Mapping Crohn's Disease Pathogenesis with Mycobacterium paratuberculosis: A Hijacking by a Stealth Pathogen.

Mycobacterium avium ssp. paratuberculosis (MAP) has been implicated in the development of Crohn's disease (CD) for over a century. Similarities have been noted between the (histo)pathological presentation of MAP in ruminants, termed Johne's disease (JD), and appearances in humans with CD. Analyses of disease presentation and pathology suggest a multi-step process occurs that consists of MAP infection, dysbiosis of the gut microbiome, and dietary influences. Each step has a role in the disease development and requires a better understanding to implementing combination therapies, such as antibiotics, vaccination, faecal microbiota transplants (FMT) and dietary plans. To optimise responses, each must be tailored directly to the activity of MAP, otherwise therapies are open to interpretation without microbiological evidence that the organism is present and has been influenced. Microscopy and histopathology enables studies of the mycobacterium in situ and how the associated disease processes manifest in the patient e.g., granulomas, fissuring, etc. The challenge for researchers has been to prove the relationship between MAP and CD with available laboratory tests and methodologies, such as polymerase chain reaction (PCR), MAP-associated DNA sequences and bacteriological culture investigations. These have, so far, been inconclusive in revealing the relationship of MAP in patients with CD. Improved and accurate methods of detection will add to evidence for an infectious aetiology of CD. Specifically, if the bacterial pathogen can be isolated, identified and cultivated, then causal relationships to disease can be confirmed, especially if it is present in human gut tissue. This review discusses how MAP may cause the inflammation seen in CD by relating its known pathogenesis in cattle, and from examples of other mycobacterial infections in humans, and how this would impact upon the difficulties with diagnostic tests for the organism.

Effect of Real-Time Environment on Mechanical Properties of Preformed Stainless Steel Archwires: An In Vivo Study.

Introduction: Clinicians should be aware of any effect the oral environment may have on archwires. Laboratory models fail to closely imitate intraoral conditions. The aim was to evaluate the change in mechanical properties of preformed stainless steel archwires after 15 weeks of exposure to the oral environment. Methods: Three commercially manufactured 0.019 × 0.025″ stainless steel archwires were evaluated. Young's modulus, yield strength, spring factor, and hardness were studied. The unexposed distal end cuts (control samples) and archwires were tested after 15 weeks of intraoral exposure (test samples). Tension tests, Vickers microhardness tests, and nanoindentation tests were carried out. Results: Normality was tested using the Shapiro-Wilk test. Statistical analyses included the paired t-test for intragroup comparisons and Kruskal-Wallis ANOVA with the post hoc Dunn test for comparison of mean percentage reduction in values. At T15, Young's modulus showed a statistically significant decrease. Changes in yield strength and spring factor were not significant for groups other than American Orthodontics wires. The reduction in hardness was significant in 3M Unitek. Vickers, tension, and nanoindentation tests demonstrated an expansive range between hardness and Young's modulus so determined. Conclusion: 3M Unitek archwires showed the highest difference in Young's modulus. Yield strength values increased in Ortho Organizers archwires. Spring factor decreased only in 3M Unitek archwires. Hardness values obtained from various tests did not produce identical results.

Computed tomography evaluation of variations in positions and measurements of appendix in patients with non-appendicular symptoms: time to revise the diagnostic criteria for appendicitis.

Purpose: To estimate the frequency distribution of different anatomical positions, and to measure the diameter, wall thickness, and length of appendix in patients with non-appendicular symptoms. Material and methods: This retrospective observational study was conducted among 1,575 patients, who had undergone computed tomography (CT) scan of abdomen for various non-appendicular signs and symptoms. Frequency of distribution of different anatomic locations and measurements of various morphologic parameters were recorded. Results: The most common location of appendix was retrocecal, followed by sub-cecal, post-ileal, and pelvic locations. The mean length of appendix was 66.7 mm (range, 6.3-123 mm), and the diameter was 6.3 mm (range, 2.8-11.3 mm). Diameter of > 6 mm was noted in 48.12% patients. The mean wall thickness was 2.37 mm, ranging 1.2-4.2 mm. The most common intra-luminal content was air-mixed with hypodense or hyperdense material observed in 70.5% of cases. Conclusions: Although an appendix with diameter less than 6 mm may be considered normal, a diameter above 6 mm has an overlap between a normal and inflamed appendix. Therefore, it should be considered in association with clinical and secondary findings to avoid overdiagnosis and unnecessary appendicectomies. We strongly recommend that diameter-based CT criteria to diagnose appendicitis should be revised and standardized.

