentha, produce aromatic "essential" oils. These lipophilic substances, predominantly terpenes, are produced by capitate or peltate glandular trichomes that occur on the leaf and stem surfaces (Amelunxen, 1964). They can be simply extracted by crushing the leaves and stems or more completely through distillation. The volatile composition is affected by short chain terpenes that constitute the main fraction especially C10 mono- and C15 sesquiterpenes, which overwhelmingly affect the flavor and taste of these species.

Mints with unique essential oil profiles are valued by the herb, nursery, and pharmaceutical trades. More than 275 accessions of the mint collection of the NCGR were screened by gas chromatography for 37 separate essential oil profiles (Bergstein, 1983). The signature component of native spearmint oil is the C6-oxygenated pmenthane monoterpene (-)-carvone (Figure 6). The oil distilled from 'Black Mitcham' peppermint contains predominantly C3 oxygenated monoterpenes, with (-)-menthone and (-)-menthol being the most prominent metabolites. Essential oil analyses indicated that about half of the NCGR accessions labeled as M. aquatica accumulate (+)-menthofuran as the most abundant

monoterpene (with occasionally high levels of (-)-limonene and/ or 1,8-cineole as well), while the remainder had variable oil profiles and need to be further investigated (Vining et al., 2019). Oils from M. suaveolens accessions are high in either (-)-carvone, piperitenone oxide, or trans-piperitone oxide (Vining et al., 2019). The oil types of M. longifolia accessions are quite diverse, with different C6- or C3-oxygenated monoterpenes dominating the profile (Vining et al., 2005).

While the oil composition varies significantly depending on growing location, regional weather, harvest dates, and processing technology (Lawrence, 2006), recent assessments of NCGR accessions and cultivars were performed under controlled conditions to ensure comparability. These data sets can be searched online as descriptors through GRIN-Global (https:// npgsweb.ars-grin.gov/gringlobal/method.aspx?id=496325).

# DISEASE RESISTANCE

Verticillium wilt disease perpetually plagues the mint industry, and therefore breeding for durable wilt resistance is a longstanding goal. Verticillium wilt is a vascular wilt disease caused by the soil-borne fungus Verticillium dahliae. 'Black Mitcham' peppermint is highly wilt susceptible. However, the cultivar is also a sterile hexaploid, which hinders traditional breeding techniques. Other genetic mutation and recombination techniques have been performed over the years.

An irradiation program, working in collaboration with nuclear facilities in the 1960s, resulted in the release of two new peppermint cultivars with relatively higher wilt resistance: 'Todd's Mitcham' (Todd et al., 1977) and 'Murray Mitcham' (Murray and Todd, 1972). In the 1990s–2000s, the Mint Industry Research Council initiated a genetic engineering project with the objective of genetically transforming peppermint cultivars to confer verticillium wilt resistance. However, despite remarkable technical successes in improving oil yield and composition (but not verticillium resistance) (Lange et al., 2011; Lange, 2015), this research was discontinued due to concerns about market acceptance of genetically modified organisms.

### MOLECULAR ANALYSIS

Multi-locus dominant markers such as amplified fragment length polymorphism (AFLP), random amplified polymorphic DNA (RAPD), and intersimple sequence repeat (ISSR) markers have been used with a small number of mint accessions for assessment of genetic diversity and relationships (Khanuja et al., 2000; Gobert et al., 2002; Shasany et al., 2002; Shiran et al., 2004; Vining et al., 2005; Sabboura et al., 2016; Jedrzejczyk and Rewers, 2018; Choupani et al., 2019) and for cultivar identification (Fenwick and Ward, 2001). Species-specific start codon targeted (SCoT) markers were also developed and used to assess genetic diversity in 12 accessions from four mint species (Khanm et al., 2017). Few co-dominant simple sequence repeat FIGURE 6 | C6-oxygenated p-menthane monoterpene (-)-carvone. (SSR) markers are available for mint (Kumar et al., 2015; Vining et al., 2019). Kumar et al. (2015) identified 54 SSRs from publicly available expressed sequence tag (EST-SSR) sequences of M. ×piperita that generated clear amplicons in 13 accessions from this species. Three SSRs with long core repeats amplified in representative samples from four species including M. arvensis, M. citrata, M. longifolia, and M. spicata, indicating transferability among species.

We recently screened these three SSRs in addition to 48 other primer pairs designed from a draft genome assembly of M. longifolia CMEN 585, from South Africa (Vining et al., 2017) in an eight-member testing panel (three accessions each of M. suaveolens and M. aquatica and two accessions of M. longifolia) (Vining et al., 2019). Screening the eight-member testing panel with these 51 SSRs identified nine new primer pairs that were polymorphic and appeared easy to score (Figure 7). These nine SSRs were thus used in two multiplexes to genotype 49 accessions propagated from the NCGR collection that included 24 accessions of M. aquatica, 23 accessions of M. suaveolens, and the two M. longifolia plants in the testing panel. The nine SSRs developed in this study separated the accessions mostly according to species and identified each accession as unique. Three sets of accessions of M. aquatica were closely related and were distinguished by a single allele each: CMEN 116, CMEN 117; CMEN 110, CMEN 111; and CMEN 121, CMEN 122. The consecutive local numbers of each pair of closely related accessions indicate they are in neighboring pots and may suggest plant contamination and will be investigated further.

Single nucleotide polymorphism (SNP) markers have not yet been reported in Mentha, and the number of SSRs remains low. More SSRs and new SNPs need to be identified and evaluated across Mentha species and are now possible due to the availability of a genome sequence (M. longifolia) (Vining et al., 2017), and the low cost of re-sequencing.

## USES OF THE COLLECTION IN BREEDING EFFORTS

From the mint industry viewpoint, improved oil quality and verticillium wilt disease resistance are two priority traits for new cultivar development. Both traits are multigenic with complex mechanisms. Mentha germplasm evaluations have therefore focused on those traits and efforts are ongoing to understand the underlying genetics. Vining et al. (2019) also reported species accessions with undeveloped anthers, resulting in apparent male sterility. This trait could be useful for developing male-sterile cultivars. The USDA NCGR Mentha collection is valuable as a source of genetic diversity for mint breeding toward these goals. Several private companies have had, or currently have, mint breeding programs that have requested accessions from the Mentha collection. While information about these programs is strictly proprietary, patent documents show cultivar releases for M. spicata: (https://patents.google.com/patent/USPP8645P/en; https://patents.google.com/patent/US20120204283A1/en; https://patents.google.com/patent/US20050044600), M. arvensis (https://patents.justia.com/patent/PP10935), and an interspecies hybrid: (https://patents.google.com/patent/USPP12030). Besides patents, future cultivars could be released under Plant Variety Protection (PVP), or as germplasm releases through the USDA.

The origin of 'Black Mitcham' peppermint, the most widely grown American cultivar in the US and Europe, is unknown, because it resulted from natural hybridization events. However, phylogenetic studies (Tucker et al., 1980; Tucker and Naczi, 2007) suggest that genotypes of M. longifolia and M. suaveolens are the diploid ancestors of M. spicata, which then further hybridized with M. aquatica to give rise to M. ×piperita. Therefore, efforts over the past 50 years have focused on evaluation and crossing of USDA NCGR accessions of M. longifolia, M. suaveolens, and M. aquatica. M. longifolia showed the most obvious phenotypic diversity, with variation in growth habit, leaf morphology, and oil type (Vining et al., 2005). M. suaveolens and M. aquatica showed relatively lower morphological and oil type diversity (Vining et al., 2019).

In V. dahliae inoculation tests, both M. longifolia and M. aquatica showed a range of wilt disease resistance to susceptibility, with a few accessions showing high susceptibility, a few showing high resistance, and most displaying mild to moderate susceptibility levels (Vining et al., 2005; Vining et al., 2019). M. suaveolens accessions, in contrast, were highly resistant, with the exception of one moderately susceptible accession (Vining et al., 2019). The contrast in overall wilt disease resistance between M. suaveolens and the other two species led to speculation that verticillium wilt disease resistance was genetically linked to a spearmint oil type. However, one carvone-type M. longifolia accession, CMEN 584, was among the most highly wilt-susceptible accessions of that species. Segregating F1 and F2 populations derived from crossing CMEN 584 with wilt-resistant M. longifolia accession CMEN 585 also showed a range of wilt resistance to susceptibility, with wilt susceptibility not associated with any particular oil phenotype (Hummer, pers. comm.). It is possible that the higher wilt resistance in M. suaveolens results from homozygosity at particular loci or even a different genetic resistance from the other two species.

