2.4.5. Micro-Interactions

Micro-interaction refers to the animations and configuration adjustments that occur when a user interacts with something [102]. There are four stages involved in setting micro-interactions: First, a micro-interaction is started when a trigger is engaged. Second, triggers can be initiated by the user or by the system. Then, a user-initiated trigger requires the user to take action. In a system-initiated trigger, the software recognizes the presence of particular criteria and takes action. When a micro-interaction is initiated, rules dictate what occurs next. Finally, feedback informs individuals about what is happening. Feedback is defined as whatever a user sees, hears, or feels during a micro-interaction. The meta-rules of the micro-interaction are determined by Loops and Modes [103]. A device mounted on a finger was presented by Oh et al. [58] that uses physical gestures to facilitate the micro-interactions of some common and daily applications, such as setting the alarm and finding and opening an app. The authors carried out a survey to study the efficiency of their methods.

### 2.4.6. Text Recognition

The important questions that we must consider are how to use this feature and how to convey the important information only, rather than all of the information detected in the surrounding area [104]. The blob is a collection of pixels whose intensity is different from the other nearby pixels. Although the MSER (maximally stable external region) can detect the blob faster, the SWT (stroke width transform) algorithm can detect characters in an image with no separate learning process [104]. Shilkrot et al. [105] developed FingerReader, a reading support system for visually impaired people to assist impaired persons in reading printed texts with a real-time response. This gadget is a close-up scanning device that can be worn on the index finger. As a result, the gadget reads the printed text one line at a time and then provides haptic feedback and audible feedback. The Text Extraction Algorithm, which is integrated with Flite Text-To-Speech, was utilized by the authors of [106]. The proposed technique uses a close-up camera to retrieve the printed text. The trimmed curves are then matched with the lines. The 2D histogram ignores the repeated words. The program then defines the words from the characters and transmit them to ORC. As the user continues to scan, the identified words are recorded in a template. As a result, the system keeps a note of those terms in the event of a match. However, when the user deviates from the current line, they receive audible and tactile feedback. Moreover, if the device does not discover any more printed text blocks, the visually impaired receive signals via tactile feedback, informing them of the line's ending. SeeNSpeak [107] supports VoiceOver and can audibly interpret text from the photographs of books, newspapers, posters, bottles, or any item with text. The app can also use a wide range of target languages to translate the detected text.

### 2.4.7. Information Services

In the context of location-based services, a beacon is a tiny hardware device that allows data to be transmitted to mobile devices within a certain range. Most apps require that receivers have Bluetooth switched on and that they download the corresponding mobile app and have location services turned on. Moreover, they require that the receiver accepts the sender's messages. Beacons are frequently mounted on walls or other surfaces in the area as small standalone devices. Beacons can be basic, sending a signal to nearby devices, but they can also be Wi-Fi- and cloud-connected, with memory and processing resources. Some are equipped with temperature and motion sensors [108]. Perakovic et al. [60] used the beacon technology to inform the visually impaired of the required information, such as

notifications about possible obstacles, location of an object, and information about a facility or discounts, and to provide navigation in indoor environments.

### 2.4.8. Braille Display and Printer

Braille technology is an assistive technology that helps blind or visually impaired individuals to perform basic tasks, such as writing, internet searches, braille typing, text processing, chatting, file downloading, recording, electronic mail, song burning, and reading [109]. Major challenges include the high cost of some current braille technologies and the large and heavy format of some braille documents or books with embossed paper. Braille is a representation of the alphabet, numbers, marks of punctuation, and symbols, composed of cells of dots. In a cell, there are 6–8 possible dots, and a single letter, number, or punctuation mark is created by one cell.

Displayer is an electromechanical mechanism for viewing braille characters that commonly utilizes round-tipped pins lifted through holes on a flat surface, which is often called a refreshable braille display or braille terminal. The visually impaired use it instead of a monitor. Via the braille display, they can insert commands and text, and it conveys text and images on the screen to them by modifying or refreshing the braille characters on the keyboard. They can browse the internet, draft documents, and use a computer in general. Up to 80 characters on the screen can be shown on a braille display, which can be updated when the user moves the cursor across the monitor using the command keys, cursor routing keys, or Windows and screen reader controls. Braille displays of 40, 70, or 80 characters are typically available. For most occupations, a 40-character display is appropriate and sufficient.

There are other important devices that can be used by the visually impaired, especially in the case of learning or employment in the office, such as the Refreshable Braille Display and Braille Embosser. A braille printer or a braille embosser is a device that uses solenoids to regulate embossing pins. It extracts data from computing devices and embosses the information on paper in braille. It produces tactile dots on hard paper, rendering written documents that are clear to the blind. Depending on the number of characters depicted, the cost of braille displays varies from USD 3500 to USD 15,000. In 2012, sixty-three studies aimed at finding new ways to developed refreshable braille were conducted by the Transforming Braille Group. Orbit Reader 20 is the result of these studies, with a 20-cell refreshable braille display [110] that currently costs USD 599. However, Orbit Reader 20 is the basic version and has limited braille characters.

Special braille paper is needed for braille embossers, which is heavier and more expensive than standard printer paper. More pages with the same volume of data are required for braille printing compared to a standard printer. They are also sluggish and noisier. Some braille printers are capable of printing single- or double-sided pages. Although embossers are relatively simple to use, they can be messy and can somewhat differ from one device to another in regard to the quality of the finished product [111]. Braille displays range in price from USD 3500 to USD 15,000, depending on the number of characters depicted. The cost of a braille printer is relative to the volume of braille it generates. Low-volume braille printers cost between USD 1800 and USD 5000, whereas high-volume printers cost between USD 10,000 and USD 80,000 [112].

### 2.4.9. Money Identifier App

Blind people have difficulty determining the value of the banknotes in their possession, and they usually ask and rely on others to discover the value of the banknotes, which exposes them to the risk of theft or fraud. Money identifier apps are a type of software that can recognize the denomination of banknotes used as currencies. The "Cash Reader: Bill Identifier" app [113] can identify a wide range of currencies. However, it requires a monthly payment subscription. MCT Money Reader [114] is another app that can recognize currencies, including Saudi Riyal, with a cost of SR 58.99 for lifetime use.

### 2.4.10. Light Detection

The Light Detector [115] translates any natural or artificial light source it encounters into sound. The software locates the light by aiming the mobile camera in its direction. Depending on the strength of the light, the user can notice a greater or lower tone. It is useful for helping the visually impaired to determine if the lights at home are on or off or to if the blinds are drawn by moving the device upwards and downwards.

### 2.4.11. External Assistance App

Be My Eyes [116] is an app with which blind or visually impaired users can request help from sighted volunteers. Once the first sighted user accepts the request, a live audio and video call is established between the two parties. With a back-camera video call function, the sighted aide can assist the blind or visually impaired. However, the app depends on an insufficient number of volunteers and has privacy issues because the users share videos and personal information during the connection.

### 2.4.12. Multifunctional App

Sullivan+ (blind, visually impaired, low vision) [117] depends on the camera shots of the mobile and analyzes them using the AI mode, which automatically seeks the top results that match the pictures taken. The app supports the following functions: text recognition, facial recognition, image description, color recognition, light brightness, and a magnifier. However, its capacities for facial and object recognition need further improvements. Visualize-Vision AI [118] makes use of different neural networks and AI to identify pictures and texts. The software is intended to provide visual assistance to the visually disabled, while still providing a developer mode that enables various AIs to be explored. Another app that can identify an object using artificial neural networks was explored in [119].

A visually impaired person can find an object by calling the name of the object, and the app finds it. Seeing Assistance Home [120] allows users to use an electronic lens for partially visually impaired persons, providing color identification, light source detection, and the ability to scan and produce barcodes and QR codes. VocalEyes AI [121] can assist the visually impaired in the following functions: object recognition; reading text; describing environments, label brands, and logos; facial recognition; emotion classification; age recognition; and currency recognition. LetSee [122] has three functions, including money recognition, which supports several currencies but does not support the Saudi Riyal; plastic card recognition; and light measurement tools to help users to locate sources of light, such as spotlights, cameras, or windows. The higher the brightness of the light is, the louder the sound the user hears is. TapTapSee [123] supports object recognition, barcode and QR code reading, auto-focus notification, and Flash toggle. Aipoly Vision [124] provides its service, including full object recognition features, for monthly fees of USD 4.99. The software also has the functions of currency recognition, text reading, color recognition, and light detection. However, the software is only supported by designated iPhone and iPad devices.


**Cerebrospinal Fluid Abnormalities in Viral Encephalitis**

Hakan Ekmekci, Fahrettin Ege and Serefnur Ozturk

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54590


**2.3 Globally shared systems**

Sharing virtual environments with global access is mainly based on the resources of the internet and web technologies. According to Du et al. [22], by sharing globally available collaborative environments, it is possible to reach a large group of users for remote collaboration. This, of course, is also expanding the gaming business.

Global collaborative virtual environments use the computer network infrastructure (**Figure 4**). The users/players can interact with each other via this infrastructure. Instead of local physical space, globally shared space is used. Each user/player is able to access this space via a separate computing system [23]. Users/players connect to the server node via the network infrastructure, within which they communicate and interact with other users/players or game environments in real time [24]. Independence from the physical space of the user/player is the main advantage of these environments.