Persistent left superior vena cava-An alternative feasible technique during Senning procedure.

Although rarely performed today in most centers, Senning procedure continues to be a good option for patients with transposition of great arteries presenting late with either regressed left ventricle or pulmonary hypertension. There are many subsets of patients including those having deficient atrial septal tissue, situs inversus, dextrocardia, and atrial isomerism which require complex modifications of technique. One such subset is patients having bilateral superior vena cavae (SVC), which requires coronary sinus cutback and creating a wide flap for the posterior venous baffle which unduly increases the complexity of the surgery. We describe an alternative way of rerouting a persistent left SVC by reimplanting onto the left atrial appendage which forms the part of the systemic atrium after the atrial switch surgery.

Usability and accessibility-based quality evaluation of Indian airline websites: An MCDM approach.

A tourist may be one of the most diverse kinds of consumer, including many people with disabilities. As a technologically driven industry, the tourism industry focused more on providing online services during the COVID-19 pandemic, where physical activity is limited and people practice social distancing. A company's success may be large extend depend on the quality of the website through which they supply their services. The primary goal of the study presented in this paper is to evaluate the overall quality of Indian commercial airline websites. This study evaluated the seven websites of passenger airlines on usability and accessibility parameters using an online diagnostic tool. Page size, load time, response time, broken links, contrast errors were used as the usability parameters, and the TAW tool was used to evaluate the websites' compliance with WCAG 2.0. The paper proposes a system for determining the best website by utilizing the Technique for Order of Preference by Similarity to Ideal Solution (TOPSIS), The Analytic Hierarchy Process (AHP), and the Fuzzy AHP methods. The result shows that Indian airline websites have many usability issues, and none of the websites adheres to WCAG 2.0 accessibility guidelines. Friedman's test is applied to compare the ranking given by various MCDM techniques, resulting in no significant difference in the various ranking methods adopted.

Impact of COVID-19 on cancer care in India: a cohort study.

BACKGROUND: The COVID-19 pandemic has disrupted health-care systems, leading to concerns about its subsequent impact on non-COVID disease conditions. The diagnosis and management of cancer is time sensitive and is likely to be substantially affected by these disruptions. We aimed to assess the impact of the COVID-19 pandemic on cancer care in India. METHODS: We did an ambidirectional cohort study at 41 cancer centres across India that were members of the National Cancer Grid of India to compare provision of oncology services between March 1 and May 31, 2020, with the same time period in 2019. We collected data on new patient registrations, number of patients visiting outpatient clinics, hospital admissions, day care admissions for chemotherapy, minor and major surgeries, patients accessing radiotherapy, diagnostic tests done (pathology reports, CT scans, MRI scans), and palliative care referrals. We also obtained estimates from participating centres on cancer screening, research, and educational activities (teaching of postgraduate students and trainees). We calculated proportional reductions in the provision of oncology services in 2020, compared with 2019. FINDINGS: Between March 1 and May 31, 2020, the number of new patients registered decreased from 112 270 to 51 760 (54% reduction), patients who had follow-up visits decreased from 634 745 to 340 984 (46% reduction), hospital admissions decreased from 88 801 to 56 885 (36% reduction), outpatient chemotherapy decreased from 173634 to 109 107 (37% reduction), the number of major surgeries decreased from 17 120 to 8677 (49% reduction), minor surgeries from 18 004 to 8630 (52% reduction), patients accessing radiotherapy from 51 142 to 39 365 (23% reduction), pathological diagnostic tests from 398 373 to 246 616 (38% reduction), number of radiological diagnostic tests from 93 449 to 53 560 (43% reduction), and palliative care referrals from 19 474 to 13 890 (29% reduction). These reductions were even more marked between April and May, 2020. Cancer screening was stopped completely or was functioning at less than 25% of usual capacity at more than 70% of centres during these months. Reductions in the provision of oncology services were higher for centres in tier 1 cities (larger cities) than tier 2 and 3 cities (smaller cities). INTERPRETATION: The COVID-19 pandemic has had considerable impact on the delivery of oncology services in India. The long-term impact of cessation of cancer screening and delayed hospital visits on cancer stage migration and outcomes are likely to be substantial. FUNDING: None. TRANSLATION: For the Hindi translation of the abstract see Supplementary Materials section.

