From tap to table: An assessment of drinking water quality in Perak, Malaysia.

INTRODUCTION: A study on the quality of drinking water was conducted at Air Kuning Treatment Plant In Perak, Malaysia, based on a sanitary survey in 14 sampling points stations from the intake area to the auxiliary points. This was to ensure the continuous supply of clean and safe drinking water to the consumers for public health protection. The objective was to examine the physical, microbiological, and chemical parameters of the water, classification at each site based on National Drinking Water Standards (NDWQS) and to understand the spatial variation using environmetric technique; principal component analysis (PCA). MATERIALS AND METHODS: Water samples were subjected to in situ and laboratory water quality analyses and focused on pH, turbidity, chlorine, Escherichia coli, total coliform, total hardness, iron (Fe), aluminium (Al), zinc (Zn), magnesium (Mg) and sodium (Na). All procedures followed the American Public Health Association (APHA) testing procedures. RESULTS: Based on the results obtained, the values of each parameter were found to be within the safe limits set by the NDWQS except for total coliform and iron (Fe). PCA has indicated that turbidity, total coliform, E. coli, Na, and Al were the major factors that contributed to the drinking water contamination in river water intake. CONCLUSION: Overall, the water from all sampling point stations after undergoing water treatment process was found to be safe as drinking water. It is important to evaluate the drinking water quality of the treatment plant to ensure that consumers have access to safe and clean drinking water as well as community awareness on drinking water quality is essential to promote public health and environmental protection.

Prediction of toxicity outcomes following radiotherapy using deep learning-based models: A systematic review.

PURPOSE: This study aims to perform a comprehensive systematic review of deep learning (DL) models in predicting RT-induced toxicity. MATERIALS AND METHODS: A literature review was performed following the PRISMA guidelines. Systematic searches were performed in PubMed, Scopus, Cochrane and Embase databases from the earliest record up to September 2022. Related studies on deep learning models for radiotherapy toxicity prediction were selected based on predefined PICOS criteria. RESULTS: Fourteen studies of radiotherapy-treated patients on different types of cancer [prostate (n=2), HNC (n=4), liver (n=2), lung (n=4), cervical (n=1), and oesophagus (n=1)] were eligible for inclusion in the systematic review. Information regarding patient characteristics and model development was summarized. Several approaches, such as ensemble learning, data augmentation, and transfer learning, that were utilized by selected studies were discussed. CONCLUSION: Deep learning techniques are able to produce a consistent performance for toxicity prediction. Future research using large and diverse datasets and standardization of the study methodologies are required to improve the consistency of the research output.

CADEN: cellular automata and DNA based secure framework for privacy preserving in IoT based healthcare.

In the present E-healthcare industry, data breaches result in substantial economic losses due to cyber-attacks and hence create a trust deficit between the industry and users. The healthcare industry has rapidly adopted IoT frameworks but the trust deficit and privacy concerns limit its utilization among the masses. Along with privacy protection, content authentication is an important requirement in a number of critical applications and fragile watermarking provides an effective solution. However, existing fragile watermarking techniques lack the accuracy of tamper detection and hence are not reliable enough in terms of security and privacy of the data. This paper presents a novel low-complexity block-based fragile watermarking technique with high security against cyber-security attacks. This is achieved by embedding a fragile watermark in the host image using pixel domain blocking approach. The security of embedded watermark has been taken care of by using Cellular Automata and DNA based ENcryption (CADEN) framework to scramble the watermark bits using various secret keys. Experimental investigations show that besides being highly secure, the proposed technique is fragile to various signal processing and geometric attacks. The comparative analysis shows that the proposed scheme, despite having lower complexity, offers better efficiency in terms of imperceptibility, tamper detection and localization compared to other state-of-the-art techniques. Besides, the fragile watermark embedding makes the system capable to preserve the secret information in case of an attack with an average BER of 40%.

The panniculus carnosus muscle: a missing link in the chronicity of heel pressure ulcers?

