**Author details**

therapeutic strategies such as consolidation and maintenance treatments as well as total or continuous therapy [1–5, 24–29]. Currently, the following novel therapies are available for patients with MM: (1) immunomodulatory agents such as thalidomide, lenalidomide, and pomalidomide; (2) proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib; (3) monoclonal antibodies such as daratumumab and elotuzumab; and (4) histone deacetylase inhibitors such as panobinostat and vorinostat [1–5, 26–29]. Other novel therapeutic options that are available for patients with RR-MM include chimeric antigen receptor T cells as well as other cellular and immunotherapies such as the use of specific antigen-presenting cells to overcome immune

Several studies and meta-analyses have shown that the most beneficial induction therapies in terms of overall response rate, overall survival (OS), and progression-free survival (PFS) in transplant-eligible patients with newly diagnosed MM are (1) bortezomib, lenalidomide, and dexamethasone (VRD), (2) bortezomib, cyclophosphamide, and dexamethasone, and (3) bortezomib, thalidomide, and dexamethasone [1, 33–35]. However, the standard induction therapy in patients with newly diagnosed MM is the VRD triplet regimen [4, 8]. Also, autologous HSCT is the standard of care for transplant eligible patients either upfront or at relapse [4, 8, 27]. Therefore, HD chemotherapy followed by autologous HSCT, which is an integral part in the treatment of the disease, is considered the standard of care for patients with MM who are eligible for HSCT [36–39]. With the recent advances in supportive care, autologous HSCT has been extended to include older patients with MM and those with comorbid medical conditions such as renal failure (RF) [37, 38]. Nevertheless, autologous HSCT and novel therapies are complementary to each other in the management of patients with MM [37, 40]. Studies have shown that post-HSCT consolidation and maintenance treatments can further improve the outcome of patients with MM [8, 27, 41]. In particular, the use of either proteasome inhibitors such as bortezomib or immunomodulatory drugs such as lenalidomide in the maintenance therapy is associated with increased OS and PFS [42–46]. However, for transplant-eligible patients, stratified maintenance therapy based on risk features and depth of response is recommended [47]. Monitoring disease response at various stages of treatment is essential, and studies have shown that monitoring of minimal residual disease (MRD) is associated with longer PFS and OS [48, 49]. Patients with high-risk (HR) cytogenetics require not only specific induction therapies but also autologous HSCT as well as consolidation and maintenance therapies [50, 51]. For such patients, deeper responses should be obtained as several studies and meta-analyses have shown that MRD negativity is a strong predictor of clinical outcome and is associated with

The numerous treatment modalities that are available for patients with MM have shown their efficacy, but they have their own adverse effects that include BM suppression and infectious

Also, there is very limited access to effective care in many countries particularly in sub-Saharan Africa. Additionally, the available novel therapies are rather expensive, and the economic bur-

Progression of MM is related to the underlying BM microenvironment and to the genetic heterogeneity of the disease [7, 19]. Studies have shown that the main causes of death in patients with MM are infections, comorbid medical conditions such as RF, having RR disease, and the presence

incompetence and engineered T cells as well as natural killer cell products [30–32].

long-term survival [49, 52, 53].

4 Update on Multiple Myeloma

complications that may be life-threatening [9, 10, 54].

den of the disease is huge [13, 14, 55–57].

Khalid Ahmed Al-Anazi

Address all correspondence to<EMAIL_ADDRESS>
Department of Hematology and Hematopoietic Stem Cell Transplantation, Oncology Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia


*3.5.1. Micro-contact printing (soft lithography)*

This is known as soft lithography that usually uses the relief patterns on a PDMS (polydimethylsiloxane) stamp in order to form patterns of self-assembled monolayers (SAMs) of ink on the surface of a substrate through conformal contact. This technique has wide range of application in cell biology, microelectronics, surface chemistry, micromachining, Patterning cells, patterning DNA and Patterning protein.