Globally shared environments are highly efficient in terms of sharing large-scale users/players activity as well as multipurpose deployments [9]. The most common problem in global virtual environment sharing is platform independence [25]. It is as a result of globalization that the demand for multiplatform compatibility is growing,

**Figure 4.** *Globally shared environment (LIRKIS DCI FEEI TU Košice).*

which clearly needs to solve the availability of such environments for multiple and also different user devices and systems. As the development of new XR technologies grows rapidly, it is necessary to ensure the adaptability of systems and user interfaces so that they are able to handle new technological innovations. Optimization of data sharing is also most needed, as the problem of latency between users increases in the case of a global connection. Solving these problems can positively contribute to the expansion of virtual collaboration for any purpose.


**4. Source Term Definition**

Efficient management of sediment handling operations requires sufficient knowledge of dredging and disposal methods and of main mechanisms of release that can affect the SSC transport processes for different excavation and disposal techniques. The selection of spill scenarios is a key factor for environmental assessment and approval of the work plans. Indeed, it influences the source term needed as input to far field models.

In particular, the temporal and spatial characterization of the source term is important for the comparison, on different spatial and temporal scales, of scenarios with the least probabilities of detrimental impacts on water quality and to define whether (and when) mitigation measures should be taken on future work plans (e.g., [30]). This paper is aimed at estimating the contribution to source terms of phenomena directly related to marine sediment handling activities. However, sedimentation processes and the related re-suspension of the sediment due to hydrodynamic agitation (waves and currents) can have a significant influence on the magnitude of the source terms and therefore on the sediment transport modeling (see Section 6). Some mathematical models do not explicitly include the modeling of sedimentation and re-suspension related to hydrodynamic agitation. Nevertheless, their knowledge (or monitoring) may be crucial when the choice of the type and mode of implementation of the models is concerned. Moreover, also the definition of the background (baseline) conditions for the parameters of interest (e.g., SSC and turbidity), needed to identify the related single or multiple site-specifics reference levels, can be related to the sedimentation and re-suspension related to hydrodynamic agitation.

Basically, two main approaches may be used to model the flux of fine sediments available to the far field dispersion. Computational fluid dynamics (CFD) framework may be used for detailing near-field regimes and then to get a reliable estimate of the mechanisms that govern the dynamic of the sediment fraction leaving the re-suspension/release area as a passive (dispersive) plume. Such an approach has large computational costs and the results may be hardly generalized. On the other hand, a second approach may be used within the frame of macro-scale modeling (i.e., conceptual or empirical models). A series of empirical and numerical near-field models to estimate the suspended sediment flux leaving the intervention area have been developed so far (e.g., [6,8,31–35]).

A few conceptual models to predict the resuspended sediment mass rate at the resuspension point, and thus its source strength and geometry, have been proposed for dredging actitivies (e.g., [6,31,33,34], see Lisi et al. [13] for a comprehensive review). They give an estimate of source term as a function of the site (i.e., sediment properties, water depth, currents) and operational (i.e., dredge type, dredge-head dimension) parameters.

As suggested by John et al. [30] and recalled by Becker et al. [8], the source term may be estimated either (i) by looking at the sediment concentration increase at the re-suspension area (e.g., [6]), or (ii) by providing the sediment release rate at the re-suspension area (e.g., [6]), or (iii) by taking advantage of the definition of the S-factor (e.g., [31,34]) that gives the estimate of the released sediments as a fraction of the total mass of handled sediments, or (iv) by providing the sediment flux across the area bounding the re-suspension zone (e.g., [6]). All these approaches are hard to be used in a generalized way as they are site- and operation-dependent. Indeed, the available conceptual methods for estimating the source term induced by different re-suspension sources are based on the use of tabular data, e.g., the turbidity generation unit (TGU) approach proposed by Nakai [31] and the re-suspension factor proposed by Hayes et al. [34]. On the other hand, the use of empirical formulations involve sets of dimensionless parameters related to operating and site characteristics (e.g., [6,33,36]).

As for dredging activities, a few conceptual models exist also for other sediment handling works (e.g., either open water disposal [4,35] or beach nourishments [37]).

In order to overcome the lack of engineering tools, Becker et al. [8] proposed a general approach able to provide the estimation of source term. Basically, they suggest to estimate the amount of fine-graded sediments and to distribute the release into the water column after an in-depth analysis of possible plume sources. Hence, for each phase (excavation, loading/transport and disposal) of the considered handling work, it is possible to estimate a specific source term fraction to be used as input for the far-field model if it is properly applied on the computational grid. It can be observed that this approach perfectly suits the approach proposed herein.

The results of specific in-situ analyses on the sediments to be handled allows estimating the quantity of fine-graded fraction available to the far field. The fraction expressed by either *R*74 (the fraction of sediments with grain diameter lower than 74 μm as per the fine-sediments definition of the unified soil classification system, e.g., [6]) or *R*63 (the fraction of sediments with grain diameter lower than 63 μm as per the Wentworth scale, e.g., [8]) may be used to estimate the fine sediments mass ( *mf*) available to the far field (e.g., [8]):

$$m\_f = \rho\_d V\_t \mathbf{R}\_f \tag{1}$$

where *ρd* is the dry density of the in situ material, *Vt* is the handled volume of sediments and *Rf* is the considered fine fraction (either *R*74 or *R*63). The dry mass of fine sediment released into the water column ( *mr*) can be then easily estimated by using a series of empirical parameters ( *σ*):

$$m\_{\mathbb{T}} = \sigma m\_f.\tag{2}$$

Becker et al. [8] (see their Table 1) provide reasonable values of the empirical source term fraction (i.e., *σ*) for drag-head induced re-suspension ( *σ* = 0.00–0.03), overflow induced re-suspension (*σ* = 0.00–0.20), cutter-head induced re-suspension ( *σ* = 0.00–0.04), spill from mechanical dredging (*σ* = 0.00–0.04), disposal by bottom door either mechanical ( *σ* = 0.00–0.10) or hydraulic ( *σ* = 0.00–0.05). It has to be stressed that the definition of the empirical source term fractions may take advantage of either monitoring activities or empirical formulations. Just as an example, Hayes et al. [33] proposed

an empirical formulation aimed at estimating the rate of sediment (*r*) re-suspended by cutterhead dredge as a fraction of sediment mass dredged:

$$\tau = \frac{(L\_{\rm cf} d\_{\rm c})^{1.966} \left| V\_{\rm s} \pm \pi d\_{\rm c} a \right|^{1.966} \left( V\_{\rm s} A\_{\rm E} \right)^{1.804}}{1.099 Q^{3.770}},\tag{3}$$

where *r* (%) is the fraction of sediment mass dredged expressed as a percentage (hence intimately related to the source term fraction *σc* = *r*/100), *Lc* (m) is the length of the cutterhead, *dc* (m) is the cutter diameter, *Vs* (m/s) is the swing velocity, *α* (rounds per second) is the rotational speed of the cutter, *AE* (m2) is the total surface area exposed to washing, *Q* (m3/s) is the volumetric flow rate into the dredge pipe. If overcutting is considered (i.e., the positive sign is used in the numerator of Equation (3)), Figure 3 shows the estimate of the empirical source term fraction *σc* for varying swing velocity (*Vs*) and varying rotation speed of the cutter (*α*) for a typical 16-in. (0.41 m) dredge (e.g., [33], *dc* = 1.07 m, *Lc* = 0.91 m, *AE* 1.3 m2). It could be observed that the empirical source term fraction proposed by Becker et al. [8] (dashed areas in Figure 3) is of the same order of magnitude given by the more detailed empirical formulation by Hayes et al. [33].

**Figure 3.** Empirical source term fraction (*σc*) for cutter-head induced re-suspension as a function of the swing speed (*Vs*, upper panel) and of the rotational speed of the cutter (*α*, lower panel) as estimated on the basis of the model proposed by Hayes et al. [33]. Shaded areas highlight the range suggested by Becker et al. [8].

It has to be noticed that Equation (2) gives the mass of fine sediments available to the far field. In order to get the correct estimate of the source term, a sediment flux should be provided. Then, Becker et al. [8] suggest to simply divide the mass *mr* by the time duration of the considered phase (i.e., either excavation, transport, or disposal). This highlights the importance of the analysis of the work phases. This is equally crucial when dealing with the timing and the location of the source term within the computational domain (see Section 5, Figures 4 and 5). Indeed, depending on the operational parameters of the handling works, the source term can be described by either a time-varying or constant intensity and by either a time-varying or fixed location. On the other hand, depending on the spatial resolution of the study, the source term can be described by either a punctual or a finite extent re-suspension source.

Figure 4 aims at synthesizing the main features of the source term estimation and how it can be applied to the computational domain.

**Figure 4.** Main steps of the source term module for both the estimation and the application of the source term in the computational domain.

**Figure 5.** Analytical solution obtained by using the model proposed by Di Risio et al. [39]. Typical examples for hydraulic dredging (**left**) and mechanical dredging (**right**) are shown. Constant velocity along x-direction is considered. Dashed lines depict the dredge-head path during the works execution, square markers indicate the instantaneous location of the dredge-head. Color scale refers to the suspended sediment concentration (SSC) (g/m3).


**7. Types of microneedles**

#### **7.1 Solid microneedle**

Solid microneedles are arranged as an array in a two-part system; microscopic wells are created on the skin using this microneedle just deep enough to penetrate the outermost layer of the skin, and then a transdermal patch is used to apply the drug. Collagen induction therapy is a method in dermatology, which uses solid microneedles. This method involves the repeated puncturing of the skin with microneedles, wherein the expression and deposition of elastin and collagen proteins are induced [32].