Chronic and recurring pressure ulcers (PUs) create an unmet need for predictive biomarkers. In this work, we examine the panniculus carnosus, a thin cutaneous muscle, traditionally considered vestigial in humans, and ask whether the panniculus may play a role in the chronicity and reinjury of heel PUs. To determine whether humans have a panniculus muscle layer at the heel, we dissected eight cadavers. To assess the influence of the panniculus layer on PU, we performed computational simulations of supine weight bearing. Finally, we assessed panniculus regeneration in fluorescent mice. Results show a panniculus layer present in all cadavers examined. Simulations show a thin layer of panniculus muscle causes a dramatic decrease in the volume of soft tissue experiencing high strain and stress, compared to a heel without a panniculus. Importantly, in the mouse model, the panniculus fails to regenerate after PU, even when other cutaneous layers had fully regenerated. Our work shows that the panniculus is able to redistribute load around the heel bone, which might allow it to prevent PUs. Moreover, it is highly susceptible to incomplete regeneration after PU. Poor panniculus regeneration after PU might be a predictive anatomical biomarker for recurrence, and this biomarker should be evaluated prospectively in future clinical trials.

Low Frequency Dielectric and Optical Behavior on Physicochemical Properties of Hydroxyapatite/Cornstarch Composite.

An investigation on relationship among the physicochemical, optical and dielectric properties of the hydroxyapatite/cornstarch (HA/Cs) composites with the starch proportion of 30, 40, 50, 60, 70, 80 and 90 wt% is presented in this work. The HA/Cs composites have been characterized via FTIR, XRD, DRS and impedance analyzer. This work depicts that the strong interaction is exhibited between the hydroxyapatite nanoparticles and starch as the starch proportion increases. This increment trend results in the higher crystallinity of the HA/Cs composites. The highly crystallized HA/Cs with hydroxyapatite nucleation center presents low optical properties (diffuse reflectance and optical band gap energy). The HA/Cs composite with 80 wt% starch proportion (H2C8) show higher dielectric properties (dielectric constant, loss factor and conductivity) due to the stronger interfacial interaction and close-packed HA/Cs crystalline structure. The relationship among the physicochemical, optical and dielectric properties of the HA/Cs composite is studied in this work for potential of instrumentation design.

Dielectric and material analysis on physicochemical activity of porous hydroxyapatite/cornstarch composites.

This paper provides a comprehensive analysis of the dielectric and physicochemical properties of the porous hydroxyapatite/cornstarch (HAp/Cs) composites in a new perspective. The porous composites have been characterized via SEM, FTIR, XRD and dielectric spectroscopy. The dielectric permittivity spectra were obtained in Ku-band (12.4-18.0 GHz) and it was correlated with the physicochemical properties of the porous HAp/Cs. Porous HAp/Cs composites exhibits low ε' and negative ε″, which influenced by the microstructural morphology, interaction between Hap and Cs, as well as crystalline features due to the various proportion of the HAp/Cs. The physicochemical effect of the composites results in the dielectric polarization and energy loss. This phenomenon indicates the presence of the three obvious relaxation responses in the ε' spectrum (13.2-14.0, 15.2-16.0, and 16.6-17.4 GHz) and the negative behaviours in the ε″ spectrum. The relationships between physicochemical and dielectric properties of the porous composite facilitate the development of the non-destructive microwave evaluation test for the porous composite.

Asthma control and asthma treatment adherence in primary care: results from the prospective, multicentre, non-interventional, observational cohort ASCOPE study in Malaysia.

INTRODUCTION: As the first point of contact for those presenting with asthma symptoms, primary healthcare plays a crucial role in asthma management. This is a nationwide study of assessment of asthma symptom control and adherence to asthma medication among outpatients in public health clinics in Malaysia. METHODS: This is a prospective, observational multicentre study (ASCOPE; NCT03804632). Data on asthma control, assessment of control symptoms, and adherence to treatment were collected from medical records and interviews of patients. The level of asthma control was assessed using the Global Initiative for Asthma (GINA) Assessment of Symptom Control. Adherence of patient to medication for asthma was assessed through interview of patients using four questions adapted from the Malaysian Medication Adherence Scale. RESULTS: Among the 1011 patients recruited, 416 (41%) had well controlled asthma, 388 (38%) were partly controlled, and 207 (21%) had uncontrolled asthma. Majority (81%) had mild asthma and all patients were on asthma medication. Most patients did not have spirometry data (97%) but underwent peak flow rate measurements (98%). Poor adherence occurred at all levels of asthma control but was worst among those with uncontrolled asthma. This was statistically significant across all four questions on adherence (p<0.05). For example, more patients with uncontrolled asthma forgot doses (56%) or stopped treatment (39%) than those with well-controlled asthma (44% and 27%respectively). CONCLUSIONS: Among Malaysian primary care patients with asthma, less than 50% had well-controlled asthma, and low adherence to treatment was common. More effort is needed to improve asthma control among patients in Malaysia, including those with mild asthma.

