# **Mycobacterium Tuberculosis Pathogenesis, Infection Prevention and Treatment**

Printed Edition of the Special Issue Published in *Pathogens* Riccardo Miggiano, Menico Rizzi and Davide M. Ferraris Edited by

**Mycobacterium Tuberculosis Pathogenesis, Infection Prevention and Treatment**

• Riccardo Miggiano, Menico Rizzi and Davide M. Ferraris

www.mdpi.com/journal/pathogens


**Stuart Waiton**

School of Business, Law and Social Sciences, Abertay University, Dundee DD1 1HG, UK<EMAIL_ADDRESS>Received: 13 August 2019; Accepted: 9 September 2019; Published: 17 September 2019

**Abstract:** Academic freedom is formally supported but often challenged, through activities like noplatforming and through a sentiment of sensitivity and an understanding that ideas can be harmful. This development is discussed here as a reflection of the rise of the 'vulnerable subject.' This paper demonstrates the growing importance of vulnerability as the central human characteristic in (post) modern times and with reference to law and justice practices explains the 'collapse of the harm principle.' Developed through Frank Furedi's theory of diminished subjectivity this paper demonstrates the extent to which the vulnerable subject has been institutionalised and adopted as a new (fragmented) norm. Within the framework of diminished subjectivity, the inner logic of vulnerability has a spiralling dynamic—once adopted as a norm, the vulnerable subject's answer to the question 'vulnerable to what?' constantly expands, drawing in ever more areas of life, behaviour, relationships as well as words and ideas into a regulatory framework. Concerns about overcriminalisation are understood here to be a product of this vulnerable subject, something that cannot be resolved at the level of law but must relate to the wider cultural and political sense of human progress and a defence of the robust liberal subject in society.

**Keywords:** criminalisation; harm; law; criminal justice; freedom;risk; abuse; liberal; victim; vulnerability


*3.1. Emergency Power Supply Scheme Testing*

To verify the feasibility of the proposed emergency power supply scheme and the accuracy of the stability analysis, a simulation model of the PV and battery power generation systems, RPC, and CRH3 locomotive, as shown in Figure 1, was built based on Starsim. Figure 16 shows Shanghai Yuankuan Energy's Starsim HIL real-time simulation software 5.0 and HIL real-time simulator (Modeling Tech, Shanghai, China). This system can perform small-step real-time testing on power electronic models based on state equations, switch averaging, and modeling of large and small resistors. In this paper, the model was verified using a real-time test system (MT 6020) with a 5 μs step size and 20 kHz sampling frequency.

**Figure 16.** Hardware-in-the-loop real-time testing platform.

Here are the model parameters in the above-mentioned testing system, as shown in Table 1. In this paper, the parameters in Table 1 are referred to as the original parameters. Unless otherwise specified, analysis or testing will default to using the original parameters.

#### 3.1.1. Emergency Traction Test based on Locomotive Power Failure

The upper computer calculation display is shown in Figure 17a, where *P*RPC is the output power of the PV and battery, *P*net is the output power of the substation, and *P*CRH3 is the absorbed power of one locomotive. At 1 s, the traction network unexpectedly lost power to the locomotive; after a short response time, the RPC identified the operation status of the PV and battery devices and switched to the corresponding mode to achieve the emergency power supply for the locomotive. At 2 s, the power supply to the substation was restored; to ensure passenger safety, the RPC delayed the power outage. Finally, at 2.5 s, the RPC exited the power supply or returned to the power compensation scheme. During this power outage process, the locomotive remained running, as shown in Figure 17b. If emergency-response-type locomotive traction is started in actual engineering, it can provide on-site measured data support and technical guidance for future new energy self-sufficient traction. For example, the working conditions of delayed power outages are equivalent to the actual test of changing to the substation supply when the new energy self-sufficient traction encounters an accident.

**Figure 17.** Emergency response traction power supply: (**a**) system energy flow; (**b**) locomotive voltage and current.


**3. Methodology**

In order to understand the SSC approach using the project teaching method, I observed the planning of some of these projects in real teaching situations, thereby delineating their limits and possibilities in this area.

The SSC approach used in combination with integrated projects was observed in a private school that provides both Secondary and Technical Vocational education and is located in the state of Rio Grande do Sul, Brazil.

Data were collected by administering questionnaires containing open‐ended questions to the 42 teachers with the objective of obtaining information on the conception that these teachers had of SSC, and of their constraints and potentials for teaching. This questionnaire was also designed to provide an understanding of teachers' concepts with regard to organization and application of projects conducted in the school and the constraints and potentials for using them in teaching. Fourteen teachers completed the questionnaires.