Transgressive segregation, a phenomenon in which progeny traits differ from those of either parent, is well documented in oil types resulting from Mentha crosses (Tucker, 2012). Since both monoterpene profile and verticillium wilt resistance are polygenic traits, transgressive segregation can be expected for verticillium wilt resistance as well. With the advent of the M. longifolia reference genome, the genetic underpinnings of these traits are now actively being studied. The complex regulatory mechanisms governing both and verticillium wilt resistance will be a challenge to breeding

In conclusion, mint has a long history of human use and influence and relatively recent (within the past century) increasing attention by mostly private breeding programs. With the advent of genome sequencing, efforts are underway to develop molecular markers for alleles of monoterpene biosynthesis genes and for verticillium wilt disease resistance

Vining et al.

FIGURE 7 | Example of SSR genotyping with M. aquatica.

genes. Going forward, marker assisted selection will increase in importance to mint breeding programs.

### AUTHOR CONTRIBUTIONS

All authors contributed equally to this manuscript.

### FUNDING

Funding for the collection, maintenance, distribution, and evaluation of the NCGR Mentha collection was provided by USDA ARS PWA CRIS 2072-21000-049-00D.

### REFERENCES

Doebley, J. F., Gaut, B. S., and Smith, B. D. (2006). The molecular genetics of crop domestication. Cell 127, 1309–1321. doi: 10.1016/j.cell.2006.12.006

### ACKNOWLEDGMENTS

We appreciate the taxonomic assistance of Henrietta Chambers and Arthur Tucker in species determinations of the NCGR Mentha collections. We appreciate the technical assistance of James Oliphant, Jeanine DeNoma, Debra Hawkes, Melissa Fix, and Sunny Green.

### SUPPLEMENTARY MATERIAL

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpls.2020.01217/ full#supplementary-material

Fuchs, L. (1543). De historia stirpium commentarii insignes (Basel, Switerland).

Yasudori, T. (984). 醫心方, Ishinpō Tokyo, Japan.

Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The handling editor declared past co-authorship with several of the authors [NB, KV].

Copyright © 2020 Vining, Hummer, Bassil, Lange, Khoury and Carver. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

digital media

of impactful research

article's readership


**Meet the editor**

Georgios Androutsopoulos completed his Degree in Medicine in 1995, at National and Kapodestrian University of Athens. He received his Medical Specialization and completed his Doctorate of Medicine, at University of Patras. He started his academic career in 2012, as Lecturer and Consultant of Obstetrics and Gynecology at University of Patras. In 2014, he became Assistant Pro-

fessor and Consultant at the same University and holds the position until today. Currently, he is the Head of the Division of Gynecological Oncology of the University of Patras. He has academic and clinical experience as well as heavy research and educational workload. Moreover, he has active participation in Undergraduate Educational Program as well as in Residency Training Program of the University of Patras.

Contents

**Preface VII**

**of Cesarean Section? 3** Georgios Androutsopoulos

**Section 2 Epidemiology - Indications 7**

Chapter 2 **Trends in Cesarean Section 9** Andres Sarmiento

**Section 3 Surgical Technique 41**

**Section 4 Complications 79**

**Evidence Based? 43**

Chapter 6 **Complications of Cesarean Operation 81**

Enrique Rosales Aujang

Chapter 1 **Introductory Chapter: Is It Time to Reconsider the Importance**

Chapter 3 **Value of Caesarian Section in HIV-Positive Women 23** Simona Claudia Cambrea and Anca Daniela Pinzaru

Chapter 4 **The Surgical Technique of Caesarean Section: What is**

Jan-Simon Lanowski and Constantin S. von Kaisenberg

Chapter 5 **Pros and Cons of Myomectomy during Cesarean Section 65** Cengiz Tokgöz, Şafak Hatirnaz and Oğuz Güler

**Section 1 Introduction 1**


**3. Study 2: exploratory (pilot) randomised control study (RCT)**

### **3.1 Research design**

The study was initially going to be carried out as a randomised control trial (RCT) for 24 months. The RCT study design is considered to be the highest level of scientific testing as it minimises patient control bias [25]. However, halfway through the recruitment process, it became apparent that the numbers required to achieve an RCT would not be met due to a number of factors that were out of the control of the research team. These factors included a drop in patient referrals due to a reform in the referral process from primary care into secondary care, a lack of engagement by treatment centres in terms of not fully understanding which healthcare professionals could refer patients into the trial and a small number of eligible participants who matched the study inclusion criteria. Therefore, after the discussions with the consultants, brace clinicians and research team, it was decided that the best solution to these problems would be to continue the trial as a prospective study with a control group for 6 months. There are several reasons for the reduction in the trial time scale. Firstly, it took over 13 months to gain NHS ethics; secondly, the participant referrals dramatically decreased after the first 12 months due to NHS reforms, and therefore any new entries into the trial would not have finished their treatment program before the scholarship of the primary author concluded. Therefore, recruitment was halted after 18 months. As a result of this, the data presented in this work are from 6 months of data collection.

### **3.2 Recruitment of participants**

The participants for the study were recruited and identified by consultants, physiotherapists and spinal nurses when they attended their regular orthopaedic clinics. When attending these appointments, the patients were screened by their consultants to ensure they were suitable and matched the study criteria. Participants for the study were initially going to be recruited from three different treatment centres; however, only one referred any participants into the trial. Once a participant was referred into the trial, they were randomised into either the treatment or control group; this was done through a computer randomisation program. Participants in the treatment group received the soft brace in addition to the standardised assessment tools described below.

### **3.3 Participant inclusion/exclusion**

To ensure that appropriate patients were recruited for the trial, after a number of discussions amongst the research team, brace manufacturers, surgeons and physiotherapists, a set of inclusion and exclusion criteria was drawn up. This was to ensure

that the participants would be able to fully partake in the trial without having any additional problems or issues placed upon them as a result of participating.


*4.2. Determinants of Adoption of Climate Change Adaptation Strategies*

The R2 of 0.2503 for the overall model indicates that 25.03% of the variation in the choice of adaptation strategy mix (dependent variable) was due to the variations in the different social and economic factors of the households (explanatory variables). Though this value is low, the pseudo R2 for MNL models to explain social and behavioral outcomes, e.g., adaptation choices of households in Bobirwa sub-district, are usually low as shown by studies elsewhere [23,52]. The low R2 also suggests that there could be other relevant factors not included in the model which may explain the adaptation choices by households in the study. In the study area, these could include the mean annual temperature, mean annual precipitation, drought severity and recurrence, the extent of government programs such as Ipelegeng ("cash-for-labour") and ISPAAD, market development, migration and extent of human-wildlife conflicts. Those attributes with *p*-values below 0.05 significantly influence the adaptation choices of households in Bobirwa sub-district. Whether a variable has a positive (negative) or a significant (non-significant) influence on the adoption of any adaptation strategy should not imply a "cause-effect" relationship. However, where causality exists, this could be an important entry point for transforming current adaptation initiatives to be more effective and sustainable [53].

#### 4.2.1. Gender of Household Head

The non-significant effect of the gender of the main decision-maker on the adoption of any strategy (*p* > 0.05) indicates that the differences in the adoption of any strategy were not statistically different between female and male decision-makers at the household level. Female decision-makers at the household level were less likely to take up Land, Soil, and Water + Livestock-related Adaptations; Crop Adaptations Only; Crop + Livestock-related Adaptations; and Crop + Livestock + Land, Soil, and Water Conservation Adaptations compared to male-headed households as shown by the negative coefficient. These findings contrast those from other studies which found gender of the main decision-maker to significantly influence their choice of adaptation strategies among farming communities [13,30,54].

Although female decision-makers in households in Bobirwa sub-district were more likely to adopt livestock production and management practices as the only adaptive response, women and young people mostly reared chickens and small livestock such as goats. This could be due to the low feed demands by chickens and small livestock compared to large livestock such as cattle [44,55]. Studies such as [26] also found that male-headed households in Southern Africa were more likely to diversify livestock and crop production including other off-farm activities to manage the impacts of climate change than their female counterparts. Therefore, female-headed households in Bobirwa sub-district could be limited by the numerous household chores, childcare as well as the demanding nature of many agricultural adaptations. Such multiple tasks reduce the time for women to take up diversified adaptations as revealed by the negative relationship between female decision-makers at the household level and the adoption of several adaptation strategies.