#### **7.2 Hollow microneedle**

These are similar to solid microneedles with respect to the material. They act like a reservoir containing the drug to be delivered to the site directly. The flow rate of the microneedle influences the drug delivery; therefore, a flawed design or excessive swelling may cause clogging of the array. Hollow microneedles have a higher probability of collapsing under pressure, thus failing to deliver drugs [32].

#### **7.3 Coated microneedle**

Coated microneedles are designed using metals or polymers, similar to that of solid microneedles. Here the drug is directly applied to the microneedle, unlike in other cases where patches or applicators are used. To ensure the proper delivery of the drug, thickening agents or surfactants are used to cover coated microneedles. The chemicals that are used on coated microneedles are known as irritants. There is sometimes the risk of local inflammation in the area where the array was used. In such cases, the array can be removed immediately without harming the patient [32].

#### **7.4 Dissolvable microneedle**

In the case of dissolvable microneedles, they encapsulate the drug using a nontoxic polymer, which is dissolved completely when it enters the skin. Fibroin is a polymer that is derived from silk protein. This fibroin can be molded into structures of microneedles and also dissolves once into the body; therefore, in the recent past, researchers and pharmaceutical companies have started to study its mechanisms and potential [32].

#### **7.5 Hydrogel-forming microneedles**

This type of microneedles has no drug in itself. They follow the technique of swelling in the skin to allow the diffusion of the drug inside the reservoir layer attached to the microneedle for dermal microcirculation for systemic absorption [32].

The various types of microneedles explained above are shown in **Figure 19**.

*Minimally Invasive Microneedle: A Novel Approach for Drug Delivery System and Infected… DOI: http://dx.doi.org/10.5772/intechopen.105771*

#### **Figure 19.**

*A schematic representation of five different types of microneedles: solid removable, coated, dissolving, hollow, and hydrogel-forming microneedles [32].*


*Article* **Analysis of Prior Aspirin Treatment on in-Hospital Outcome of Geriatric COVID-19 Infected Patients**

**Khaoula Zekri-Nechar 1, José Barberán 2, José J. Zamorano-León 3,\*, María Durbán 4, Alcira Andrés-Castillo 1, Carlos Navarro-Cuellar 5, Antonio López-Farré 1, Ana López-de-Andrés 3, Rodrigo Jiménez-García 3 and Carlos H. Martínez-Martínez 1**

**Abstract:** *Background and Objectives*: Aspirin (ASA) is a commonly used antithrombotic drug that

**\*** Correspondence<EMAIL_ADDRESS>Tel.: +34-91-394-1523

has been demonstrated to reduce venous thromboembolism. The aim was to analyze if geriatric COVID-19 patients undergoing a 100 mg/day Aspirin (ASA) treatment prior to hospitalization differ in hospital outcome compared to patients without previous ASA therapy. *Materials and Methods*: An observational retrospective study was carried out using an anonymized database including geriatric COVID-19 patients (March to April 2020) admitted to Madrid Hospitals Group. A group of COVID-19 patients were treated with low ASA (100 mg/day) prior to COVID-19 infection. *Results*: Geriatric ASA-treated patients were older (mean age over 70 years; *n* = 41), had higher frequency of hypertension and hyperlipidemia, and upon admission had higher D-dimer levels than non-ASAtreated patients (mean age over 73 years; *n* = 160). However, patients under ASA treatment did not show more frequent pulmonary thromboembolism (PE) than non-ASA-treated patients. ASA-treated geriatric COVID-19-infected patients in-hospital < 30 days all-cause mortality was more frequent than in non-ASA-treated COVID-19 patients. In ASA-treated COVID-19-infected geriatric patients, anticoagulant therapy with low molecular weight heparin (LMWH) significantly reduced need of ICU care, but tended to increase in-hospital < 30 days all-cause mortality. *Conclusions*: Prior treatment with a low dose of ASA in COVID-19-infected geriatric patients increased frequency of in-hospital < 30 days all-cause mortality, although it seemed to not increase PE frequency despite D-dimer levels upon admission being higher than in non-ASA users. In ASA-treated geriatric COVID-19-infected patients, addition of LMWH therapy reduced frequency of ICU care, but tended to increase in-hospital < 30 days all-cause mortality.

**Keywords:** aspirin; COVID-19; elderly population; low molecular weight heparin; pulmonary thromboembolism; mortality; hospital stay

## **1. Introduction**

Thrombotic complications and a hypercoagulable state are frequent in SAR-CoV-2 (COVID-19), strongly contributing to mortality. Venous thrombotic embolisms (VTE) have been observed in patients who were otherwise asymptomatic and in hospitalized COVID-19-infected patients in whom up 20% to 30% of critically ill patients could develop VTE [1]. Moreover, published retrospective series of cases of COVID-19 patients have shown frequent elevation of D-dimer, which has been related to acute pulmonary thrombosis, dramatically worsened the prognosis [2].

Several reports have shown that older people were at a higher risk of COVID-19 complications, with higher rates of hospitalization, intensive care unit admissions, and

**Citation:** Zekri-Nechar, K.; Barberán, J.; Zamorano-León, J.J.; Durbán, M.; Andrés-Castillo, A.; Navarro-Cuellar, C.; López-Farré, A.; López-de-Andrés, A.; Jiménez-García, R.; Martínez-Martínez, C.H. Analysis of Prior Aspirin Treatment on in-Hospital Outcome of Geriatric COVID-19 Infected Patients. *Medicina* **2022**, *58*, 1649. https://doi.org/10.3390/ medicina58111649

Academic Editors: Yusra Habib Khan, Tauqeer Hussain Mallhi, Tahir Mehmood Khan and Muhammad Salman

Received: 6 October 2022 Accepted: 10 November 2022 Published: 15 November 2022

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

**Copyright:** © 2022 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/).

death [3,4]. Among other proposed hypotheses to explain the higher vulnerability of older people to worse COVID-19 prognosis and higher frequency of hospitalization there have been a weaker immune response, obesity, fragility, etc. [5]. At present, it is evident that age of people infected by COVID-19 has decreased, probably because a greater number of older people have already received their vaccination. However, at present, it is difficult to predict the future ability of vaccines to prevent possible new mutations in the virus that may confer them immunity escape and increased infectivity. Therefore, it is important to not stop analyzing effects and impact of currently used antithrombotic drugs.

Aspirin (ASA) is without doubt the main antithrombotic drug in the world to prevent thrombotic events including venous thrombosis. For example, the multinational and prospective Pulmonary Embolism Prevention (PEP) study, where patients undergo surgery for hip fracture or elective arthroplasty, found that 160 mg of ASA daily reduced the risk of symptomatic VTE by ~36% when compared with placebo [6]. Other studies as Warfarin and Aspirin (WARFASA) and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) trials, in which patients underwent initial anticoagulation therapy before randomly being assigned to low-dose ASA or placebo, also demonstrated significant reduction in VTE recurrence with ASA [7,8].

ASA is often prescribed for secondary prevention in patients with cardiovascular diseases and other comorbidities that, in older patients with COVID-19, might be associated with higher mortality [9]. However, to our knowledge, there are very few studies analyzing the effect of ASA on the outcome of COVID-19-infected patients, and even less in the older population. Moreover, in most of the studies, ASA was added as in-hospital active treatment against COVID-19. In this regard, for example, a work carried out in critically ill COVID-19 patients analyzed the effects of in-hospital treatment of ASA combined with low molecular weight heparin (LMWH) [10]. Paradoxically, this study concluded higher incidence of VTE and worse in-hospital outcome after combined treatment of ASA with a therapeutic dose of LMWH [10]. Another study also suggested that there was no significant difference in terms of mortality under ASA treatment of COVID-19-infected patients [11]. The study did not clearly report whether the use of ASA was an active prescription or a history of exposure [11]. Moreover, the possible influence of ASA in the older population infected by COVID-19 was not previously analyzed.

Therefore, the main aim of the present study is to retrospectively analyze if geriatric COVID-19 patients taking daily low ASA (100 mg/day) doses prior to hospitalization have their <30 days in-hospital outcome affected compared to non-ASA-treated geriatric patients.

### **2. Materials and Methods**

### *2.1. Included Patients*

This retrospective study was carried out using an anonymized database provided by Madrid Hospitals Group. Data are from COVID-19-infected patients admitted to their hospital net who kindly made available their medical information to some Spanish researchers within the program: COVID-19 data saves lives in Spain.

The study included 201 consecutive patients aged 60 admitted for hospitalization between 7 March and 4 April, 2020 (initiation of the first COVID-19 wave in Spain) with clinical and radiological data compatible with COVID-19 (On 25 March the Spanish Health Secretary recommended not to confirm COVID-19 infection by reverse transcriptase polymerase chain reaction (RT-PCR) when clinical and radiological presentation was typical). Therefore, only in patients included before these data or patients without the typical clinical and radiological presentation COVID-19 infection was confirmed by RT-PCR.

Exclusion criteria were hospital stays >30 days and admission platelet count lower than 25 × 109 platelets/L. These criteria were based on guidelines recommendation of prophylactic dose of LMWH in COVID-19 patients and the follow-up of patients with short hospitalization stay [12,13].