Safety Assessment of Methanol Extract of Melastoma malabathricum L. Leaves following the Subacute and Subchronic Oral Consumptions in Rats and Its Cytotoxic Effect against the HT29 Cancer Cell Line.

Methanol extract of Melastoma malabathricum (MEMM) has been traditionally used by the Malay to treat various ailments. In an attempt to develop the plant as an herbal product, MEMM was subjected to the subacute and subchronic toxicity and cytotoxicity studies. On the one hand, the subacute study was performed on three groups of male and three groups of female rats (n = 6), which were orally administered with 8% Tween 80 (vehicle control group) or MEMM (500 and 1000 mg/kg) daily for 28 days, respectively. On the other hand, the subchronic study was performed on four groups of rats (n = 6), which were orally administered with 8% Tween 80 (vehicle control group) or MEMM (50, 250, and 500 mg/kg) daily for 90 days, respectively. In the in vitro study, the cytotoxic effect of MEMM against the HT29 colon cancer cell line was assessed using the MTT assay. MEMM was also subjected to the UHPLC-ESI-HRMS analysis. The results demonstrated that MEMM administration did not cause any mortality, irregularity of behaviour, modification in body weight, as well as food and water intake following the subacute and subchronic oral treatment. There were no significant differences observed in haematological parameters between treatment and control groups in both studies, respectively. The in vitro study demonstrated that MEMM exerts a cytotoxic effect against the HT29 colon cancer cell line when observed under the inverted and phase-contrast microscope and confirmed by the acridine orange/propidium iodide (AOPI) staining. The UHPLC-ESI-HRMS analysis of MEMM demonstrated the occurrence of several compounds including quercetin, p-coumaric acid, procyanidin A, and epigallocatechin. In conclusion, M. malabathricum leaves are safe for oral consumption either at the subacute or subchronic levels and possess cytotoxic action against the HT29 colon cancer cells possibly due to the synergistic action of several flavonoid-based compounds.

Physician-patient interaction satisfaction and its influence on medication adherence and type-2 diabetic control in a primary care setting.

INTRODUCTION: Medication adherence has been found to be an important determinant in achieving glycaemic control in Type 2 Diabetes (T2DM) patients. In other patient populations, physician-patient interaction satisfaction was found to influence medication adherence. It is then important to identify if this is also a factor amongst T2DM patients on insulin as poor adherence was associated with increased all-cause mortality. METHODS: This was a cross sectional study involving 197 T2DM patients on insulin from two government primary health clinics in Gombak. Physician-patient interaction satisfaction was assessed using Skala Kepuasan Interaksi Perubatan (SKIP-11) consisting of 3 subdomains (Distress Relief, Rapport and Interaction Outcome). Medication adherence level was measured using a single item selfreport question. Data analysis for descriptive, inferential and multivariate analysis statistics were performed. RESULTS: The mean age of the study participants was 57.12 (SD: 9.27). Majority were Malay, female, unemployed with mean BMI of 27.5. Majority reported full adherence (62.9%). High scores in the Interaction Outcome subdomain was associated with better adherence. Factors associated with high scores in this subdomain included patient education level, number of oral hypoglycaemic agent and type of insulin regime taken. This study also found that high scores in the Interaction Outcome domain is associated with lower HbA1c (p<0.05). CONCLUSION: Physician-patient interaction satisfaction is an important factor in achieving better medication adherence which also leads to better glycaemic control in this group of patients. There is a need to identify strategies to improve satisfaction in this domain to improve patient adherence.

Prevalence of menopausal symptoms, its effect to quality of life among Malaysian women and their treatment seeking behaviour.