Considering that female decision-makers only had higher chances of adopting Livestock-related Adaptations Only; Land, Soil, and Water Conservation Adaptations Only; and Crop + Land, Soil, and Water Conservation Adaptations, it may suggest that women in Bobirwa sub-district still face challenges in accessing resources such as land, relevant information and capital compared to male-headed households. Despite the high ownership of information communication channels such as mobile phones, television sets, and radios among the surveyed households, information asymmetry between males and females is very high among many rural farming communities as shown by studies elsewhere in Africa [13,34,56]. This could suggest that less relevant or inadequate information is shared through these channels. In addition, with only 32.3% of female heads of households being full-time farmers, where most of the household heads were females (79.7%) in a rural farming community, this further highlights the limits imposed on rural women by the several roles they perform.

As most of the heads of households were part-time farmers, both men and women in Bobirwa were expected to have limited time to fully implement most of the agricultural practices despite being the main decision-makers. However, unlike in other studies where women and children were mostly implementers of adaptation practices and decisions made by males, in Bobirwa sub-district, it is important for decision-makers to make adaptation decisions and policies which resonate well with women and young people. Being the majority of the household decision-makers, women can easily influence and inform the type of adaptations that require government support for them to be more effective. With the Government of Botswana culture of participatory decision-making through consulting communities in a bottom-up approach [57], adaptation policy and planning can easily cater for the gendered challenges within communities.

#### 4.2.2. Age of Household Head

The negative influence of age of the main decision-maker on all the seven adaptation strategies shows that aging hinders the adoption of any of the current adaptation strategies. However, aging only significantly reduced the adoption of Land, Soil, and Water Conservation Adaptations and that of Crop + Land, Soil, and Water Conservation Adaptations. These findings are different from previous studies like [25] where the age of the main decision-maker in the household was shown to significantly enhance adaptation to climate change by farmers in the Nile Basin of Ethiopia. The limitations imposed by aging in Bobirwa sub-district could be attributed to the reduced planning horizons and agility as people grow older. Therefore, elderly farmers were less likely to take up long-term adaptation decisions, particularly those involving demanding tasks. Despite the findings, elderly heads of households in Bobirwa sub-district could play a significant role in promoting successful adaptations by passing on the knowledge and experience acquired over the years to young people who are not only energetic but still have longer planning horizons. Young people are also more likely to integrate such knowledge with emerging adaptation measures.

With adult heads of households (41–60 years) more likely to adopt Land, Soil, and Water Conservation Adaptations Only; Land, Soil and Water + Livestock-related adaptations; Crop Adaptations Only; Crop + Land, Soil, and Water Conservation Adaptations and Crop

+ Livestock + Land, Soil, and Water Conservation Adaptations compared to young heads of households (<40 years), this shows that adult farmers were more experienced than young farmers [25]. Importantly, this could mean that the peak of adoption was reached in adulthood (41–60 years) and declined among the elderly. Studies by [23,34,58] also found age to be a proxy of, and correlated to, experience. Therefore, despite the declining adoption of adaptations with age, adult and elderly farmers in Bobirwa sub-district could be more knowledgeable and experienced about the dynamics of climate change adaptation than younger farmers.

#### 4.2.3. Dry Land Cropped Area

The negative influence of increasing the cropped area on the adoption of all adaptation strategies except livestock adaptations could be influenced by the surveyed household heads being mostly part-time farmers. Bigger farms require more resources and time to implement the various agronomic practices which part-time farmers may not have. Since most of the households (62.3%) had annual incomes below BWP5000 (US \$450), these could be inadequate for financing adaptation practices. Therefore, increasing the cropped area could be further limited by the low incomes. The emigration of at least two economically active household members in search of employment opportunities in neighboring towns and cities often results in households composed of more children and the elderly whose labour may not be available for farming. A high composition of children adds a strain on women—who usually have multiple household chores—through providing care which limits the time available to implement the numerous agronomic adaptation practices.

Although agricultural expansion was viewed by local communities as an adaptation to more severe droughts, the results suggest that bigger farms, which require more time and effort to implement various agronomic and adaptation practices, were a barrier to climate change adaptation in Bobirwa sub-district. Therefore, smaller farms require less time and effort for land preparation and implementing the various agronomic practices given the small household sizes (5) and low ownership of donkeys (26.1%), which are solely used for draft power in the study area. Despite the majority of households (63.8%) reporting that they owned agricultural land privately with papers, croplands in Bobirwa sub-district are communally owned and can be partitioned for other members as the human population grows [27]. Therefore, households could be reluctant to invest in meaningful and lasting adaptation strategies on their farms. This could be a barrier to the implementation of various adaptations on larger farms which may be targeted for partitioning than smaller farms.

The increased chances of the adoption of livestock-related adaptations with bigger cropped areas could be attributed to the complementarity between livestock and crop production. Livestock such as donkeys provide draft power for tillage while crop residues from crop production are increasingly used for feeding livestock during the dry season. Therefore, bigger farms encourage farmers to undertake livestock practices as an adaptation strategy as there exists a mutual relationship between the provision of draft power from livestock while residues from crops are used to supplement livestock feeds especially when pastures are scarce. A study by [46] reported that as part of the pre-drought preparations in Bobonong (village in Bobirwa), farmers stored crop residues of sorghum and maize for their livestock. Similarly, as a response to the declining availability of natural pastures, households could stock up and feed their livestock with crop residues from bigger farm sizes even with crop failure.

### 4.2.4. Household Size

The negative influence of bigger household sizes on the adoption of all the adaptation strategies, except one on crop and livestock adaptations in sub-district, could be attributed to the low composition of able-bodied and economically active members due to emigration. Although bigger household sizes have been shown to improve the adoption of adaptations by studies such as [59], the contrasting results from this study are likely due to the high composition of children, the elderly, and women. This is mainly due to the emigration of mostly young and adult members of the household who could be providing labour on the farms.

Young people living and working in neighboring towns and cities, particularly young women, often leave their children under the care of their parents or grandparents and return to the cities. This often leaves most households with many minors who require childcare which further limit time for working in the fields. As effective adaptations to climate change often require farmers to undertake several activities beyond their usual seasonal routines, this requires more labour and time resources which are limited by emigration of able-bodied household members. For instance, land, soil, and water conservation practices are usually labor-intensive. Therefore, households with several able-bodied members who are available to work on the farm may be able to take up several climate change adaptation measures than those households with fewer such members. There is a need for government programs to enhance livestock production, particularly donkeys which provide draft power for tillage. Government programs such as the ISPAAD, which assist poor farmers with free tillage and other inputs, also need to assist local communities to own tractors which they can control and schedule. This can increase the effectiveness of the programme and the timing of activities.

### 4.2.5. Climate Information

The very high access to climate and agricultural information (91%) by surveyed households in Bobirwa sub-district is attributed to the high ownership of cellular phones (94.5%), television sets (63.5%), and radios (51.6%). This is shown by the high proportion of households who were influenced or informed by radio or TV programme (78.1%) to adopt new farming practices. The high literacy level as shown by more than 72% of household heads with formal education further suggests that people were able to comprehend the messages sent through cell phones, radios, television sets, and print media. Therefore, the positive influence of access to climate information on the adoption of all the adaptation strategies could be attributed to the high ownership of communication gadgets and high literacy levels. High access to climate information by the surveyed households is also attributed to face-to-face interaction with extension officers (71%), village chiefs (*DiKgosi*) (41.9%), other successful farmers (39.7%), and farmer organizations (23.2%). [26] also reported a high uptake of adaptation measures among smallholder farmers who perceived changes in climate in southern Africa.

Although formal education was shown to enhance the adoption of Livestock-related Adaptations Only; Land, Soil, andWater+Livestock-related Adaptations; Crop+Land, Soil, andWater Conservation Adaptations; and Crop + Livestock + Land, Soil, and Water Conservation Adaptations, the effect was not significant. This may suggest that information on climate change and adaptation acquired through formal education could be inadequate to significantly enable effective adaptations in the study area. A study by [60] in 11 African countries noted that perceiving climate change was critical to decision-making and choosing the appropriate strategies to adopt. There may be need for improving the education curriculum to include climate change adaptation studies at all levels of formal education up to the tertiary level to enhance the adoption of adaptation practices that are more informed, effective and relatively inexpensive. The negative influence of formal education on the adoption Land, Soil, and Water Conservation Adaptations Only; Crop Adaptations Only; and Crop + Livestock-related Adaptations could therefore be due to less relevant information acquired over the years.