As clinical outcomes, parameters considered included <30 days in-hospital all-cause mortality, requirement of admission to intensive care unit (ICU), diagnosis of pulmonary embolism (PE), length of hospital stay 30 days longer. PE was assessed by pulmonary computed tomography (CPTA). Upon admission, C-reactive protein and D-dimer levels were also considered.

COVID-19-infected patients admitted for hospitalization were considered and divided into two groups: 1. COVID-19-infected patients who were taking cardiovascular doses of ASA (100 mg/day) prior to COVID-19 infection and 2. COVID-19-infected patients without prior ASA treatment. Only the patients who were taking ASA before hospital admission continued receiving 100 mg/day ASA during hospitalization.

From admission and during hospitalization some patients received LMWH (bemiparin sodium, Rovi Lab. Madrid. Spain. 2.500–10.000 UI). Patients who, upon admission, had not been treated with LMWH did not receive anticoagulating therapy during their hospitalization course.

The study was approved by the local Ethical Committee (Code: 21/084-E. Approval date: 17 February 2021) and conducted in accordance with the Declaration of Helsinki.

### *2.2. Statistical Analysis*

Categorical variables were expressed as frequency and percentage and compared by Chi-square test. Continuous variables were expressed as mean ± standard error of mean (S.E.M). Student t-test was used to compare quantitative variables. A *p* value < 0.05 was considered significant. The statistical analysis was performed with the SPSS software version 25.0.

### **3. Results**

### *3.1. Comparison among Patients under ASA Treatment before Hospital Admission*

The mean age of the studied COVID-19 patients was over 73 years old (Table 1). COVID-19 patients under ASA treatment before hospital admission were slightly but statistically significantly older than the patients who were not undergoing ASA treatment prior hospitalization (Table 1). Gender was not different among analyzed geriatric COVID-19 patients that were or were not taking ASA (Table 1).

Upon admission, geriatric COVID-19 patients under ASA treatment more frequently had hypertension or dyslipidemia compared to geriatric patients without previous ASA therapy (Table 1). There was a similar frequency of diabetic mellitus patients between the two analyzed groups.

In the in-hospital follow up, patients taking ASA prior to hospitalization had a higher frequency of <30 days all-cause mortality than patients without ASA treatment (Table 1). The other analyzed parameters such as need of ICU care, PE development, and length of hospital stay were not different among the geriatric COVID-19-infected patients that were or were not taking ASA before hospitalization (Table 1).

Upon admission, D-dimer levels, but not C-reactive protein, were significantly higher in COVID-19 patients taking ASA than in those without ASA (Table 1). It was noteworthy that in patients with prior ASA treatment, upon-admission D dimer levels were similar among patients discharged alive and those who died in <30 days of follow up (D-dimer upon admission μg/L: ASA-treated dead patients: 2.18 ± 0.63; ASA-treated discharged patients: 1.97 ± 0.48, *p* = 0.494). Moreover, in the group of ASA-treated COVID-19 patients, in-hospital < 30 days all-cause mortality was more frequently observed in patients showing higher C-reactive protein levels upon admission (C-reactive protein upon admission (mg/L): ASA-treated < 30 days dead patients: 139.02 ± 26.12; discharged patients: 83.73 ± 16.11, *p* = 0.033).

### *3.2. Effect of LMWH Therapy in Geriatric Patients Who Were Taking ASA before Hospitalization*

A number of geriatric patients (*n* = 32) taking ASA before hospitalization were treated with LMWH upon admission (Table 2). As Table 2 shows, these LMWH-treated geriatric ASA patients were of similar age and gender compared to those ASA patients who were not treated with LMWH (Table 2). It should be pointed out that the patients who, upon admission, were not treated with LMWH never received LMWH during hospitalization follow up. Moreover, four patients taking ASA were from admission treated with therapeutic doses of LMWH (5.000–10.000 IU) continuing this dosage during the follow-up. In addition, 28 of the 32 analyzed ASA-treated patients, upon admission received prophylactic dosage of LMWH (2.500–3.500 IU) but during in-hospital follow up in 6 of them LMWH dosage was increased reaching therapeutic LMWH dose.

**Table 1.** Effect of previous Aspirin treatment on in-hospital outcome of geriatric COVID-19 infected patients.

Age, length of hospital stays, D-dimer, and C-reactive protein values are expressed as mean ± SE.

In addition, with the aim of identifying the possible additional effect of anticoagulant treatment, closely associated with antiplatelet treatment with ASA, on <30 days in-hospital outcome, it was analyzed potential effect of LMWH treatment on hospital admission in geriatric COVID-19-infected patients taken daily Aspirin (100 mg/day) (Table 2). Geriatric COVID-19 patients taking ASA who received LMWH therapy less frequency required ICU care than patients taking ASA who did not receive LMWH (Table 2). Length hospital stay was similar between the geriatric COVID-19 patients taking ASA treated or no with LMWH. Frequency of PE tended to be slightly higher in the patients taking ASA that were treated with LMWH although it did not reach statistical significance (Table 2). Among geriatric COVID-19 ASA patients, <30 days all-cause in-hospital mortality almost reached statistics significant as comparing those who were treated or not with LMWH. In fact, ASA patients who did not receive LMWH tended to show less frequency of <30 days all-cause mortality that patients taking ASA who received LMWH therapy (Table 2).

Upon admission D-dimer and C-reactive protein levels were similar among patients taking ASA who were treated or not with LMWH (Table 2).

Two geriatric COVID-19 patients taking ASA undergoing to LMWH treatment had a hemorrhagic event (drop in hemoglobin levels > 5 g/dL but without clinical hemorrhage sign).

**Table 2.** Effect of LMWH treatment on hospital admission in geriatric COVID-19-infected patients taken daily Aspirin (100 mg/day).

Age, Length hospital stays, D-dimer and C-reactive protein values are expressed as mean ± SEM. may have a footer.

### **4. Discussion**

This retrospective study suggested that geriatric patients who were taking a low daily ASA dose (100 mg/day) prior to COVID-19 infection and during hospitalization showed higher frequency of <30 days all-cause mortality than those geriatric COVID-19 patients not taking ASA before or during the hospitalization course. As compared with COVID-19 infected geriatric patients not previously treated with ASA, patients under ASA treatment showed higher D-dimer levels upon admission. However, the incidence frequency of PE was not different among them.

The World Health Organization reported that over 95 % of fatalities caused by COVID-19 in Europe had been individuals aged over 60 [14]. In Spain, during the most critical period of the first wave of COVID-19 disease, older age was the main risk factor for severity of COVID-19 disease [15]. Although mean age of infected patients in the following COVID-19 waves was significantly lower, probably because a larger proportion of older people were vaccinated, it is not possible to discard that COVID-19 mutations may favor the infection of these particular special vulnerable population. Therefore, while waiting for new specific drugs against COVID-19 to be developed, it is important to continue to study more "classic" commonly used drugs that may have a certain effect against the deleterious effects of COVID-19 infection.

It is recognized that viral infections, as COVID-19 infections, are commonly accompanied by platelet activation and aggregation [16]. In this regard, it was reported that ASA had an impact on both DNA and RNA viruses, although, certainly, these studies were carried out in vitro and using high ASA doses [17,18].

The elderly population has a high frequency of use of ASA within their daily treatments. However, to our knowledge, in the elderly population, possible associations between prior use of low-dose ASA and in-hospital progression of COVID-19 infection were not analyzed. In fact, the reported studies about effects of ASA on COVID-19-infected patients were carried out in critically ill COVID-19 patients of a wide range of ages, suggesting that patients under ASA treatment had higher VTE incidence and mortality [19]. However, a meta-analysis of six eligible studies which included patients of all ages concluded that use of low-dose ASA was independent of reduced mortality of COVID-19 patients [20].

In the present study, geriatric COVID-19 patients taking ASA (100 mg/day) prior to hospital admission, with the daily ASA treatment continuing during hospitalization follow up, had higher <30 days in-hospital all-causes mortality than those patients not taking ASA. Contrarily, different studies reported that active prescription of low-dose aspirin during or prior to hospitalization was associated with reduced risk of mortality among patients with COVID-19 [20,21]. These apparently paradoxical results could be related to difference in age of population and/or difference in the prevalence of cardiovascular comorbidities, which have been widely associated with worse COVID-19 outcome [22,23]. Following the same line of evidence, in COVID-19 patients with coronary artery disease no differences in <30 days all-cause mortality was found among those taking low dose ASA and those without ASA treatment [24].

COVID-19 disease has been associated with increased risk of VTE [25]. COVID-19-infected geriatric patients under ASA treatment showed higher D-dimer levels upon admission than those without ASA treatment. However, PE frequency was similar among them. It could be related to evidence showing low dose ASA may reduce VTE [26].

Guidelines recommend a prophylactic dose of LMWH as treatment for all COVID-19 patients requiring hospitalization, in the absence of any contraindications such as active bleeding and platelet count lower than 25 × 109 platelets/L [12]. Interestingly, a recent report has identified heparan sulfate, a glycosaminoglycan molecule like heparin, as coreceptor for COVID-19, further supporting that exogenous heparin may provide therapeutic benefits for patients with COVID-19 infection [27]. Moreover, as mentioned above, the WARFASA and ASPIRE trials demonstrated that, in patients under anticoagulant therapy, low-dose ASA led to a significant reduction in VTE [7,8]. Therefore, we analyzed if early addition of LMWH to ASA-treated geriatric COVID-19-infected patients may improve their hospital outcome.