INTRODUCTION: This study aimed to determine the prevalence of menopausal symptoms, its effect to the quality of life and their treatment seeking behaviour in a multiracial community in Malaysia. METHODS: This is a cross-sectional study involving postmenopausal women in Klang Valley, Malaysia. Data was obtained by face-to-face interview using standardised questionnaires on sociodemographic data, Menopause Rating Scale questionnaire, effect to quality of life and treatment sought. RESULTS: A total of 258 women, including Malays (82%), Indians (14.1%) and Chinese (3.9%) were recruited. The median age was 58 (range 45-86) years old. Joint and muscular discomfort (73.3%) and fatigue (59.3%) were the most prevalent symptoms. Significant association with ethnicity were demonstrated with Malays was found to have 3.1 times higher incidence of sexual problems than Indians, (Odds Ratio (OR) 3.103; 95%CI 1.209, 7.967) and Indian had 2.6 times higher incidence of irritability compared to Malays (OR 2.598; 95%CI 1.126, 5.992). Fifty-two percent of women felt that menopausal symptoms affected their quality of life but there were only 2.7% who were severely affected. There were 24.8% of women who sought treatment and only 20.3% of those who took hormone replacement therapy. There was no significant association found between their treatment seeking behaviour in association with ethnicity, age, parity, marital and occupational status. CONCLUSION: Menopausal symptoms were prevalent among menopausal women, although only a small group of women who were severely affected. There was a lack of tendency in seeking treatment for menopausal symptoms among the women.

Mechanical, thermal and morphological characterisation of 3D porous Pennisetum purpureum/PLA biocomposites scaffold.

The mechanical, thermal, and morphological properties of a 3D porous Pennisetum purpureum (PP)/polylactic acid (PLA) based scaffold were investigated. In this study, a scaffold containing P. purpureum and PLA was produced using the solvent casting and particulate leaching method. P. purpureum fibre, also locally known as Napier grass, is composed of 46% cellulose, 34% hemicellulose, and 20% lignin. PLA composites with various P. purpureum contents (10%, 20%, and 30%) were prepared and subsequently characterised. The morphologies, structures and thermal behaviours of the prepared composite scaffolds were characterised using field-emission scanning electron microscopy (FESEM), Fourier transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA). The morphology was studied using FESEM; the scaffold possessed 70-200µm-sized pores with a high level of interconnectivity. The moisture content and mechanical properties of the developed porous scaffolds were further characterised. The P. purpureum/PLA scaffold had a greater porosity factor (99%) and compression modulus (5.25MPa) than those of the pure PLA scaffold (1.73MPa). From the results, it can be concluded that the properties of the highly porous P. purpureum/PLA scaffold developed in this study can be controlled and optimised. This can be used to facilitate the construction of implantable tissue-engineered cartilage.

Cold plasma inactivation of chronic wound bacteria.

Cold plasma is partly ionized non-thermal plasma generated at atmospheric pressure. It has been recognized as an alternative approach in medicine for sterilization of wounds, promotion of wound healing, topical treatment of skin diseases with microbial involvement and treatment of cancer. Cold plasma used in wound therapy inhibits microbes in chronic wound due to its antiseptic effects, while promoting healing by stimulation of cell proliferation and migration of wound relating skin cells. In this study, two types of plasma systems are employed to generate cold plasma: a parallel plate dielectric barrier discharge and a capillary-guided corona discharge. Parameters such as applied voltage, discharge frequency, treatment time and the flow of the carrier gas influence the cold plasma chemistry and therefore change the composition and concentration of plasma species that react with the target sample. Chronic wound that fails to heal often infected by multidrug resistant organisms makes them recalcitrant to healing. Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (Pseudomonas aeruginosa) are two common bacteria in infected and clinically non-infected wounds. The efficacies of the cold plasma generated by the two designs on the inactivation of three different isolates of MRSA and four isolates of P. aeruginosa are reported here.

Diabetes telemonitoring reduces the risk of hypoglycaemia during Ramadan: a pilot randomized controlled study.

AIM: This pilot study evaluated the short-term benefits of a telemonitoring-supplemented focused diabetic education compared with education alone in participants with Type 2 diabetes who were fasting during Ramadan. METHODS: In this pilot mixed-method study, we identified 37 participants and randomly allocated them to either a telemonitoring group (n = 18) or a group receiving Ramadan-focused pre-education only (usual care; n = 19). The telemonitoring group received goal-setting and personalized feedback. RESULTS: The telemonitoring group was less likely to experience hypoglycaemia than the usual care group (odds ratio: 0.1273; 95% confidence interval: 0.0267-0.6059). No significant differences were noted in glycaemic control at the end of study. Participants viewed telemedicine as a more convenient alternative although technological barriers remain a concern. CONCLUSIONS: The results of this study reinforce the need for monitoring as well as educational initiatives for Muslims with diabetes who fast during Ramadan. Telemonitoring offers an attractive option requiring further research. (Clinical Trial Registry No. NCT02189135).