The quality and spatial resolution of climate information are also critical particularly for crop-related adaptations where the timing of certain operations is an important factor. The non-significant influence of climate information on the adoption of appropriate adaptation strategies could be due to the high spatial resolution of climate information by the Meteorological Services Department (MSD). For instance, weather information and seasonal forecasts in Botswana are often generalized and focus on the district levels to be of much relevance to decision-making at the sub-district, village, and farm levels. There is a need for the MSD to issue more localized weather and climate information which are more relevant at the farm level. With multiple information channels accessible to households (e.g., cellular phone, television, and radio) and the high literacy levels in Bobirwa sub-district, these could enhance the sharing of more localized, detailed, and relevant weather and climate information as well as climate change adaptation strategies.

With households depending mainly on traditional knowledge (41.3%) and meteorological services (58.4%) for climate information, the two climate information sources need to be complementary. The influence of non-formal and traditional knowledge on the adoption of agricultural adaptations among rural communities need to be well understood, validated, and synchronized with scientific information from formal institutions such as MSD. In addition to observing changes in vegetation, crop phenology, and growth patterns, information from the MSD, Ministry of Agriculture and other relevant institutions could significantly influence decisions at the household level and enhance the timely adoption of more appropriate adaptation measures.

Decentralized weather forecasting could allow more localized, relevant, and timely forecasting that can allow stakeholders and local communities to synchronize the traditional indicators with the scientific information from MSD. Extension information from the Ministry of Agriculture also needs to be current to enable farmers to adopt crops and practices suitable to the agroecological conditions in the study area that agricultural adaptations can be impactful [46].

#### 4.2.6. Household Wealth

Several variables in the model were indicators of household wealth, i.e., remittances, annual income, the proportion of remittances financing adaptations, as well as the number of rooms in the main house. Nonetheless, it was important to examine their individual effects. The negative influence of remittances, annual income, and the number of rooms in the main house on the adoption of almost all the adaptation strategies suggests that wealthier households in Bobirwa sub-district had less direct dependence on agriculture and ecosystem products. This is consistent with previous studies which showed that poor households were more dependent on the ecosystem products than wealthier households [61,62]. Therefore, as household wealth increases, households in Bobirwa sub-district were more likely to buy household food requirements and pay for other requirements than producing themselves.

Other studies have shown a positive influence of wealth and higher incomes on the adoption of agricultural adaptation in South Africa [43], Niger [39], and Zimbabwe [13]. The surveyed households in Bobirwa sub-district were therefore less likely to depend on the ecosystem products, particularly from agriculture and woodlands, with increasing income. Higher incomes enable households to purchase their food requirements than produce it themselves given the severe droughts. Therefore, increasing opportunities for off-farm incomes could effectively reduce the dependence on natural ecosystems and help with conservation efforts. Reduced human dependence on ecosystem products can allow biodiversity regeneration, enhance the condition of local ecosystems and improve the delivery of provisioning ES.

#### 4.2.7. Occupation and Employment Status of Household Head

The positive influence of being a full-time farmer on the adoption of all adaptation strategies except Land, Soil, and Water Conservation, unlike part-time farmers, is attributed to more disposable time resources to practice or implement these adaptations. Although formal employment is usually associated with sustained and reliable income, annual income and remittances have already been shown to have a negative influence on the adoption of almost all the adaptation strategies. However, other positive, non-monetary benefits of formal employment among household members in the study area are related to access to recent, up-to-date, and relevant climate and agricultural information which allows them to make informed decisions using experience gained in a formal setting. Other studies have shown that household members working outside their communities were not only bringing new information, ideas, and technologies but were also influential in the decision-making of their households [7,63].


**8. Conclusion**

terms of their severity and regarding the predominant disturbance of certain social cognitive domains. According to Henry, while testing empathy and ToM skills, it is also recommended to perform in parallel direct mapping of underlying MS‐related neuropathology for detecting a link between structural brain pathology and social cognitive impairments. Pöttgen estab‐ lished a deficient ability to reason about the mental state of others (ToM) and to have insight into the emotional stages and feelings of others (empathy) in the early stages of RRMS [21, 22], even in patients who have no substantial neuropsychological deficits. Emotional prosody comprehension may also be disrupted in the early stages of RRMS [6]. It is argued that this is the earliest social cognitive impairment in patients with MS. Deteriorated emotional percep‐ tion at this early stage can create a difficulty in perceiving nuances, such as sarcasm, irony and sincerity, which may lead to interpersonal problems. To confirm these observations, interna‐ tional research with larger groups of patients is required. Data from this study indicate that one year after diagnosing a patient with CIS and RRMS, they experience diminished power of attention and memory speed, which is related to a capacity for fewer working hours, fatigue, depression and may have a negative impact, as opposed to self‐efficacy, which affects working hours positively. The level of ToM abilities and their relation to the above‐mentioned conse‐

Information on social cognition impairments and different forms of MS is still scarce. The main controversies that we encountered in the course of reviewing the material on the topic are about how the grade of disturbance of social cognition skills relates to the state of general cognition, on the one hand, and to the grade of physical disability and/or the duration of the disease, on the other. These issues remain disputable due to the small size of patient cohorts and the lack of homogeneity within the groups of conducted studies. Moreover, the majority of studies on social cognition skills in MS assess the patients' social cognitive skills at a given point without following up on their development over time. This prevents us from making conclusions about their dynamics during the course of the disease or taking into account the effect of a therapeutic and/or rehabilitation approach. Extensive long‐term follow‐up studies with well‐defined inclusion criteria, consistent sample characteristics and a wide range of clinical and imaging measurements could establish which domains of ToM change in the

We devoted a lot of time to reviewing studies on social cognition also in other neurodegener‐ ative and mental diseases. We were impressed with the extensive research in skills for interpersonal problem solving, for recognizing social cues, for detecting situational character‐ istics and for solving situation connection tasks. Our opinion is that a similar approach towards social cognitive impairments in MS would throw additional light on the objective evaluation of the patient's dealing with real situations in a social context. Even studies on the relation between social cognition disturbances and functional outcome define this relation in general terms, without specifying which domains of social cognition should refer to which functional outcome domains. Resolving these issues in the MS field is a challenge for scientists requiring uniform strategies, long‐term follow‐up, creativity and interdisciplinary cooperation among

quences have not been followed up.

244 Trending Topics in Multiple Sclerosis

researchers.

course of the disease, in what way and at to what extent.

Social cognitive impairments are a common finding in patients with MS and are often manifested at the initial stages of the disease. Both empathy and ToM deficits, regardless of physical disability, lead to psychosocial consequences such as failure to achieve life goals, limitations to employment and leisure activities, inadequacy in social relationships and daily activities [58, 61]. The preservation of a better quality of life in patients with MS requires special attention to the above mentioned aspects of the disease. Timely recognition of the deficit and adequate rehabilitation of social cognition would help patients enjoy a fulfilling social life for a longer time.


**1. Introduction**

In recent years, there has been a dramatic growth in the number of generalisations of well-known probability distributions. Most notable generalizations are achieved by (i) inducting power parameters in well established parent distributions, (ii) extending the classical distribution by modification in their functions, (iii) introducing special functions such as W[K(x)] as generators and (iv) by compounding of distributions. This heaped surge of generalized families is due to the flexibility in modelling phenomenons related to the changing scenarios of contemporary scientific field including demography, actuarial, survival, biological, ecological, communication theory, epidemiology and environmental sciences. However, a clear understanding of the applicability of these models in most applied areas is necessary if one is to gain insights into systems that can be modeled as random processes. The model, thus obtained, acquires improved empirical results to the real data that is collected adaptively.

Although there exist many functions which act as generators to produce flexible classes of distributions, in this project, we will emphasize generalizations in which a ratio of survival function (sf) has been used in some form, commonly known as the odd ratio. In the reference [1], a proportional odd family *viz. a viz.* the Marshall Olkin-G (MO-G) was generalized by sf *K*(*x*) = 1 − *K*(*x*), where *K*(*x*) is the distribution function (cdf) of parent distribution, with the induction of a tilt parameter. Gleaton and Lynch, in the reference [2],

**Citation:** Khan, S.; Balogun, O.S.; Tahir, M.H.; Almutiry, W.; Alahmadi, A.A. An Alternate Generalized Odd Generalized Exponential Family with Applications to Premium Data. *Symmetry* **2021**, *13*, 2064. https:// doi.org/10.3390/sym13112064

Academic Editor: Zhivorad Tomovski

Received: 19 September 2021 Accepted: 14 October 2021 Published: 1 November 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

used the odd function as generator when they defined a log odd family (OLL-G). In the reference [3], defined the odd Weibull family, as an asymptotically equivalent log-logistic model for larger values of *θ*, the scale parameter. The reference [4] used the Transformed -Transformer (TX) family, due to the reference [5], to define odd Weibul-G families of distribution. Since then, a myriad of distributions has been generalized using odd function. Some of the important families include [6–31], among others.