In geriatric patients taking ASA, anticoagulant treatment was significantly associated only with reduced frequency of ICU care as compared with ASA-treated patients who did not receive LMWH. In LMWH-treated patients taking ASA, >30 days all-cause mortality tended to be higher than in those ASA patients who did not receive LMWH therapy, although it did not reach statistical significance probably due to the limited sample size. In this regard, there are many discrepancies in the results of COVID-19 patients treated with anticoagulation with respect to promotion of changes in mortality risk. Previous studies which included all ages of COVID-19-infected patients have reported reduction of in-hospital mortality as a result of anticoagulant therapy, particularly in patients with severe disease [28]. However, other reports have found no differences in mortality between heparin users and nonusers, and there was an observed mortality reduction in critically ill patients [29], although, even in these critical COVID-19 populations treated with prophylatic or therapeutic dose LMWH, controversial results were reported [30,31]. In addition, it was analyzed if the effect of LMWH treatment on the mortality may be based on the condition of patients (ICU care or not ICU care). Results revealed that mortality significantly decreased in patients who took LMWH without ICU care (76% vs. 24%); however, this reduction was not observed in those patients under LMWH who needed ICU care (48% vs. 52%). This interesting finding was supported by previous studies [32,33].

In this regard, authors suggest that D-dimer levels should guide more aggressive thromboprophylaxis regimens using higher doses of heparin, although studies have also reported that the mortality rate of patients from both prophylactic and therapeutic LMWH- treated groups was similar when patients were classified according to D-dimer results [31]. In our study, D-dimer levels upon admission were similar among geriatric patients taking ASA prior to COVID-19 infection who were treated or not with LMW during hospitalization.

### *Study Limitations and Comments*

The present study has some limitations and the results should be interpreted with caution. As mentioned, data was obtained from an anonymized database made freely available to some researchers by the Madrid Hospital Group and, therefore, recruitment of new data to increase sample size was not possible. Therefore, sample size is a limiting factor for the result interpretation. In addition, confounding factors may exist that were not included in the database. In this regard, patients subjected to aspirin treatment usually have, as a main indication, the involvement of peripheral, coronary, neurologic, or renal arteriosclerosis. Therefore, it would be plausible to find higher mortality in those patients who were not taking aspirin prior to hospital admission. In addition, several factors influencing death in patients with COVID-19 were not considered. However, it would be plausible to consider the admissions to ICU as approximation of severity of COVID-19 and, therefore, of factors influencing death in patients with COVID-19. Relative to the patients taking ASA, a study limitation is that we did not know how long they were under the antithrombotic treatment prior to hospitalization for COVID-19 and their compliance to the therapeutic regimen. However, all these patients were taking daily ASA before being infected with COVID-19. Moreover, we could not assess if the platelets of all the included ASA-treated patients responded to ASA. In this regard, it is demonstrated that patients with ASA-resistant platelets have higher incidence of thrombotic events than patients with ASA-sensitive platelets [34]. Being aware of these limitations, there is no doubt about the need to carry out specific studies in one of the populations most vulnerable to COVID-19, the elderly population.

### **5. Conclusions**

To conclude, geriatric COVID-19 patients who underwent prior antiplatelet treatment with ASA had a higher frequency of in-hospital < 30 days all-cause mortality than non-ASA-treated patients. It could be probably related to higher frequency of comorbidities associated with worse prognosis of COVID-19. Moreover, despite ASA-treated patients having higher D-dimer levels upon admission, they showed similar frequency of PE compared to COVID-19-infected geriatric patients who were not taking ASA, despite the fact that the latter had lower D-dimer levels upon hospital admission. Administration of LMWH to geriatric COVID-19-infected patients taking ASA before hospitalization reduced the frequency of ICU care, but tended to increase < 30 days all-cause mortality with respect to patients taking ASA and who, during hospitalization, never received LMWH therapy.

**Author Contributions:** Conceptualization, K.Z.-N., J.B., J.J.Z.-L. and A.L.-F.; methodology, J.B. and M.D.; formal analysis, K.Z.-N., J.J.Z.-L., A.L.-d.-A. and R.J.-G.; writing—original draft preparation, K.Z.-N. and J.J.Z.-L.; writing—review and editing, C.H.M.-M., A.A.-C. and C.N.-C. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was approved by the local Ethical Committee (Code:21/084-E. Approval date 17 February 2021) and conducted in accordance with the Declaration of Helsinki.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** This study was carried out using an anonymized database provided by Madrid Hospitals Group. Data are from COVID-19-infected patients admitted in their hospital net that they made kindly available to some Spanish researchers within the program: COVID-19 data saves lives in Spain.

**Acknowledgments:** This work was supported by the GenObIA Consortium (S2017/BMD-3773) of the Community of Madrid, Spain. We thank HM Hospitals group for kindly making your COVID-19 patient database available to us. This study is a part of the "Grupo de Investigación en Biomedicina Predictiva e Investigación Traslacional de las Enfermedades Respiratorias, Cardiovasculares y Metabólicas (Code 970793) of the Complutense University from Madrid, Spain. Authors also want to thank Begoña Larrea for her editorial assistance.

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

### **References**


**RICE - TECHNOLOGY AND PRODUCTION**

Edited by **Amanullah** and **Shah Fahad**

#### **Rice - Technology and Production**

http://dx.doi.org/10.5772/64480 Edited by Amanullah and Shah Fahad

#### **Contributors**

Norinsan Kamil Othman, Denni Asra Awizar, Zulhusni Dasuki, Kok Yeow You, Li Ling You, Chen Son Yue, Hou Kit Mun, Chia Yew Lee, Leonardo Behak, Muna Ilowefah, Jamilah Bakar, Hasanah Ghazali, Kharidah Muhammad, Mercedes Salazar-Hernández, Carmen Salazar-Hernández, Rocio Lona-Ramos, Enrique Elorza, Agustín H. Rocha-Ramírez, Dr. Amanullah, Shah Fahad

#### **© The Editor(s) and the Author(s) 2017**

The moral rights of the and the author(s) have been asserted.

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#### **Notice**

Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book.

First published in Croatia, 2017 by INTECH d.o.o. eBook (PDF) Published by IN TECH d.o.o. Place and year of publication of eBook (PDF): Rijeka, 2019. IntechOpen is the global imprint of IN TECH d.o.o. Printed in Croatia

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Rice - Technology and Production Edited by Amanullah and Shah Fahad p. cm. Print ISBN 978-953-51-3029-1 Online ISBN 978-953-51-3030-7 eBook (PDF) ISBN 978-953-51-5480-8


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## IntechOpen Book Series Infectious Diseases

### Volume 14

### Aims and Scope of the Series

This series will provide a comprehensive overview of recent research trends in various Infectious Diseases (as per the most recent Baltimore classification). Topics will include general overviews of infections, immunopathology, diagnosis, treatment, epidemiology, etiology, and current clinical recommendations for managing infectious diseases. Ongoing issues, recent advances, and future diagnostic approaches and therapeutic strategies will also be discussed. This book series will focus on various aspects and properties of infectious diseases whose deep understanding is essential for safeguarding the human race from losing resources and economies due to pathogens.


**A Cluster of Paragonimiasis with Delayed Diagnosis Due to Difficulty Distinguishing Symptoms from Post-COVID-19 Respiratory Symptoms: A Report of Five Cases**

**Jun Sasaki 1,\*, Masanobu Matsuoka 1, Takashi Kinoshita 1, Takayuki Horii 1, Shingo Tsuneyoshi 1, Daiki Murata 1, Reiko Takaki 1, Masaki Tominaga 1, Mio Tanaka 2, Haruhiko Maruyama 2, Tomotaka Kawayama 1 and Tomoaki Hoshino 1**

**Abstract:** Paragonimiasis caused by trematodes belonging to the genus *Paragonimus* is often accompanied by chronic respiratory symptoms such as cough, the accumulation of sputum, hemoptysis, and chest pain. Prolonged symptoms, including respiratory symptoms, after coronavirus disease 2019 infection (COVID-19) are collectively called post-COVID-19 conditions. Paragonimiasis and COVID-19 may cause similar respiratory symptoms. We encountered five cases of paragonimiasis in patients in Japan for whom diagnoses were delayed due to the initial characterization of the respiratory symptoms as a post-COVID-19 condition. The patients had consumed homemade drunken freshwater crabs together. One to three weeks after consuming the crabs, four of the five patients were diagnosed with probable COVID-19. The major symptoms reported included cough, dyspnea, and chest pain. The major imaging findings were pleural effusion, pneumothorax, and nodular lesions of the lung. All the patients were diagnosed with paragonimiasis based on a serum antibody test and peripheral blood eosinophilia (560–15,610 cells/μL) and were treated successfully with 75 mg/kg/day praziquantel for 3 days. Before diagnosing a post-COVID-19 condition, it is necessary to consider whether other diseases, including paragonimiasis, may explain the symptoms. Further, chest radiographic or blood tests should be performed in patients with persistent respiratory symptoms after being infected with COVID-19 to avoid overlooking the possibility of infection.