Natural radioactivity and effective dose due to the bottom sea and estuaries marine animals in the coastal waters around Peninsular Malaysia.

Malaysia is among the countries with the highest fish consumption in the world and relies on seafood as a main source of animal protein. Thus, the radioactivity in the mostly consumed marine animals such as fishes, crustaceans and molluscs collected from the coastal waters around Peninsular Malaysia has been determined to monitor the level of human exposure by natural radiation via seafood consumption. The mean activity concentrations of naturally occurring radionuclides (226)Ra ((238)U), (228)Ra ((232)Th) and (40)K ranged from 0.67 ± 0.19 Bq kg(-1) (Perna viridis) to 1.20 ± 0.70 Bq kg(-1) (Rastrelliger), from 0.19 ± 0.17 Bq kg(-1) (Teuthida) to 0.82 ± 0.67 Bq kg(-1) (Caridea) and from 34 ± 13 Bq kg(-1) (Caridea) to 48 ± 24 Bq kg(-1) (Teuthida), respectively. The mean annual committed effective dose due to the individual radionuclides shows an order of (228)Ra > (226)Ra > (40)K in all marine samples. The obtained doses are less than the global internal dose of 290 µSv y(-1) set by the United Nations Scientific Committee on the Effects of Atomic Radiation, discarding any significant radiological risks to the populace of Peninsular Malaysia.

Muntingia calabura: a review of its traditional uses, chemical properties, and pharmacological observations.

CONTEXT: Different parts of Muntingia calabura L. (Elaeocarpaceae), or "kerukup siam" in Malay, have been reported to possess medicinal value, supported by a number of scientific studies. OBJECTIVE: To gather all information related to the ethnomedicinal uses, phytochemical compositions, and pharmacological activities of M. calabura and present them as a comprehensive and systematic review article. MATERIALS AND METHODS: Literature has been retrieved from a number of databases (e.g., Pubmed, Science Direct, Springer Link, etc.). General web searches were also carried out using Google and Yahoo search engines by applying some related search terms (e.g., Muntingia calabura, phytochemical, pharmacological, extract, and traditional uses). The articles related to agriculture, ecology, and synthetic work and those using languages other than English or Malay have been excluded. The bibliographies of papers relating to the review subject were also searched for further relevant references. RESULTS AND DISCUSSION: The literature search conducted using the above-mentioned Internet search engines only lead to the identification of 36 journals published as early as 1987. From the articles reviewed, M. calabura possessed various pharmacological activities (e.g., cytotoxic, antinociceptive, antiulcer, anti-inflammatory), which supported the folklore claims and could be attributed to its phytoconstituents. CONCLUSION: Muntingia calabura possesses remarkable medicinal value, which warrants further and in-depth studies. Therefore, this review paper is presented to help guide researchers to plan their future studies related to this plant in the hope of isolating potential leads for future drug development.

Amelioration of paracetamol-induced hepatotoxicity in rat by the administration of methanol extract of Muntingia calabura L. leaves.

Muntingia calabura L. is a tropical plant species that belongs to the Elaeocarpaceae family. The present study is aimed at determining the hepatoprotective activity of methanol extract of M. calabura leaves (MEMC) using two models of liver injury in rats. Rats were divided into five groups (n=6) and received 10% DMSO (negative control), 50 mg/kg N-acetylcysteine (NAC; positive control), or MEMC (50, 250, and 500 mg/kg) orally once daily for 7 days and on the 8th day were subjected to the hepatotoxic induction using paracetamol (PCM). The blood and liver tissues were collected and subjected to biochemical and microscopical analysis. The extract was also subjected to antioxidant study using the 2,2-diphenyl-1-picrylhydrazyl-(DPPH) and superoxide anion-radical scavenging assays. At the same time, oxygen radical antioxidant capacity (ORAC) and total phenolic content were also determined. From the histological observation, lymphocyte infiltration and marked necrosis were observed in PCM-treated groups (negative control), whereas maintenance of hepatic structure was observed in group pretreated with N-acetylcysteine and MEMC. Hepatotoxic rats pretreated with NAC or MEMC exhibited significant decrease (P<0.05) in ALT and AST enzymes level. Moreover, the extract also exhibited good antioxidant activity. In conclusion, MEMC exerts potential hepatoprotective activity that could be partly attributed to its antioxidant activity and, thus warrants further investigations.