Focussing on the origins and motivations of our proposed scheme, the authors in [32] proposed the odd generalized exponential family (which we refer to OGE-G) as a better alternative to generalized exponential (GE) family using Lehmann Alternative-I (LA-I). The cdf of the two parameter OGE-G family is mentioned below:

$$F\_{\rm OGE-G}(\mathbf{x}; \mathfrak{a}, \lambda, \mathfrak{v}) = \left(1 - \mathbf{e}^{-\lambda \frac{K(\mathbf{x}; \mathfrak{v})}{\overline{K}(\mathbf{x}; \mathfrak{v})}}\right)^{\mathfrak{a}}, \quad \mathbf{x} > 0, \mathfrak{a} > 0, \lambda > 0.$$

In the reference [33], an odd family of GE was proposed so-called generalized odd generalized exponential family (which we refer to OGE1-G). The cdf of OGE1-G family is presented as:

$$F\_{\rm OGE1-G}(\mathbf{x}; \mathfrak{a}, \boldsymbol{\beta}, \boldsymbol{\psi}) = \left(1 - \mathbf{e}^{-\frac{K^{\alpha}(\mathbf{x}; \boldsymbol{\psi})}{1 - K^{\alpha}(\mathbf{x}; \boldsymbol{\psi})}}\right)^{\beta}, \quad \mathbf{x} > 0, \boldsymbol{\alpha} > 0, \beta > 0.$$

Because of its capacity to simulate variable hazard rate function (hrf) forms of all traditional types in lifetime data analysis, we believe OGE-G offers a sensible combination of simplicity and flexibility. However, the relevance of OGE1-G to lifespan modelling in domains such as reliability, actuarial sciences, informatics, telecommunications, and computational social sciences (just to highlight a few) is still debatable. According to the reference [34], the Lehmann Alternative-II (LA2) approach has received less attention. This motivated us to use LA2 approach to develop the exponentiated odd generalized exponential (OGE2-G), in the same vein as OGE-G and OGE1-G. Adhering to the framework defined in the reference [5], if *T* follows GE random variable (rv), then the cdf of OGE2-G family is mentioned below:

$$F\_{\rm OGE2-G}(\mathbf{x}; \mathbf{a}, \boldsymbol{\beta}, \boldsymbol{\psi}) = \left[1 - \mathbf{e}^{-\frac{1 - \overline{\mathbf{Z}}(\mathbf{x}; \boldsymbol{\psi})^{\mathbf{a}}}{\overline{\mathbf{Z}}(\mathbf{x}; \boldsymbol{\psi})^{\mathbf{a}}}}\right]^{\beta}, \quad \mathbf{x} > \mathbf{0}, \mathbf{a}, \beta > 0 \tag{1}$$

where *α* and *β* are shape parameter and *ψ* is the vector of baseline parameter.

Consider the following points to emphasise the model's distinctiveness; (i) In the literature, the proposed model in its current form has not been studied to the best of our knowledge, (ii) From an analytical standpoint, the OGE2-G family has a significantly better configuration and practicality than OGE-G and OGE1-G for inverted models with minimal chance to counter non-identifiability issues, (iii) The OGE2-G has several curious connections to other families. When *α* approaches 0, *F*(*x*; *α*, *β*, *ψ*) tends to GE with *λ* = 1, when *α* = 1 *F*(*x*; *α*, *β*, *ψ*) tends to OGE-G, if *α* → 0 and *β* = 1 then *F*(*x*; *α*, *β*, *ψ*) tends to odd exponential (OE) (iv) This new dimension allowed us to explore models which are naturally constituted by LA2. The generalizations, thus attained, produced skewed distributions with much heavier tails enabling its practicality in risk evaluation theory with far better results, (v) The successful application of OGE2-G family motivates future research, as it outperforms nine well-established existing models, (vi) We present a physical explanation for *X* when *α* and *β* are integers. Consider there be a parallel system consisting of *β* identically independent components. Suppose that the lifetime of a rv *Y* with a specific *K*(*x*; *ψ*) with *α* components in a series system such that the risk of failing at time *x* is

represented by the odd function as 1−*K*(*x*;*ψ*)*α K*(*x*;*ψ*)*α* . Consider that the randomness of this risk is represented by the rv *X*, then we can assume the following relation holds

$$\Pr(\mathbf{Y} \le \mathbf{x}) = \Pr(X \le \frac{1 - \overline{\mathbb{K}}(\mathbf{x}; \boldsymbol{\psi})^a}{\overline{\mathbb{K}}(\mathbf{x}; \boldsymbol{\psi})^a}) = F(\mathbf{x}; \boldsymbol{\mathfrak{a}}, \boldsymbol{\beta}, \boldsymbol{\psi}) \; \mathsf{A}$$

explicitly given in Equation (1). The OGE2-G family is offered and explored in this research, emphasising its diversity and scope for application to real life phenomenons. The major features of the OGE2-G family, including the pdf, hrf, qf, and ten unique models from OGE2-G family presented in Table 1, are provided in the first half. Then, certain mathematical properties of the OGE2-G such as series expansion of the exponentiated pdf, moments, parameter estimation, order statistics, Rényi entropy, stress-strength analysis and stochastic dominance results are investigated. Furthermore, Fréchet is specified as baseline model termed as OGE2-Fréchet (denoted as OGE2Fr) and the maximum likelihood (ML) technique is then used to construct statistical applications of the special model. We choose to study OGE2Fr specifically as its nested model include inverse-Rayleigh (IR) and inverse exponential (IE), favoring its suitability over sub-models as well. It is applied to fit two sets of premium data from actuarial field. Using key performance indicators, we reveal that OGE2Fr outperforms nine competing models. A portion pertinent to specific risk measures, with an emphasis on the value at risk (VaR) and the expected shortfall (ES), is presented. Eventually, the estimation of risk measures for the examined data sets is then discussed, with the proposed methodology yielding a rather satisfying result. Equation (1) can be useful in modelling real life survival data with different shapes of hrf. Table 1 lists 1−*K*(*x*;*ψ*)*α K*(*x*;*ψ*)*α* and the corresponding parameters for some special distributions which are considered to be the potential sub-models of OGE2-G family.

**Table 1.** Distributions and corresponding 1−*K*(*x*;*ψ*)*α K*(*x*;*ψ*)*α* functions.

The following is a breakdown of how the paper is constructed. In Section 2, we acquaint the readers to the new family with basic properties and ten potential baseline models which can become members of OGE2-G family. Section 3 is comprised of the mathematical properties of the OGE2-G family. Section 4 progresses by taking Fréchet (Fr) as sub-model to propose OGE2Fr and related statistical and inferential properties. Section 5 specifies two applications of actuarial data sets with emphasis on risk evaluation (premium returns) and the proposed model's veracity is established. Furthermore, the

model is applied to compute some actuarial measures. Section 6 is the final section, with some annotations and useful insights.

### **2. The OGE2G Family**

In this segment, basic statistical properties of the newly proposed family characterized by the cdf, in Equation (1) are presented. Functional forms of ten sub models are also defined.