Figure 9 represents the process of Micro-contact printing. This process involves the application of ink to stamp, application of stamp to surface, removal of stamp and residues rinsed off

**Figure 9.** Schematic of the Micro-contact printing process (Courtesy: IBM Zurich)

Advantages of Micro-contact printing:

Limitation in Micro-contact Printing:

### *3.5.2. Nano-imprint lithography*

Nanoimprint lithography (NIL) is an emerging process that can produce sub-10nm features. It is a simple process that uses a mould to emboss the resist with the required pattern. After embossing the resist, compressed resist material is removed using anisotropic etching and the substrate exposed. It can produce features at extremely small resolutions that cover a large area with a high throughput and relatively low cost, which is main advantage of this technique. It can be adapted to transfer all components needed to create a thin film transistor on a plastic substrate. It involves pressing and heating a thin film between a patterned template and a substrate. Upon heating, the patterned film adheres only to the substrate [ref Fig. 10]. This has high throughput and is relatively inexpensive compared to developing extreme deep UV lithography for commercial viability. It is also flexible enough to be used at chip level with several layers or at the wafer level when single layer is required. It can give resolutions lower than 10nm with high throughput at low cost. One of the current barriers to production at these resolutions is the development of mould. It can be used for fabricating nanoscale photodetectors, silicon quantum-dot, quantum wire and ring transistors (Chou, S.Y. 1996)

**Figure 10.** Schematic diagram of the steps involved in the nanoimprint lithographic process [Courtesy: Source: AZo‐ Nano]


**Agnieszka Szparaga 1, Sylwester Tabor 2, Sławomir Kocira 3,\*, Ewa Czerwi ´nska 4, Maciej Kubo ´n 2, Bartosz Płóciennik 1 and Pavol Findura 5**

Received: 14 August 2019; Accepted: 27 October 2019; Published: 1 November 2019

**Abstract:** This study aimed at determining the survivability of probiotic bacteria cultures in model non-dairy beverages subjected or not to the fermentation and storage processes, representing milk substitutes. The experimental material included milks produced from desiccated coconut and non-dehulled seeds of hemp (*Cannabis sativa* L.). The plant milks were subjected to chemical and microbiological evaluation immediately after preparation as well as on day 7, 14, and 21 of their cold storage. Study results proved that the produced and modified plant non-dairy beverages could be the matrix for probiotic bacteria. The fermentation process contributed to increased survivability of *Lactobacillus casei* subsp. *rhamnosus* in both coconut and hemp milk. During 21-day storage of inoculated milk substitutes, the best survivability of *Lactobacillus casei* was determined in the fermented coconut milk. On day 21 of cold storage, the number of viable *Lactobacillus casei* cells in the fermented coconut and hemp milks ensured meeting the therapeutic criterion. Due to their nutritional composition and cell count of bacteria having a beneficial effect on the human body, the analyzed groceries—offering an alternative to milk—represent a category of novel food products and their manufacture will contribute to the sustainable development of food production and to food security assurance.

**Keywords:** probiotic; non-dairy beverages; survivability; fermentation; bacteria; coconut; hemp; sustainable food production