Natural product of wild Zingiberaceae Elettariopsis slahmong: biopesticide to control the vector of banana blood disease bacterium in West Sumatera, Indonesia.

Banana is one of the most important food crops in Indonesia. Its production is greater than any other agricultural commodity. With the population of 230 million in 2010, banana was consumed up to three million tons in this country. However, Banana Blood Disease Bacterium (BDB), one of the most devastating banana pathogens in the world, which is only found in Indonesia, threatens not only the growth of this plant but also the lives and the livelihoods for most of the Indonesian society. BDB is caused by a lethal bacteria, Ralstonia solanacearum Phylotype-4, which infects a wide range of bananas, from bananas used for consumption to wild bananas. In West Sumatera, the disease killed 1.40% of bananas in 1998, and then increased dramatically to 37.9% in 2003. The total banana production dropped to 62% in this province. The search for controlling the vector has led to the pre-investigation of Wild Zingiberaceae Elettariopsis slahmong C.K. Lim which has a stink bug odour similar to a methidathion insecticide. The plant was collected around the conservation area of Lembah Anal in West Sumatra. The goal of this study was to investigate the effectiveness of natural insecticides compound contained in E. slahmong against D. melanogaster. This study tested the effect of E. slahmong on the mortality, anti-feedant and repellent levels against Drosophila melanogaster, the vector of BDB. The essential oil of E. slahmong was obtained by steam distillation of fresh rhizomes, pseudo stems and leaves. We found that the extract of E. slahmong significantly affected the mortality of D. melanogaster of 30-40% and also acted as an antifeedant (with success rate of 73-93%) and repellent (with success rate of 99-99.6%). The long- term objective of this study is to develop green biopesticide to control BDB in Indonesia, based on an environmentally friendly pest management.

Relationship between circulating levels of IFN-gamma, IL-10, CXCL9 and CCL2 in pulmonary and extrapulmonary tuberculosis is dependent on disease severity.

Protection against Mycobacterium tuberculosis infection is dependent on T cell and macrophage activation regulated by cytokines. Cytokines and chemokines produced at disease sites may be released into circulation. Data available on circulating cytokines in tuberculosis (TB) is mostly on pulmonary TB (PTB) with limited information on extrapulmonary disease (EPul-TB). We measured interferon-gamma (IFN-gamma), interkeukin-10 (IL-10), CXCL9 and CCL2 in sera of patients (n = 80) including; PTB (n = 42), EPul-TB (n = 38) and BCG vaccinated healthy endemic controls (EC, n = 42). EPul-TB patients comprised those with less severe (LNTB) or severe (SevTB) disease. Serum IFN-gamma, IL-10 and CXCL9 levels were significantly greater while CCL2 was reduced in TB patients as compared with EC. IFN-gamma was significantly greater in PTB as compared with LNTB (P = 0.002) and SevTB (P = 0.029). CXCL9 was greater in PTB as compared with LNTB (P = 0.009). In contrast, CCL2 levels were reduced in PTB as compared with LNTB (P = 0.021) and SevTB (P = 0.024). A Spearman's rank correlation analysis determined a positive association between IFN-gamma and IL-10 (rho = 0.473, P = 0.002) and IFN-gamma and CXCL9 (rho = 0.403, P = 0.008) in the PTB group. However, in SevTB, only IFN-gamma and CXCL9 were positively associated (rho = 0.529, P = 0.016). Systemic levels of cytokines are reflective of local responses at disease sites. Therefore, our data suggests that in PTB increased IFN-gamma and CXCL9 balanced by IL-10 may result in a more effective cell mediated response in the host. However, elevated inflammatory chemokines CXCL9 and CCL2 in severe EPul-TB without concomitant down modulatory cytokines may exacerbate disease related pathology and hamper restriction of M. tuberculosis infection.