**Keywords:** pulmonary paragonimiasis; *Paragonimus westermani*; COVID-19; post-COVID-19 condition; delayed diagnosis; case cluster

## **1. Introduction**

Paragonimiasis is a food-borne parasitic disease caused by trematodes belonging to the genus *Paragonimus*, for which the majority are found in Asia. Humans can become infected by consuming raw or uncooked freshwater crabs, crayfish, or the meat of wild boars or deer. Although some cases are asymptomatic, the presenting symptoms typically include cough, the accumulation of sputum, and chest pain [1]. Delayed diagnosis has been reported due to the presence of atypical symptoms or an abnormal clinical course [2].

The coronavirus disease 2019 (COVID-19) pandemic has led to the delayed diagnosis of various diseases, including lung cancer [3], gynecological cancer [4], breast cancer [4,5], and gastrointestinal cancer [6]. COVID-19 can cause prolonged symptoms such as dyspnea and cough after infection, resulting in a post-COVID-19 condition [7]. As the number of postacute COVID-19 patients has increased, so has the importance of excluding the possibility of other respiratory infections in individuals with persistent respiratory symptoms.

**Citation:** Sasaki, J.; Matsuoka, M.; Kinoshita, T.; Horii, T.; Tsuneyoshi, S.; Murata, D.; Takaki, R.; Tominaga, M.; Tanaka, M.; Maruyama, H.; et al. A Cluster of Paragonimiasis with Delayed Diagnosis Due to Difficulty Distinguishing Symptoms from Post-COVID-19 Respiratory Symptoms: A Report of Five Cases. *Medicina* **2023**, *59*, 137. https:// doi.org/10.3390/medicina59010137

Academic Editor: Brian Oliver

Received: 20 November 2022 Revised: 24 December 2022 Accepted: 9 January 2023 Published: 10 January 2023

**Copyright:** © 2023 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/).

Herein, we report a cluster of five Japanese cases of paragonimiasis in which a diagnosis was delayed due to the mischaracterization of the symptoms as a post-COVID-19 condition.

#### **2. Case Report**

The clinical characteristics of the patients considered are summarized in Table 1. Of the patients, three were women and two were men, with a mean age of 39.2 years (range, 36–42 years). Cases 1 and 2 were housemates, and Cases 3 and 4 were a married couple. None of the patients had any relevant medical history, smoking history, or bronchial asthma. One patient (Case 4) had a history of allergic pollinosis.

**Table 1.** Clinical findings of the five cases considered.

COVID-19, coronavirus disease 2019; CT, computed tomography; IgE, immunoglobulin E; PZQ, praziquantel; WBC, white blood cell count. \* Patients had been in close contact with persons with COVID-19 without a confirmatory test.

All five patients consumed raw freshwater crabs (self-prepared drunken crabs) at a dinner party that they had attended together. One to three weeks after the party, four of the five patients presented to our hospital with complaints regarding a cough and were diagnosed with confirmed or likely COVID-19 (for two patients, this was confirmed by an antigen test). The mean time from the symptoms' onset to the initial visit to our hospital was 5.4 months.

Three patients presented to their primary care physicians complaining of respiratory symptoms before visiting our hospital. All three patients were considered to be affected by post-COVID-19 symptoms. Of the three patients, two were placed under observation and one (Case 1), who had asthma-like symptoms including a fluctuating cough and dyspnea, was treated with inhaled corticosteroids (ICS)/long-acting β2 agonist (LABA) and 15 mg of oral prednisolone (PSL) for 3 weeks. The inhalation of ICS/LABA led to a temporary improvement in his symptoms.

At our hospital, the reported symptoms included cough (all patients), dyspnea (three patients), chest pain (two patients), fatigue (one patient), epigastric pain (one patient), and abdominal discomfort (one patient). Physical examination revealed a slight fever in Case 1 and bilateral decreases in breath sounds of the lower lung in Cases 1 and 4. Blood tests showed increased levels of eosinophils ranging from 560 to 15,610/μL (9.8–71.5%) in all five patients and increased levels of immunoglobulin E (IgE) ranging from 1857 to 3487 IU/L in three of the five patients. In contrast, C-reactive protein levels were near normal. Chest radiography and computed tomography (CT) showed pleural effusion (all patients), pneumothorax (three patients), nodular lesions with a cavity (one patient) and without cavity (one patient), infiltration of the lung (one patient), ascites (one patient), and a linear low attenuation area of the liver (one patient) (Figure 1A–E).

**Figure 1.** Imaging findings of cases. (**A**) Chest computed tomography (CT) of Case 1 showing a right-sided lung nodule and pleural effusion at the patient's initial visit; (**B**) chest CT of Case 2 showing left-sided infiltration of the lower lung and pneumothorax 2 months prior to visiting our hospital; (**C**) chest X-ray of Case 3 showing left pleural effusion and pneumothorax; (**D**) chest CT of Case 4 showing a right-sided lung nodule with cavity, pleural effusion, and pneumothorax (arrow); (**E**) contrast-enhanced abdominal CT of Case 5 showing a linear low attenuation area of the liver, likely representing a pathway for worm migration.

Pleural effusion fluid was examined in two patients. Both patients had exudative effusions, with a predominance of eosinophils and lymphocytes in Case 4 and lymphocytes in Case 5, examined by manual cell counting. A bronchoscopy was performed only in Case 1. To distinguish lung cancer and tuberculosis, a transbronchial lung biopsy of a right-sided nodule was performed. The biopsy specimen showed inflammatory changes, mainly eosinophils, without parasite eggs. Based on the finding of eosinophilia and the dietary history of raw freshwater crab consumption, we suggested that the symptoms were probably caused by a parasitic infection. We searched for parasite eggs in the pleural effusion and bronchial lavage fluid as well; however, we could not find any eggs. All five patients had high titers of serum *Paragonimus* IgG antibody, which was measured using a microplate enzyme-linked immunosorbent assay (ELISA). Cross-competition ELISA between *P. westermani* and *P. s. miyazakii* antigens suggested *P. westermani* infection.

All patients were treated with 75 mg/kg/day of praziquantel (PZQ) for 3 days, which led to an improvement in their symptoms and signs, including cough and dyspnea, eosinophilia, and pleural effusion. In Case 2, pleural fluid drainage was performed prior to PZQ administration.

#### **3. Discussion**

The incidence of paragonimiasis has decreased in Japan, and the number of cases diagnosed annually ranges from 17 to 49 [8]. Clustered or familial infections can occur [8,9]. According to a Japanese retrospective case review that considered 443 patients with paragonimiasis, the reported frequencies of symptoms were as follows: cough, 28.9%; sputum (including hemoptysis), 27.3%; chest pain, 18.5%; fever, 11.7%; dyspnea, 10.4%; and asymptomatic, 17.2% [1]. The most frequently observed finding on chest radiographs was pleural effusion (47.0%), followed by pneumothorax (16.9%), nodular shadows (11.5%), infiltrative shadows (8.8%), and mass shadows (6.5%) [1]. In the cases considered in this report, the symptoms and radiographic findings were consistent with those previously described. Furthermore, Case 5 appeared to have ectopic paragonimiasis in the liver.

A certain proportion of patients with COVID-19 experience sequelae after infection, which is known as long COVID [10] or post-acute COVID-19 syndrome [11]. The World Health Organization (WHO) has proposed that COVID-19-associated sequelae be referred to as a "post-COVID-19 condition" [7]. The prevalence of post-COVID-19 symptoms varies depending on the geographical area, survey method, and patient background. A Japanese cross-sectional study found the prevalence of cough, dyspnea, and chest pain to be 14.2%, 10.2%, and 2.4%, respectively (at a median duration of 29 days after the onset of COVID-19) [12]. The predominant CT pattern of COVID-19 revealed ground-glass opacity in the early stage and consolidation in later disease [13]. Pleural effusion and pneumothorax are uncommon in COVID-19 [14], a finding that differs from that of paragonimiasis. These findings were present in our patients.

In the cases considered in this study, the patients obtained freshwater crabs (the Japanese mitten crab) from a market. A meal of homemade drunken crabs was consumed by seven people. Six of the seven visited our hospital, with five suffering from paragonimiasis. Among the five patients with paragonimiasis, four had been previously diagnosed with or had been considered likely to be affected by COVID-19. Clearly, it was challenging for both patients and physicians to look past a diagnosis of a "post-COVID-19 condition". Atypical findings of eosinophilia, pleural effusion, and pneumothorax helped to exclude the possibility that the patients were afflicted by a post-COVID-19 condition, leading to the correct diagnosis of paragonimiasis. These cases highlight the importance of educating citizens regarding the safe preparation of freshwater crab. In addition, health centers should alert markets that sell infected freshwater crabs to any potential danger. Moreover, physicians should be aware they may encounter patients with paragonimiasis due to the globalization of dietary cultures.

In Case 1, the asthma-like symptoms of cough and dyspnea improved immediately after the inhalation of ICS/LABA and oral PSL, although the patient had no history of bronchial asthma or allergy. The effectiveness of ICS/LABA and PSL may contribute to the delayed diagnosis of paragonimiasis. Harada et al. [15] reported a case of bronchodilator reversibility in the acute phase of paragonimiasis. Jeon et al. [16] described bronchoscopic findings in 13 patients with paragonimiasis with intrapulmonary parenchymal lesions; in total, seven patients showed bronchial luminal narrowing and congested or edematous mucosal changes. Among the seven patients, bronchial mucosal biopsies revealed chronic inflammation with eosinophilic infiltrations in three patients. These findings are similar to those observed in patients with bronchial asthma. Dyspnea in patients with paragonimiasis might be caused by an asthma-like mechanism and not only by pleural effusion or pneumothorax.