### *2.1. Definition of pdf and hrf*

The pdf in agreement with Equation (1) is given as (2).

$$\left(f\_{\text{OGE2}-G}(\mathbf{x}; \mathfrak{a}, \mathfrak{k}, \mathfrak{\boldsymbol{\psi}})\right)^{-} = \left. a \, \mathfrak{k} \, k(\mathbf{x}; \mathfrak{\boldsymbol{\psi}}) \, \overline{\mathbf{K}}(\mathbf{x}; \mathfrak{\boldsymbol{\psi}})^{-a-1} \, \mathbf{e}^{-\left\{\frac{1-\overline{\mathbf{K}}(\mathbf{x}; \mathfrak{\boldsymbol{\psi}})^{a}}{\overline{\mathbf{K}}(\mathbf{x}; \mathfrak{\boldsymbol{\psi}})^{a}}\right\} \left[1-\mathbf{e}^{-\left\{\frac{1-\overline{\mathbf{K}}(\mathbf{x}; \mathfrak{\boldsymbol{\psi}})^{a}}{\overline{\mathbf{K}}(\mathbf{x}; \mathfrak{\boldsymbol{\psi}})^{a}}\right\} \right]^{\beta-1} \tag{2}$$

Using the results defined in Equations (1) and (2), the hrf is defined as

$$\begin{split} \tau(\mathbf{x}; \boldsymbol{a}, \boldsymbol{\beta}, \boldsymbol{\psi}) &= \quad \frac{f\_{\text{OGE2}-G}(\mathbf{x}; \boldsymbol{a}, \boldsymbol{\beta}, \boldsymbol{\psi})}{1 - F\_{\text{OGE2}-G}(\mathbf{x}; \boldsymbol{a}, \boldsymbol{\beta}, \boldsymbol{\psi})} \\ &= \quad \mathbf{a} \boldsymbol{\beta} \, k(\mathbf{x}; \boldsymbol{\psi}) \overline{\mathcal{K}}(\mathbf{x}; \boldsymbol{\psi})^{-\mathbf{a}-1} \mathbf{e}^{-\left\{\frac{1-\overline{\mathcal{K}}(\boldsymbol{x}; \boldsymbol{\psi})^{\mathbf{a}}}{\overline{\mathcal{K}}(\boldsymbol{x}; \boldsymbol{\psi})^{\mathbf{a}}}\right\}} \left[1 - \mathbf{e}^{-\left\{\frac{1-\overline{\mathcal{K}}(\boldsymbol{x}; \boldsymbol{\psi})^{\mathbf{a}}}{\overline{\mathcal{K}}(\boldsymbol{x}; \boldsymbol{\psi})^{\mathbf{a}}}\right\}}\right]^{\beta - 1} \\ & \times \left[1 - \left(1 - \mathbf{e}^{-\left\{\frac{1-\overline{\mathcal{K}}(\boldsymbol{x}; \boldsymbol{\psi})^{\mathbf{a}}}{\overline{\mathcal{K}}(\boldsymbol{x}; \boldsymbol{\psi})^{\mathbf{a}}}\right\}\right)^{\beta - 1}\right] \end{split} \tag{3}$$

The hazard rate is just a calculation of the change in survivor rate per unit of time. Hence, its importance in reliability and survival analysis is crucial. The hrf has some characteristic shapes which include monotonic (increasing, decreasing), non-monotonic (bathtub or upside down bathtub) or constant. Standard statistical distribution yield maximum three shapes, but OGE2-G family can yield a diverse range of shapes (including increasing-decreasing-increasing) depending upon the choice of special model. For further details on hrf, see [35].

### *2.2. Quantile Function and Potential Sub-Models*

The OGE2-G family may be readily approximated by reversing Equation (1) as shown below: If indeed the distribution of *u* is uniform *u*(0, 1), therefore

$$\mathbf{x} = Q\_K \left[ 1 - \left\{ 1 - \log \left( 1 - u^{1/\beta} \right) \right\}^{-1/a} \right]. \tag{4}$$

Equation (4) can be useful to define statistical measures such as median, skewness, and kurtosis based on quartiles, deciles, or percentiles. These measures facilitates to concisely define the skewness and kurtosis measures which are significant tool to comprehend the shape(s) of the distribution.

Theorem 1 shows how the OGE2 family is related to other distributions.

\*\*Theorem 1.\*\*  $Let \ X \sim \text{OGE2-G}(\mathfrak{a}, \beta; \mathfrak{\psi})$ , then

 $(a) \text{ If } Y = 1 - \overline{\mathcal{K}}(\mathfrak{x}; \mathfrak{\psi})^{\mathfrak{a}}, \text{ then } F\_Y(y) = \left(1 - \mathbf{e}^{-\frac{\underline{\chi}}{1 - \underline{\chi}}}\right)^{\mathfrak{f}}, \quad 0 < y < 1, \text{ and}$
 $(b) \text{ If } Y = \frac{1 - \overline{\mathcal{K}}(\mathfrak{x}; \mathfrak{\psi})^{\mathfrak{a}}}{\overline{\mathcal{K}}(\mathfrak{x}; \mathfrak{\psi})^{\mathfrak{a}}}, \text{ then } Y \sim \text{GE}(1, \beta).$

### **3. Mathematical Properties of OGE2-G Family**

To capture the family's modelling capacity, numerous mathematical features of the OGE2-G are examined in this section. Some of the key results established in this section are then applied in Section 5.

### *3.1. Linear Expansion of cdf*

We provide a useful expansion for (1) in terms of linear combinations of exp-G density functions using the following series expansion as

$$(1-z)^{\eta-1} = \sum\_{i=0}^{\infty} \frac{(-1)^i \Gamma(\eta)}{i! \Gamma(\eta-i)} z^i,$$

whereas the expansion holds for all |*z*| < 1 and *η* > 0 a non-integer value. Then, the cdf of OGE2-G class in (1) can indeed be phrased with

$$F(\mathbf{x}) = \sum\_{i=0}^{\infty} \frac{(-1)^i \Gamma(\beta + 1)}{i! \, \Gamma(\beta + 1 - i)} \mathbf{e}^{-i} \left(\frac{\frac{1 - \mathbb{E}^{\mathbf{d}}}{\mathbb{E}^{\mathbf{d}}}}{\mathbb{E}^{\mathbf{d}}}\right) . \tag{5}$$

Using series expansion and power series expansion in Equation (5), will yield the following cdf

$$F(\mathbf{x}) = F(\mathbf{x} : \mathfrak{a}, \boldsymbol{\beta}, \boldsymbol{\psi}) = \sum\_{\ell=0}^{\infty} \mathfrak{J}\_{\ell} H\_{\ell}(\mathbf{x}) \, , \tag{6}$$

where *H*(*x*) = *K*(*x*; *ψ*) (for ≥ 1) denotes the cdf of exp-G distribution with power parameter and

$$\xi\_{\ell} = (-1)^{\ell} \sum\_{i,j=1}^{\infty} \sum\_{k=0}^{j} (-1)^{i+j+k} \frac{\Gamma(\beta+1)}{i! j! \Gamma(\beta+1-i)} \binom{j}{k} \binom{\alpha(k-i)}{\ell} \dots$$

Through differentiating Equation (6) the OGE2-G family density, we may express it as a combination of exp-G densities.

$$f(\mathbf{x}:\boldsymbol{\alpha}, \boldsymbol{\beta}, \boldsymbol{\psi}) = \sum\_{i,j=1}^{\infty} \xi\_{\ell}^{\boldsymbol{\alpha}} h\_{\ell}(\mathbf{x})\,. \tag{7}$$

where *h*(*x*) = *K*−1(*x*; *ψ*) *k*(*x*; *ψ*) is the exp-G pdf with power parameter . As a result, numerous features of the proposed model may be deduced from the exp-G distribution's attributes. Most modern computation frameworks, such as MathCad, Maple, Mathematica, and Matlab, can efficiently handle the formulas derived throughout the article, which can currently operate using the use of analytic formulations of enormous size and complexity.

### *3.2. Numerous Types of Moments*

The fundamental formula for the *p*th moment of *X* is supplied by (7) as

$$
\mu\_p' = \sum\_{i,j=0}^{\infty} \xi\_\ell \, E(X\_\ell^p). \tag{8}
$$

where E(*Xp* ) = ∞0 *xph*(*x*)*dx*. Setting *p* = 1 in (8) can provide explicit expression for the mean of several parent distributions.

A another expression for *μp* is taken from (8) as far as the baseline qf is concerned

$$
\mu\_p' = \sum\_{i,j=0}^{\infty} \xi\_\ell \,\,\, \pi(p,\ell-1). \tag{9}
$$

where *τ*(*p*, − 1) = 10 *QG*(*u*)*p udu*.

The central moments (*μp*) and cumulants (*κp*) of *X* can follow from Equation (8) as *μp* = ∑*pk*=0 (*pk*)(−1)*k μp*1 *μp*−*k* and *κs* = *μs* − ∑*s*−1 *k*=1 (*s*−1 *k*−1) *κk μs*−*k*, respectively, where *κ*1 = *μ*1.