#### **1. Introduction**

Sustainable food production should be considered through the perspective of a better understanding of food security. In recent years, many researchers and policy makers have focused only on the physical availability of food, owing to the sufficient agricultural production [1,2]. This has partly been driven by widespread claims that we need to boost the global food production to feed the world in 2050 [3]. However according to the FAO (Food and Agriculture Organization of the United Nations) definition [4]: "food security exists when all people, at all times, have physical and economic access to sufficient, safe and nutritious food that meets their dietary needs and food preferences for an active and healthy life". Hence, it needs to be emphasized that the sustainable food production is inevitably related to the food security in its three aspects: food security, food safety, and food quality, without which the development of the food industry sector would not be possible [5,6]. Due to the current dynamic development of sciences related to food and human nutrition, a correlation has been confirmed between the health status and nutritional patterns. A well-balanced diet is the key factor in diseases prevention and treatment. The growing nutritional interests and awareness of consumers have prompted many producers to manufacture functional food [7–9]. A functional food definition covers certain strains of microorganisms being constituents of food of plant and animal origin that contain physiologically active compounds. These compounds are beneficial for human health and help minimizing the risk of chronic diseases development [10]. One of the multiple examples of functional food products are these containing microorganisms endogenous to the human gastrointestinal tract and exhibiting a positive effect on human health [11]. So far, the greatest part of probiotic products has been offered by fermented beverages made of animal milk. Currently, research is underway into other products that may be matrix for probiotic bacteria [12,13]. Consumers avoiding milk because of allergies or lactose intolerance, and consumers following a vegan diet can replace milk with other plant-based substitutes. Beverages derived from soybeans have for many years been the predominant equivalents of milk. Today, coconut, almonds, hemp, and various cereals (e.g., oats, buckwheat, and rice) are also used to produce plant-based beverages [14,15]. A drawback of these products is however their specific taste that does not suit to everyone. A solution to this problem is offered by lactic acid fermentation, which imparts a characteristic, pleasant after-taste to these products and contributes to the improvement of the digestibility [13,16]. Numerous attempts have recently been undertaken to ferment vegan beverages serving as milk substitutes using various strains of probiotic bacteria, which was expected to additionally increase their health value [16,17]. However, most of the study results reported in literature concern the feasibility of producing fermented soybean milk [13–16]. This is related to the fact, that manufacture of high quality plant-based beverages containing probiotic bacteria poses a serious challenge [18,19]. According to Yuliana et al. [20], the production of coconut-based beverages is difficult because of the suppressed growth and survivability of these probiotic microorganisms, compared to dairy beverages. Difficulties in the manufacture and fortification of hemp milk were encountered by Batkiene et al. [21]. The first ones were related to the stability of produced emulsions, whereas the latter ones to the survivability of probiotic bacteria during storage. Worthy of notice is that the production of hemp-based products has increased in recent years due to the confirmed nutritional value and low allergenicity of seeds of this plant [22]. This has been feasible owing to new varieties characterized by a low concentration of a psychoactive compound delta-9-tetrahydrocannabinol (THC) [23] and to cultivations with the use of elite category sowing material [24].

The current definition of a probiotic means those microbial strains that positively affect consumer health when taken in the right amount [25]. Accordingly to FAO/WHO guidelines, the count of probiotic bacteria cannot be less than the value corresponding to 106 cfu per 1 mL of a product through the entire period of its storage till the end of its shelf life. This value has been deemed the therapeutic minimum [26–28].

The main problems associated with the fermentation of plant beverages are related to the sensory quality of the final product and to the resistance of probiotic microorganisms. Producers encounter difficulties with the physical stability caused by milk coagulation (it occurs at the beginning or in the course of storage). The appearance of these products resembles that of low-fat yoghurt [29–32]. Additional problems concern the survivability of probiotic bacteria, which is dependent on multiple factors, including e.g., presence of other microorganisms in the product, time and conditions of strains culture and product storage, product processing technology or pH value [13,26,33,34].

Considering the above, the major objective of this study was to determine the survivability of probiotic bacterial cultures in model fermented and non-fermented stored plant beverages being milk substitutes, because today the plant-based alternative milks provide a huge perspective for the sustainable development of the healthy food market and should therefore be widely scrutinized. Evaluation of the effect of production and processing techniques, and also of fortification techniques, of plant-based beverages may serve to develop a nutritionally complete beverage with a high overall acceptability and health values.


**6. Concluding Remarks**

The present study modeled banking operations as consisting of two stylized stages—the deposit mobilization stage, and the loan financing stage—and separately estimated technical efficiency at each stage. An important feature of the study was the use of a cross-country panel dataset for efficiency measurement. To the best of our knowledge, no other study estimated technical efficiency for a panel or emerging economy banks using network DEA and directional distance functions featuring NPLs. This research design made it possible to perform regional comparisons of bank efficiency and also to investigate the impact of global macroeconomic shocks. Our results indicated that lower efficiency scores were concentrated in regions where the proportions of non-performing loans in banks' loan portfolios were higher.

The results obtained allowed not only profiling the efficient banks, but also a meaningful characterization of the macroeconomic environment conducive for achieving higher levels of bank efficiency. The efficient banks were smaller, better capitalized, and privately owned. The macroeconomic conditions conducive for bank efficiency were a growing economy, and low to moderate inflation rates (below ~5%). The financial crisis of 2007–2008 negatively impacted the technical efficiency of banks. The analysis of regional patterns of efficiency scores suggested that the most vulnerable banks were located in regions (South Asia and emerging Europe) where the proportion of non-performing loans was high.