#### **4. Conclusions**

In conclusion, physicians should consider whether diagnoses other than post-COVID-19 conditions such as paragonimiasis may explain respiratory symptoms in patients suspected to have recently been infected with COVID-19. Physicians should examine chest radiographs and blood tests in patients with persistent respiratory symptoms after COVID-19 to aid correct diagnoses.

**Author Contributions:** Conceptualization, M.M.; interpretation of imaging findings; T.H. (Takayuki Horii), S.T., D.M. and R.T.; provision of the patients' antibody test results, M.T. (Mio Tanaka) and H.M.; writing the manuscript, J.S.; editing of the manuscript, M.M., T.K. (Takashi Kinoshita), M.T. (Masaki Tominaga) and T.K. (Tomotaka Kawayama); supervision, T.H. (Tomoaki Hoshino). All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted in accordance with the Declaration of Helsinki and approved by local ethics board of the Kurume University Hospital (protocol code, 2022-090; date of approval, 16 November 2022).

**Informed Consent Statement:** Informed consent for publication of their case details was obtained from all case patients described in this report.

**Data Availability Statement:** Data supporting the study findings are available from the corresponding author on reasonable request.

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

#### **References**

**Disclaimer/Publisher's Note:** The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.


*2.5. Characterization*

The morphology of the ceramic coating and carbon steel substrate was characterized by scanning electron microscopy (SEM; JSM-6700F, JEOL, Tokyo, Japan) equipped with an energy dispersive X-ray spectroscopy (EDS, NORAN, Thermo Fisher, Waltham, MA, USA). The phase-transition occurred at different temperature was characterized by X-ray diffraction (XRD; X'Pert Pro, Philips, Amsterdam, The Netherlands) operated from 5◦ to 90◦ for 5.25 min. The weight change and thermal change during heating process were detected by TG-DTA (TG-DTA; STA449, Netzsch, Nuremberg, Germany). The TG-DTA test was operated from room temperature to 1250 ◦C at a heating rate of 10 ◦C/min. The test was conducted under flowing air.

#### **3. Results and Discussion**

#### *3.1. Performance of Coating*

The anti-oxidation performances of the coatings with different proportion of SiO2@Al were investigated by the weight loss during the heating process in muffle furnace. As shown in Figure 3, when temperatures ranged from 1050 to 1150 ◦C, a higher proportion of SiO2@Al led to a better anti-oxidation performance. However, when the proportion exceeded 10%, the enhancement of the anti-oxidation performance was not obvious. When temperatures ranged from 1200 to 1250 ◦C, the anti-oxidation performance of coating improved with the increasing amount of SiO2@Al until 10% and reduced with further SiO2@Al addition, especially at 1250 ◦C. Therefore, in view of the anti-oxidation performance and the cost, the ceramic coating with 10% of SiO2@Al was chosen as the appropriate one to conduct the following investigations.

**Figure 3.** Anti-oxidation performances of the coatings with different proportion of SiO2@Al.

The non-isothermal kinetic for sample protected by ASMA, sample protected by AS, and bare sample are shown in Figure 4. The apparent activation energy, (*E*a), was calculated by the Arrhenius equation. As shown in Equation (6), if the concentration of reactant (*B*) was constant, the reaction rate (*v*) would have a positive correlation with the reaction rate constants (k), which is the function of temperature described by Equation (7) (Arrhenius equation).

$$v = B \times \mathbf{k} \tag{6}$$

$$\mathbf{k} = \mathbf{A} \times \mathbf{e}^{(E\_\mathbf{a}/\mathcal{R}T)} \tag{7}$$

The relationship between reaction rate (*v*) and apparent activation energy (*E*a) could be deduced with Equations (6) and (7) by a logarithmic operation. The ultimate equation was described as Equations (8) and (9).

$$\text{lnk} = -\frac{E\_d}{\text{RT}} + \text{lnA} \tag{8}$$

$$
\ln \upsilon = -\frac{E\_a}{RT} + \ln \text{A} + \ln \text{B} \tag{9}
$$

where, A and B were constant. R was 8.314 J·mol−1·K−1.

Therefore, the dependent variable (ln*v*) had a linear relationship with the variable (1/*T*). As described in Equations (3) and (4), the reaction rate (*v*) could be calculated by the weight loss per unit area and the duration time of samples heated to a certain temperature. Based on the kinetic results at different temperatures as shown in Figure 4, a linear relationship was observed between ln*v* and 1/*T*. The slope of each fitting was equal to (−*E*a/R) as described in Equation (8). It was a remarkable fact that the result of the sample protected by AS was not able to be fitted by a single linear equation because there was an inflection point at about 1150 ◦C. Therefore, the kinetic of the sample protected by AS should be divided into two parts (AS1 and AS2) by 1150 ◦C.

As shown in Figure 4, the apparent activation energy (*E*a) of bare sample was 120.11 kJ/mol, while that of the sample protected by ASMA was 326.50 kJ/mol. The apparent activation energy (*E*a) of the sample protected by AS between 1025 and 1150 ◦C was 106.14 kJ/mol, which was approximate to the bare sample. The apparent activation energy (*E*a) of the sample protected by AS between 1150 and 1250 ◦C was 224.05 kJ/mol, which was between that of the sample protected by ASMA and the bare sample. Generally, higher apparent activation energy resulted in a better anti-oxidation performance of coating. Therefore, ASMA exhibited an excellent anti-oxidation performance between 1025 and 1250 ◦C, while AS only worked above 1150 ◦C. Additionally, the anti-oxidation performance of ASMA was much better than AS due to its larger apparent activation energy (*E*a). To further prove the enhancement of anti-oxidation of ASMA, the non-isothermal experiment was conducted by a continuous thermo-balance. As shown in Figure 5, compared with AS, ASMA showed an obviously better anti-oxidation performance during the temperature-rise period.

**Figure 4.** Results of non-isothermal kinetics.

**Figure 5.** Results of continuous thermo-balance from 200 to 1250 ◦C with a rate of 10 ◦C/min.

Since the serious oxidation of carbon steel always occurred over 1250 ◦C, the isothermal kinetic was conducted at 1250 ◦C. It was widely accepted that the oxidation of carbon steel followed the parabolic law [3,23,24], which meant that the oxidation process was controlled by the diffusion. The reaction constant could be calculated by Equation (10) [2].

$$\left(\Delta\omega\right)^{2} = \mathrm{H} + \mathrm{k}\_{\mathrm{P}} \times t\_{i} \tag{10}$$

Here, *ti* (s) is the duration of oxidation, Δω is the weight gain per unit area (mg/cm2), H is a constant, and kp (mg2·cm−4·s−1) is the reaction rate constant.

In this study, the linear relationship between Δω and *ti*1/2 was used to evaluate kp [2]. As shown in Figure 6, the reaction rate constant (kp) of the bare sample, the sample protected by AS, and the sample protected by ASMA was 2.09, 0.096, and 0.046 mg2·cm−4·s−1, respectively. It can be concluded that ASMA possessed a better anti-oxidation performance than AS due to its smaller reaction rate constant at 1250 ◦C.

**Figure 6.** Results of isothermal kinetics.

#### *3.2. Morphology of Coating*

The microstructure was an intuitive evidence for evaluating the compactness of coating which controlled the inner diffusion rate of oxygen. Therefore, anti-oxidation performance of coating was better with a more compact structure. The outer-surface microstructures of sample protected by the ASMA and sample protected by the AS were investigated after the thermal treatments of different temperature (900, 1150, and 1250 ◦C). As described in Figure 7, ASMA formed a compact structure at 900 ◦C and the compactness improved with the increasing of temperature until 1250 ◦C. The amount of liquid phase increased with the rising temperature, the porosity reduced and thus the sintering of coating was enhanced at the same time. However, the sample protected by AS possessed a porous structure composed of isolated particles at 900 ◦C, while the compactness improved at 1150 ◦C. The above results suggested that SiO2@Al could accelerate the sintering of the ceramic coating and enhance the compactness.

**Figure 7.** SEM images of outer-surfaces belonging to sample protected by ASMA and sample protected by AS at different temperatures.