The *r*th lower incomplete moment of *X* can be determined from Equation (7) as

$$m\_r(y) = \sum\_{i,j=0}^{\infty} \xi\_\ell^x \int\_0^{G(y)} Q\_G(u)^r \, u^{l-1} d\_u. \tag{10}$$

For most *G* distributions, the final integral may be calculated.

### *3.3. Inference Related to OGE2 Family*

The strategy of maximum likelihood (MLL) approach is used to estimate the unknown parameters of the new class. Let *x*1, ... , *xn* be *n* observations from the OGE2-G density class (2) with parameter vector Θ = (*α*, *β*, *ψ*). Then the likelihood function L(*α*, *β*, *δ*) on the domain Θ is defined as

$$\begin{aligned} \mathcal{L} &= \left[ n \log(a) + n \log(\beta) + \sum\_{i=1}^{n} \log k(\mathbf{x}\_i; \boldsymbol{\psi}) - (n+1) \log \overline{\mathcal{K}}(\mathbf{x}\_i; \boldsymbol{\psi}) \right] \\ &- V(\mathbf{x}\_i; \boldsymbol{a}, \boldsymbol{\psi}) + (\beta - 1) \sum\_{i=1}^{n} \log \left[ 1 - \mathbf{e}^{-V(\mathbf{x}; \boldsymbol{a}, \boldsymbol{\psi})} \right], \end{aligned} \tag{11}$$

where *V*(*xi*; *α*, *ψ*) = 1−*K*(*xi*;*ψ*)*α K*(*xi*;*ψ*)*α*

> The elements of the score vector *U*(Θ) are as described in the following:

.

*Uα* = *n α* − *n* ∑ *i*=1 log *K*(*xi*; *ψ*) − *V*(*α*)(*xi*; *α*, *ψ*) + *n* ∑ *i*=1 *β* − 1e−*V*(*xi*;*α*,*ψ*)*V*(*α*)(*xi*; *α*, *ψ*) 1 − e−*V*(*xi*;*α*,*ψ*) , *Uβ* = *nβ* + *n*∑*i*=1 log'1 − e−*V*(*xi*;*α*,*ψ*)(, *Uψ* = *n* ∑ *i*=1% *k* (*xi*; *ψ*) *k*(*xi*; *ψ*) & + (*α* + 1) *n*∑*i*=1% *k*(*xi*; *ψ*)*k* (*xi*; *ψ*) *K*(*xi*; *ψ*) & − *V*(*ξk* )(*xi*; *α*, *ψ*) +(*β* − 1) *n* ∑ *i*=1 /e−*V*(*xi*;*α*,*ψ*)*V*(*ξk* )(*xi*; *α*, *ψ*) 1 − e−*V*(*xi*;*α*,*ψ*) 0 ,

where *V*(*α*)(.) and *V*(*ψk* )(.) means the derivative of the function *V* with respect to *α* and *ψ*, respectively.

The next elements are produced by the components of the score vector *J*(Θ).

*Jαα* = − *n α*2 + *n* ∑ *i*=1 *k*(*xi*; *α*, *β*, *ψk*)*V*(*ψk* ) *K* ¯(*xi*; *α*, *β*, *ψk*) − *V*(*α α*) + (*β* − 1) × *n* ∑ *i*=1 e −*V*(*xi*;*α*,*ψ*)*V*(*xi*; *α*, *α*) + e−*V*(*xi*;*α*,*ψ*)(*V*(*xi*; *α*))2 (1 − e−*V*(*xi*;*α*,*ψ*))2 , *Jαβ* = *n* ∑ *i*=1 e −*V*(*xi*;*α*,*ψ*) *V α*(*xi*; *α*, *ψ*) [1 − e−*V*(*xi*;*α*,*ψ*)]2 , *Jαψ* = *n* ∑ *i*=1 *k*(*xi*; *α*, *β*, *ψ*)*k*(*xi*; *α*, *β*, *ψ*) *K* ¯(*xi*; *α*, *β*, *ψ*) − *V*(*α ψ*)(*xi*; *α*, *ψ*)+(*β* − 1) × *n* ∑ *i*=1 1e−*V*(*xi*;*α*,*ψ*)\*2*V*(*α*)(*xi*; *α*, *ψ*)*V*(*ψ*)(*xi*; *α*, *ψ*) − e−*V*(*xi*;*α*,*ψ*)*V*( *αψ*)(*xi*; *α*, *ψ*) (1 − e−*V*(*xi*;*α*,*ψ*))2 −(*β* − 1) *n* ∑ *i*=1 e −*V*(*xi*;*α*,*β*,*ψ*)*V*(*α*)(*xi*; *α*, *ψ*)*V*(*ψ*)(*xi*; *α*, *ψ*) (1 − e−*V*(*xi*;*α*,*ψ*))2 +(*β* − 1) *n* ∑ *i*=1 1e−*V*(*xi*;*α*,*ψ*)\*2*V*(*α*)(*xi*; *α*, *ψ*)*V*(*ψ*)(*xi*; *α*, *ψ*) (1 − e−*V*(*xi*;*α*,*ψ*))2 , *Jββ* = − *nβ* 2 , *Jβψ* = *n* ∑ e −*V*(*xi*;*α*, *ψ*)*V*(*ψ*)(*xi*; *α*, *ψ*) 1e−*V*(*xi*;*α*, *ψ*) ,

*Jψψ* = *n* ∑ *i*=1 *k*(*xi*;*ψ*)*k*(*xi*;*ψ*) − 1*k*(*xi*;*ψ*)\*2 1*k*(*xi*;*ψ*)\*2 + (*α* + 1) *n* ∑ *i*=1 % *k*(*xi*;*ψ*)*k*(*xi*;*ψ*){−*k*(*xi*;*ψ*)}2 *K*¯ 2((*xi*;*ψ*)) & −*V*(*ψ ψ*)(*xi*;*ψ*) − (*β* − 1) *n* ∑ *i*=1 1e−*V*(*xi*;*α*,*ψ*)*V*(*ψ*)(*xi*; *α*, *ψ*)\*2 (1 − e−*V*(*xi*;*α*,*ψ*))2 −(*β* − 1) *n* ∑ *i*=1 e −*V*(*xi*;*α*,*ψ*)*V*(*ψ ψ*)(*xi*; *α*, *ψ*) + e−*V*(*xi*;*α*,*ψ*)[*V*(*ψ*)(*xi*; *α*, *ψ*)]2 (1 − e−*V*(*xi*;*α*,*ψ*))2 +(*β* − 1) *n* ∑ *i*=1 'e−*V*(*xi*;*α*,*ψ*)(2*V*(*ψ ψ*)(*xi*; *α*, *ψ*) + 1e−*V*(*xi*;*α*,*ψ*)*V*(*ψ*)(*xi*; *α*, *ψ*)\*2 (1 − e−*V*(*xi*;*α*,*ψ*))2 ,

where *V*(*α α*)(.) is the derivative of *V*(*α*)(.) with respect to *α*, *V*(*α ψ*)(.) is the derivative of *V α*(.) with respect to *ψk* and *V ψ ψ*(.) is the derivative of *V*(*ψ*)(.) with respect to *ψ*.


*2.3. Data Analysis*

From the acquired and calibrated dynamic data (i.e., Fz, Mx and My), the UCOP coordinates, XUCOP and YUCOP, with respect to the chair origin were calculated for each phase according to Equation (1), removed of their average value for each phase, and low-pass filtered through a third-order zero phase Butterworth digital filter with a 20-Hz cut-o ff frequency. This produced, for each phase, a 2D time series, {XUCOPA,YUCOPA}, {XUCOPB,YUCOPB} and {XUCOPC,YUCOPC}, respectively. Then, the corresponding resulting distances RDA, RDB and RDC (i.e., the magnitude of the displacement of the instantaneous position of UCOP from its mean value) were calculated. From these time series, in agreement with the definitions given in [22], mean distance values (MD, MDX and MDY), RMS distance values (RDIST, RDISTX and RDISTY), range values (RANGE, RANGEX and RANGEY), Mean Velocity values (MVELO, MVELOX and MVELOY), the 95% confidence circle area value (AREA-CC), the 95% confidence ellipse area value (AREA-CE) and the sway area value (SWAREA) were calculated for every subject and for each phase. Moreover, for each parameter and for each phase, the mean value and the standard deviation were calculated for all subjects. Pairwise t-tests were conducted with phases as a grouping factor for all the calculated parameters. In order to verify whether there was a significant di fference in parameters among the three phases, a p-value < 0.05 was chosen, but also di fferent acceptable values of p (i.e., p < 0.01, p < 0.001 and p < 0.0001) were selected to indicate di fferent levels of statistical e ffect.