After collecting the teachers' responses to the questionnaire, it was necessary to conduct unstructured interviews [34] with the objective of probing in greater depth the research participants' thoughts with relation to use of SSC and the way the projects are organized at the school.

of teachers, researchers, and mediators, leaving aside their roles as transmitters of knowledge to become mediators of learning, encouraging the formation of autonomous students, capable of acting and interacting in the world in which they live. The project teaching methodology, with activities conducted within the project, leads to considerable changes in students' behav-

One of the potentials of using integrated projects is the students' involvement in the process of construction of knowledge and of seeking solutions to problematic situations, in addition to positive changes in relation to day‐to‐day attitudes and greater motivation and involve-

Although it is difficult for teachers to achieve a good balance between the elements of the triad "subject matter," "activities," and "assessment" in the classroom, students are able to demonstrate and re‐elaborate earlier concepts, which I consider to be of great importance in

Beane [33] sees curricular integration as a concept that is concerned with the possibilities for personal and social integration through a curriculum that is organized around significant problems and questions, identified in a collaborative manner by the teachers and students,

However, difficulties are encountered, especially with relation to the issue of bringing the humanities closer to the sciences. In the majority of cases, integration between these different groups of subjects proves to be a practical problem that is difficult to solve. The difficulty lies

In view of the above, the SSC approach can be considered an ideal way to achieve curricular integration in teaching, since all of the different subject areas will get the opportunity to con-

In order to understand the SSC approach using the project teaching method, I observed the planning of some of these projects in real teaching situations, thereby delineating their limits

The SSC approach used in combination with integrated projects was observed in a private school that provides both Secondary and Technical Vocational education and is located in the

Data were collected by administering questionnaires containing open‐ended questions to the 42 teachers with the objective of obtaining information on the conception that these teachers had of SSC, and of their constraints and potentials for teaching. This questionnaire was also designed to provide an understanding of teachers' concepts with regard to organization and application of projects conducted in the school and the constraints and potentials for using

ior, interest, and motivation with relation to learning the subject.

irrespective of the demarcations that separate subjects.

tribute a great deal of subject matter to the discussion.

in establishing a set of common repertoires that will enable dialogue.

them in teaching. Fourteen teachers completed the questionnaires.

ment in the learning process.

86 Science Education - Research and New Technologies

the construction of knowledge.

**3. Methodology**

and possibilities in this area.

state of Rio Grande do Sul, Brazil.

These interviews were conducted with the school's Principal, the Vice‐principal responsible for teaching and three teachers, one from each subject area (languages, humanities, and sciences), selected using the criterion of longest time teaching at the school.

The data collected were analyzed using Discursive Text Analysis [35]. This analytical resource was used to systematize information from the questionnaires and to construct an interpretation of the subject in question from the point of view of the research participants. This analysis, which is coherent with the qualitative approach chosen, facilitates comprehension of the phenomenon investigated with no intention of generalizing or explaining it.

During this analysis, the questionnaires were read and organized into units and assigned to a system of categories that provide the basis for construction of descriptive texts (metatexts) that would be used to interpret the phenomenon studied.

In order to organize these units, a labeling system was adopted in which units from questionnaires were marked with a "Q" and those from teachers with a "T." The units were numbered from 1 to 14 to represent the respondents, with no relationship between the number and the respondent. Finally, units were also labeled with the number of the questionnaire item, separated from the number of the respondent by an underscore character (\_).

Next, the interviews were transcribed but were not categorized, rather they were used as a basis for in‐depth discussion of the constraints and potentials identified in the data from the questionnaires. Data from the questionnaires and the interviews were combined to construct a metatext. To identify the teachers interviewed, I used the same numbers as for the questionnaires, adding the letter "I" to indicate interview data. The Principal is identified with the label "Prin," and the Vice‐principal responsible for teaching is identified with the label "VPT."


**13. Conclusions**

It is now evident that targeted inhibition of DNA repair and DDC proteins has numerous applications in cancer treatment. The kinases involved in the first phases of DNA damage recognition and cell cycle arrest such as: ATM, ATR, DNA-PK, and CHK1, have been demonstrated to be efficiently targeted and several inhibitors are currently being tested. Importantly, identifying new targets involved in specific pathways and new drugs could allow the development of more personalized therapeutic approaches that may result in reducing the possibility of side-effects and the occurrence of drug resistance.