#### *3.3. Protection Mechanism*

Figure 8 showed the TG-DTA data of the ASMA and AS slurry. As shown in Figure 8a, there was an endothermic peak at about 662.85 ◦C, an exothermic peak at 977.7 ◦C, and an exothermic peak at 1153.91 ◦C for ASMA slurry, while there was only a gradual exothermic trend during heating process for AS slurry. In order to interpret the possible reactions during the heating process, the phase transitions were investigated by XRD method at 500, 800, 1100, and 1250 ◦C, which were near the endothermic or exothermic temperature. Compared with Figure 9a,b, it was found that no specific phase formed between 500 and 800 ◦C, thus the endothermic peak at 662.82 ◦C could be attributed to the melting of Al powders in SiO2@Al. Phases of Si and Al3.21Si0.47 were newly formed within ASMA when temperature increased from 800 to 1100 ◦C, which indicated that an exothermic reaction occurred as described in Equation (11) and it gave rise to the exothermic peak at 977.7 ◦C [25]. Compared with Figure 9c,d, it was remarkable that mullite and cristobalite formed within ASMA when temperature ranged from 1100 to 1250 ◦C. Therefore, the exothermic peak at 1153.91 ◦C might result from the exothermic reaction expressed as Equations (12) and (13) [26,27]. In contrast, there was no new phase formed within AS during the whole heating process except for cristobalite. To sum up, the Al powders in SiO2@Al melted at 662.85 ◦C and reacted with SiO2 on its surface, which generated local high temperature and the sintering of ceramic raw materials, thus contributing to its excellent anti-oxidation performance, which was consistent with the non-isothermal kinetics. Besides, mullite and cristobalite formed at 1150 ◦C could further enhance the coating compactness and improve the anti-oxidation performance above 1150 ◦C [19]. However, ceramic raw materials just sintered above 1150 ◦C within AS, and thus showed an unobvious anti-oxidation effect below this temperature.

$$4\text{Al} + 3\text{SiO}\_2 \rightarrow 3\text{Si} + 2\text{Al}\_2\text{O}\_3 \tag{11}$$

SiO2 (amorphous) → SiO2 (cristobalite) (12)

$$\text{3Al}\_2\text{O}\_3 + 2\text{SiO}\_2 \to \text{3Al}\_2\text{O}\_3 \cdot 2\text{SiO}\_2 \tag{13}$$

**Figure 8.** TG-DTA curves of (**a**) ASMA and (**b**) AS.

**Figure 9.** Comparisons of XRD result of the sample protected by ASMA and AS slurry at dffierent temperatures: (**a**) 500 ◦C, (**b**) 800 ◦C, (**c**) 1100 ◦C, (**d**) 1250 ◦C.

According to the SEM-EDS results of coating cross-sections exhibited in Figure 10, both the coatings were able to prevent the carbon steel substrate from oxidization at 1250 ◦C. Compared with Figure 11a,b, ASMA was composed of a hercynite layer, a mullite layer, and a ceramic layer with high aluminum content, while AS consisted of a Fe3O4 layer, an olivine layer composed of FeO and 2FeO·SiO2, a ceramic layer composed of Al2O3 and cristobalite. Equations (14) or (15) possibly occurred to form the hercynite (Al2O3·FeO) within ASMA. As reported in the literature [28], the structure of hercynite could be expressed as (Fe2+1−*x*Al3+*x*)tet(Al3+2−*x*Fe2+*x*)octO4 where 0 < *x* < 0.25, while that of Fe3O4 could be expressed as (Fe3+)tet(Fe3+Fe2+)octO4 [29]. Referring to Freer and O'Reilly [30], the diffusion activation energy of Fe2+ at octahedral site and tetrahedral site were 0.2(±0.05) eV and 0.71

(±0.09) eV, which indicated that the diffusion of iron ions within hercynite was slower than Fe3O4 due to the lower fraction of Fe2+ occupied the octahedral site. Therefore, hercynite also played a significant role for enhancing the anti-oxidation ability of ASMA. However, hercynite was easily oxidized as shown in Equation (16) under oxidation condition. As mentioned in Section 3.1, the compactness of ASMA was greatly improved with the addition of SiO2@Al, which effectively prohibited the inner diffusion of oxygen. As a result, the hercynite layer could be stable within the ceramic coating. The result agreed well with the finding in isothermal kinetic experiment.

$$3\text{Al}\_2\text{O}\_3 \cdot 2\text{SiO}\_2 + 3\text{FeO} \rightarrow 3\text{Al}\_2\text{O}\_3 \cdot \text{FeO} + 6\text{SiO}\_2\tag{14}$$

$$\text{Al}\_2\text{O}\_3 + \text{FeO} \rightarrow \text{Al}\_2\text{O}\_3 \cdot \text{FeO} \tag{15}$$

$$4\text{Al}\_2\text{O}\_3 \cdot \text{FeO} + \text{O}\_2 \rightarrow 4\text{Al}\_2\text{O}\_3 + 2\text{Fe}\_2\text{O}\_3\tag{16}$$

**Figure 10.** SEM-EDS images of cross-sections belonging to (**a**) the sample protected by ASMA and (**b**) the sample protected by AS at 1250 ◦C.

**Figure 11.** SEM images with results of EDS measurements performed on selected areas of cross-sections belonging to (**a**) sample protected by ASMA and (**b**) sample protected by AS at 1250 ◦C.


*2.2. Balance Calibration*

In order to provide quality measurements, the aerodynamic balance was calibrated before each experiment. The calibration routine employed for this work assumed a linear response of the load cells, so a direct (exact solution) method was chosen to determine the correlation coefficients. The calibration, which implied a two-stage procedure to determine the calibration matrix, was completed under "no wind" conditions. In the first stage, the prototype was just mounted in the balance and a measurement was performed at free load, defining the zero-loading state. In the second stage, several measurements were performed with the balance loaded with known weights. Specifically, 3 load cases (LC) were carried out:

From each load case, three outputs (one for each load cell) were obtained providing a 9 equation and 9 unknowns system to represent the direct correlation between loads and measured components. Matrix algebra can be applied to streamline this process in the following way.

First, a force matrix *FLC* is defined with the three load cases, with one column for each component and one row for each load case.

$$F\_{LC} = \begin{pmatrix} F\_{x\_1} & 0 & 0 \\ 0 & F\_{y\_2} & 0 \\ 0 & F\_{y\_3} & F\_{y\_3}b \end{pmatrix} \tag{1}$$

where *F* is the applied load, *x* and *y* are the horizontal and vertical directions, respectively, in the balance coordinate system, and *b* is the horizontal distance to the axis in load case 3.

With the output of the single load cell being associated with the measurements in the horizontal direction in these experiments, referred to as "signal 1" (*s*1), and the other two, associated with the measurements in the vertical direction, referred to as "signal 2" (*s*2) and "signal 3" (*s*3), the output of the balance in the zero-loading state can be posed as a vector *SLC*0 containing the values recorded in each load cell.

$$S\_{LC\_0} = \begin{pmatrix} S\_{1\_0} & S\_{2\_0} & S\_{3\_0} \end{pmatrix} \tag{2}$$

Following this, the matrix *SLC* is defined with the load cells' output for the three load cases, yielding:

$$S\_{LC} = \begin{pmatrix} s\_{1,1} & s\_{1,2} & s\_{1,3} \\ s\_{2,1} & s\_{2,2} & s\_{2,3} \\ s\_{3,1} & s\_{3,2} & s\_{3,3} \end{pmatrix} \tag{3}$$

Then, the calibration matrix *K* with the coefficients that relate the output of the three load cells with the forces and moment is:

$$K = \begin{pmatrix} k\_{1,1} & k\_{1,2} & k\_{1,3} \\ k\_{2,1} & k\_{2,2} & k\_{2,3} \\ k\_{3,1} & k\_{3,2} & k\_{3,3} \end{pmatrix} \tag{4}$$

Finally, applying the linear response assumption, the equation system is thus stated as:

$$F\_{LC} = \left[S\_{LC} - S\_{LC\_0}\right] \cdot K \tag{5}$$

where the no-load signals are discounted as the system offset. From this matrix system, matrix *K* can be directly deduced as *K* = [*S* − *S*0] −1 ·*Fxyz*, thus obtaining the direct relation between load cell outputs and measured forces.

Once the calibration matrix is determined, it can be employed to obtain the forces acting on the models from the signals measured during the operation of the wind tunnel using a generalization of Equation (5) for a single-point measurement:

$$F\_{xyz} = \left[\mathcal{S} - \mathcal{S}\_0\right] \cdot \mathcal{K} \tag{6}$$

where *Fxyz* and *S* are now row vectors with three columns.

As the calibration used is a linear, two-point method, the balance was additionally tested before the aerodynamic measurements' campaign to evaluate its accuracy. Figure 2 shows the response of the calibrated balance (y-axis) to 5 different known weights in the

lower part of the balance range (x-axis), where the linearity of these types of sensors is mostly critical.

**Figure 2.** Balance response to a range of known weights using a two-point, linear calibration method.

The figure shows that the calibration method used provides a sufficiently accurate linear response, even for the lower part of the balance range. The response in this range is better in the horizontal direction because its range is half than the others, so it is better prepared to measure small forces. This is especially interesting to the case of airfoil testing, as drag forces are much lower than lift ones.

During the aerodynamic measurements campaign, the balance was calibrated before each experiment and tested after with known weights to validate the balance calibration. This reduces the influence of random errors produced by differences in the testing environment temperature, differences in the set-up assembly, etc. Up to 13 calibrations were performed during the campaign, providing useful statistical data of the balance performance. Table 2 shows the mean, standard deviation, maximum and median value of the relative errors between the known weights and the measured weights those 13 calibrations.

**Table 2.** Relative error statistics of 13 calibrations performed during the measurements campaign.

The mean relative error obtained was around 1%, slightly higher in the horizontal direction and slightly lower in the vertical direction. However, as the standard deviation reveals, there was some variability in the quality of the calibrations; hence, the mean is not very representative of the real performance of the balance. Note that although all 13 calibrations have been included in this analysis, a quality requirement was established in 1%. Thus, calibrations with errors above this, such as the one that achieved the maximum error shown in Table 2, were discarded and repeated. Nevertheless, as the median indicates, these discarded cases were not common and the typical balance calibration errors were about 0.8% for the horizontal direction, 0.4% for the vertical direction, and 0.3% for the moment. In these calibrations, the loads were adjusted to the expected measured forces; hence, in contrast with the previous figure, the vertical and moment errors are lower. The higher error in the horizontal force is probably due to the higher difficulty to produce a pure horizontal load, as opposed to the simplicity of vertical loading.