**2. Syntheses and/or fabrications of low melting temperature solders**

In this section, we show how low melting temperature solders, consisting of various elements with higher melting temperatures, such as Sn (melting point of 231.9°C), In (melting point of 156.6°C), and Bi (melting point of 271.5°C), can be fabricated and/or synthesized using metallurgy principles or nanotechnology theory [8]. For example, the formation of an eutectic alloy with 42 wt.% Sn and 58 wt.% Bi can lead to a melting point decrease to 138°C due to the shift to the eutectic temperature [3, 4]. Due to the melting point drop according to the size decrease, the size reduction effect can also be used to synthesize a low melting point solder [4].

Low melting temperature Sn–In solder nanoparticles were successfully synthesized through a surfactant-assisted one-step chemical reduction method [9]. Different synthesis parameters, including pH, stirring speed, and surfactant concentration, were used to control the size, shape, and uniformity of the Sn–In solder nanoparticles [9]. At low In composition (20 wt.% In), the Sn–In solder nanoparticles were composed of InSn4 alloy and β-Sn phase [9]. When the In content increased to 30 wt.%, the Sn–In solder nanoparticles were composed mainly of InSn4 , with a melting temperature of 115.5°C [9]. This low melting temperature indicates a new eutectic point for the Sn–In solder nanoparticle system, which is lower than that of the bulk alloy system (around 50 wt.% In) [9]. At higher In compositions, the Sn–In solder nanoparticles are composed of both InSn4 and In phase [9].

**1. Introduction**

8 Recent Progress in Soldering Materials

More advanced solder bumps with low melting temperatures are crucial for use in flexible, bendable, and stretchable interconnection technology [1, 2]. In particular, the use of wearable devices requires the development of novel solders that can be reflowed at low temperature to avoid thermal damage to the usually temperature-sensitive components in these flexible devices, such as organic light-emitting diodes (OLEDs), polymer light-emitting diodes (PLEDs), and so on [3–6]. Thus, it is worthwhile to design a low melting temperature solder for more advanced interconnection technology and thus to impart more reliability to the solder bumps between future organic- or polymer-based microchips and flexible substrates. Furthermore, the continuous pursuit of multifunctionality in microelectronics has caused a significant increase in the number of solder bumps, to the level of 10,000 per chip [7]. It also has decreased the bump size to as small as 20 μm [7]. Thus, solder bumps with enhanced electrical and thermomechanical properties are needed to meet these demands. With these uses in mind, the properties of conventional solder materials with high melting temperatures (180–230°C) have been under scrutiny due to their reference characteristics, and whether implementing currently used soldering methods or inventing new ones, solution strategies to

overcome problems associated with novel solder materials have been implemented.

**2. Syntheses and/or fabrications of low melting temperature solders**

the size reduction effect can also be used to synthesize a low melting point solder [4].

nanoparticles were composed of InSn4

Low melting temperature Sn–In solder nanoparticles were successfully synthesized through a surfactant-assisted one-step chemical reduction method [9]. Different synthesis parameters, including pH, stirring speed, and surfactant concentration, were used to control the size, shape, and uniformity of the Sn–In solder nanoparticles [9]. At low In composition (20 wt.% In), the Sn–In solder

alloy and β-Sn phase [9]. When the In content increased to

In this section, we show how low melting temperature solders, consisting of various elements with higher melting temperatures, such as Sn (melting point of 231.9°C), In (melting point of 156.6°C), and Bi (melting point of 271.5°C), can be fabricated and/or synthesized using metallurgy principles or nanotechnology theory [8]. For example, the formation of an eutectic alloy with 42 wt.% Sn and 58 wt.% Bi can lead to a melting point decrease to 138°C due to the shift to the eutectic temperature [3, 4]. Due to the melting point drop according to the size decrease,

In this chapter, we focus on the electrical and thermo-mechanical properties of novel solder materials with a specific range of low melting temperatures (<150°C). Emerging carbon reinforcement materials, such as carbon nanotubes (CNTs), graphenes, and their nanocomposites, are also briefly discussed and linked to the increasing development of composite solder materials (in addition to their low melting temperatures). In particular, strategies for improving the performance of solder materials are proposed, along with the provision of insight into classic metallurgy principles. To engineer the properties of low melting temperature solder materials in intended directions, new approaches using nanostructures, nanocomposites, alloying, and doping are also suggested.

To increase the compatibility and usefulness of the low melting point solder, eutectic Bi–43Sn nanowires with diameters of 20, 70, and 220 nm were fabricated by a hydraulic pressure injection process using anodic aluminum oxide templates [10]. Their microstructure investigation showed that the fabricated nanowires are composed of alternating Bi and Sn segments along the wire axes [10].

Novel Sn–Bi nanocomposites reinforced with reduced graphene oxide nanosheets (RGONs) were successfully fabricated by a simple, scalable, and economical electrochemical deposition method [11]. The Sn–Bi nanocomposites, reinforced with reduced graphene oxide nanosheets, had fine grain size as well as reduced graphene oxide nanosheets dispersed throughout the Sn–Bi matrix [11].

For the microstructural transformation and thermoelectrical improvement of Sn–Bi solder, MWCNT was reinforced using the electrochemical codeposition method [11]. Electron microscopy analysis can confirm that pristine MWCNTs were trapped in the deposited composites [11].

Bi-based solder powders with three chemical compositions (binary Bi–Sn, ternary Bi–Sn–In, and quaternary Bi–Sn–In–Ga alloy systems) were fabricated using a gas atomization technique; subsequently, the powders were further ball-milled to fabricate smaller-sized particulates; in particular, the diameter of those in the Bi–Sn–In–Ga powders became less than 10 μm with an irregular shape due to the nature of intrinsic brittleness, the degree of surface oxidation, and the formation of Ga intermetallic compound (IMC), all of which produced fractures of the Ga-containing powders [3].

Ternary Bi–Sn–In micropowders and nanoparticles were prepared as a composite solder material via gas atomization process and a chemical reduction method, respectively [3, 4]. To be specific, two types of Bi-based micropowders, composed of binary Bi–Sn and ternary Bi–Sn–In, were fabricated using a gas atomizer [4]. Then, the gas-atomized powders were classified using a series of standard sieves to obtain powders of a specific size range [4]. Bi (III) nitrate pentahydrate, Sn (II) 2-ethylhexanoate, In (III) nitrate hydrate at a Bi/Sn/In weight ratio of 43.5/31.5/25.0, and 1,10-phenanthroline were added to methanol, and the solution was stirred for 2 h [4]. Then, sodium borohydride was added, and the reaction continued at 50°C for 1 h [4]. The as-synthesized nanoparticles were centrifuged at 4000 rpm for 15 min, washed with methanol, and then dried in a vacuum oven for 24 h [4].


**7. Conclusion**

Spirotetramat acts as a biosynthesis inhibitor of lipids and presents good activity against the most important aphids including whitefly. The activity of spirotetramat predominates in the immature stages of development in aphids, causing on occasion an incomplete ecdysis and causing a reduction in productiveness and fertility. The results suggest that spirotetramat can be used in a secure program of integrated pest management involving biological control, however, in this respect there is contradictory information; each case should be evaluated independently depending on the organism used for biological control.

Once spirotetramat is found inside the plant, it is transformed to its enol form and to the metabolite cetohydroxy, both are two main degradation compounds. The possibility of leaching of spirotetramat into subterranean waters is low according to the results; the proba‐ bility of accumulating in the soil is also very low. On the other hand, based on the results in aquatic environment, under certain conditions there can exists the possibility of accumulation in this system; for this reason adequate care should be taken in applications near aquatic systems. Furthermore, no reports were located that indicated the possibility of spirotetramat accumulation in the air. Lastly, up to this moment there have been proteomic studies suggest‐ ing certain forms of resistance to spirotetramat in cotton aphids.


**Author details**

Zeeshan Ansar Ahmed1 \*, Imran Ahmed Siddqui2 and Sadia Sultan3

Address all correspondence to<EMAIL_ADDRESS>
1 Molecular Pathology Section, Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Karachi, Pakistan

2 Memon Medical Institute, Karachi, Pakistan

3 National Medical Complex, Karachi, Pakistan