Another promising application is the combinatorial treatment which takes advantage of simultaneous inhibition of related pathways, leading to an increase of efficacy as compared to the drugs alone. Recently, there is an emerging paradigm that DNA damage, which frequently occurs in cancer cells, leads to the expression of interferon and chemokines activating immune cells in the tumor microenvironment [202]; therefore, immunotherapy combined with drugs inhibiting DNA-repair proteins is now one of the most promising therapies. Numerous ongoing clinical trials are investigating efficacy of these treatments; for instance, PARP inhibitors combined with immune inhibitors (see clinical trials NCT03834519, NCT03851614, NCT03602859, and NCT03308942). Moreover, the efficacy of PARP inhibitors in HR-deficient cancers underlines the importance of the discovery of new synthetically lethal interactions and how these could be exploited in specific cancers, hence promoting development of personalized therapies. The progression in CRISPR/Cas9-based screening has made possible systematic analysis for synthetic lethal drug targets in human cancers leading to the identification of novel genetic cancer targets and eventually the development of effective drugs specific for different pathogenic conditions [203,204].

Finally, DNA damage is repaired by a protein network that is deeply connected; uncovering these connections might generate novel targets to increase efficacy of current in use therapies and overcome resistance development.

**Author Contributions:** All the authors were involved in curation of the manuscript. S.L. and A.G. collect data and wrote the article. A.P. contributed to designing and editing of the manuscript. S.L. was also involved in preparing the figures and tables. T.C. reviewed the manuscript and contributed to organize the conclusions. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by grants assigned to AG by the "Fondazione Pisa" (127/16) and to AP by Associazione Italiana Ricerca sul Cancro (AIRC\_IG19917). SL was supported by a fellowship from Fondazione Umberto Veronesi (Post-Doctoral Fellowship 2020).

**Acknowledgments:** The authors wish to thank all the members of the laboratories for suggestions and comments. Special thanks to Marcella Simili and Michael Minks for critical reading and language editing.

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


**6. Use of immunoglobulins in the prevention of neonatal sepsis**

88 Neonatal Bacterial Infection

favouring immunoglobulin therapy.

CI; 6, 33) to avoid one death.

efficacy of IVIG.

neonates and especially preterm infants, therapy with polyclonal immunoglobulins should be understood much more as a substitutional therapy than as an adjunctive therapy as for adults or older children (43). Comparing the two treatment modalities (IgGAM vs. IgG) in neonates, Kreymann et al. (30) only found a slight difference without statistical significance. A major limitation of this meta-analysis is the inclusion of the study of El Nawawy (32), who originally included infants of 1 to 24 months of age hospitalized at a pediatric intensive care unit, of which 50 were proven septic patients. This study strongly influenced study results

Ohlsson and Lacy (44) recently reviewed IVIG for suspected or subsequently proven infection in neonates including randomized or quasi-randomized controlled trials comparing IVIG treatment to placebo or no intervention in newborn infants below 28 days of age. They found 10 studies meeting their inclusion criteria that differed to the above mentioned analysis (30) by additional including the small study of Christensen et al. (45) and a new study by Ahmend et al. (46) and not including the studies by El Nawawy (32), Gökalp (38), and Gunes (31).The results showed a statistically significant reduction in mortality in cases of proven and also of suspected infection with a NNT of 10 infants (95%

IVIG preparations with high concentrations of antibodies to bacteria that are commonly isolated from neonates in specific local settings or geographical areas may be more effective in reducing adverse outcomes (44). However, the use of antistaphylococcal immunoglobulins to prevent staphylococcal infection in very low birth weight infants has

A very recent study published by the International Neonatal Immunotherapy Study (INIS) Collaborative group enrolled 3493 infants with birth weight less than 1500g receiving antibiotics for suspected or proven serious infection and randomly assigned them to receive two infusions of either IgG immune globulin (at a dose of 500 mg per kilogram of body weight) or matching placebo 48 hours apart (48). The researchers found no significant between-group difference in the rates of death or major disability at the age of two years (39 and 39%, respectively). Similarly, there were no significant differences in the rates of secondary outcomes including the incidence of subsequent sepsis episodes. In the 2-years follow-up of the study participants there were no differences in the rates of major or nonmajor disability or of adverse events. Thus, IgG IVIG was not found to be helpful in diminishing the risk of major complications or adverse outcomes in neonates with suspected or proven sepsis. The duration of hospital stay also did not differ between groups (48).

The clinical efficacy of IgM-enriched IVIG (currently there is only one preparation available, Pentaglobin®) has been reviewed by Norrby-Teglund et al. (49) for both adult and paediatric/neonatal patients. The authors concluded that patients most likely to benefit are Gram-negative septic shock patients. Therefore it is important to emphasize that selection of study patients as well as microbiological aetiology are of high relevance affecting the

recently been reviewed and is currently not recommended (47).

There have been published a lot of studies and reviews on the preventive use of IVIG in preterm infants and I herewith report ("pars pro toto") two multicenter randomized, double-blind, placebo-controlled trial published early in the New England Journal of Medicine (50,51) with divergent results and the latest Cochrane Review (52).

Baker et al. (50) included 588 infants with a birth weight of 500 - 1750 g and age of 3 - 7 days from six centres in the U.S. between 1987 and 1988. The trial was randomized, double-blind, placebo-controlled with 287 infants having received 500 mg/kg of IVIG at enrolment (age 3 to 7 days), one week later, and then every 14 days until a total of five infusions had been given or until hospital discharge, whichever came first, and 297 controls having received an equal volume of a sterile solution of 5 % albumin and 0.9 % sodium chloride. Outcomes included proven infection - clinical findings of sepsis and at least one of the following: a positive blood culture of either bacteria or fungi (the isolation of a pathogen from a normally sterile other body site or urine obtained by suprapubic or bladder catheterization, or the isolation of virus from an infant with clinical deterioration), necrotizing enterocolitis stage II or III, intraventricular haemorrhage grade 1 to 4, bronchopulmonary dysplasia, death, and total days in hospital. There were 50 episodes of sepsis among 287 infants (17.4%) in the IVIG group and 75 episodes of sepsis among 297 infants (25.3%) in the placebo group. The cumulative relative risk reduction was 0.7 (CI 95% 0.5-0.9).

In a prospective, multicenter, two-phase controlled trial, Fanaroff et al. (51) stratified 2416 infants according to birth weight (501 to 1000 g and 1001 to 1500 g) and randomly assigned to an IVIG (n = 1204) or a control group (n = 1212). Control infants were given placebo infusions during phase 1 of the study (n = 623) but were not given any infusions during phase 2 (n = 589). Infants weighing 501 to 1000 g at birth were given 900 mg of immune globulin per kilogram of body weight, and infants weighing 1001 to 1500 g at birth were given a dose of 700 mg per kilogram. The immune globulin infusions were repeated every 14 days until the infants weighed 1800 g, were transferred to another center, died, or were sent home from the hospital. Nosocomial infections of the blood, meninges, or urinary tract occurred in 439 of the 2416 infants (18.2 %): 208 (17.3 %) in the immune globulin group and 231 (19.1%) in the control group (relative risk, 0.91; CI 95% 0.77 to 1.08). Septicemia occurred in 15.5% of the immune globulin recipients and 17.2% of the controls. The predominant organisms included gram-positive cocci (53%), gram-negative bacilli (22.4%), and candida species (16%). Adverse reactions were rarely observed during the infusions. Immune globulin therapy had no effect on respiratory distress syndrome, bronchopulmonary dysplasia, intracranial hemorrhage, the duration of hospitalization, or mortality. The incidence of necrotizing enterocolitis was 12% in the immune globulin group and 9.5" in the control group. Thus, the authors concluded that the prophylactic use of IVIG failed to reduce the incidence of hospital-acquired infections in very-low-birth-weight infants (51).

The prophylactic administration of intravenous immunoglobulins (IVIG) to prevent nosocomial infections has been studied in >5,000 neonates from 19 studies enrolled in randomised controlled trials (52). The results of these meta-analyses showed a statistically significant reduction in sepsis (number needed to treat – NNT - 36) and/or any serious infection (NNT 31), but no reduction in mortality from infection. The reviewers concluded that IVIG administration resulted in a 3% reduction in sepsis and a 4% reduction in any serious infection of one or more episodes. Nevertheless it was not associated with reductions in other important outcomes including necrotizing enterocolitis intraventricular haemorrhage, or length of hospital stay. Most importantly, IVIG administration did not have any significant effect on mortality from any cause or from infections. There were no adverse events observed to be associated with prophylactic use of IVIG. From a clinical perspective a 3-4% reduction in nosocomial infections without a reduction in mortality or other important clinical outcomes might be of marginal importance and has to be outweighed by the costs and the values assigned to the clinical outcomes (52). This Cochrane review ends with the statement that there is no justification for further randomized trials testing the efficacy of previously studied IVIG preparations to reduce nosocomial infections in preterm and/or low birth weight infants. In contrast, these results should encourage basic scientists and clinicians to pursue other avenues to prevent nosocomial infections (52).

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