Putting Crohn's on the MAP: Five Common Questions on the Contribution of Mycobacterium avium subspecies paratuberculosis to the Pathophysiology of Crohn's Disease.

For decades, Mycobacterium avium subspecies paratuberculosis (MAP) has been linked to the pathogenesis of Crohn's disease. Despite many investigations and research efforts, there remains no clear unifying explanation of its pathogenicity to humans. Proponents argue Crohn's disease shares many identical features with a granulomatous infection in ruminants termed Johne's disease and similarities with ileo-cecal tuberculosis. Both are caused by species within the Mycobacterium genus. Sceptics assert that since MAP is found in individuals diagnosed with Crohn's disease as well as in healthy population controls, any association with CD is coincidental. This view is supported by the uncertain response of patients to antimicrobial therapy. This report aims to address the controversial aspects of this proposition with information and knowledge gathered from several disciplines, including microbiology and veterinary medicine. The authors hope that this discussion will stimulate further research aimed at confirming or refuting the contribution of MAP to the pathogenesis of Crohn's disease and ultimately lead to advanced targeted clinical therapies.

Functional regions of the peroxin Pex19 necessary for peroxisome biogenesis.

The peroxins Pex19 and Pex3 play an indispensable role in peroxisomal membrane protein (PMP) biogenesis, peroxisome division, and inheritance. Pex19 plays multiple roles in these processes, but how these functions relate to the structural organization of the Pex19 domains is unresolved. To this end, using deletion mutants, we mapped the Pex19 regions required for peroxisome biogenesis in the yeast Pichia pastoris Surprisingly, import-competent peroxisomes still formed when Pex19 domains previously believed to be required for biogenesis were deleted, although the peroxisome size was larger than that in wild-type cells. Moreover, these mutants exhibited a delay of 14-24 h in peroxisome biogenesis. The shortest functional N-terminal (NTCs) and C-terminal constructs (CTCs) were Pex19 (aa 1-150) and Pex19 (aa 89-300), respectively. Deletions of the N-terminal Pex3-binding site disrupted the direct interactions of Pex19 with Pex3, but preserved interactions with a membrane peroxisomal targeting signal (mPTS)-containing PMP, Pex10. In contrast, deletion of the C-terminal mPTS-binding domain of Pex19 disrupted its interaction with Pex10 while leaving the Pex19-Pex3 interactions intact. However, Pex11 and Pex25 retained their interactions with both N- and C-terminal deletion mutants. NTC-CTC co-expression improved growth and reversed the larger-than-normal peroxisome size observed with the single deletions. Pex25 was critical for peroxisome formation with the CTC variants, and its overexpression enhanced their interactions with Pex3 and aided the growth of both NTC and CTC Pex19 variants. In conclusion, physical segregation of the Pex3- and PMP-binding domains of Pex19 has provided novel insights into the modular architecture of Pex19. We define the minimum region of Pex19 required for peroxisome biogenesis and a unique role for Pex25 in this process.

Unusual association between corrected transposition of great arteries and supracardiac total anomalous pulmonary venous connection: a rare combination never reported before.

We describe the case of a 52-day-old child who was diagnosed with a rare combination of corrected transposition of great vessels - hypoplastic right ventricle with supracardiac total anomalous pulmonary venous connection.

De novo peroxisome biogenesis: Evolving concepts and conundrums.

Peroxisomes proliferate by growth and division of pre-existing peroxisomes or could arise de novo. Though the de novo pathway of peroxisome biogenesis is a more recent discovery, several studies have highlighted key mechanistic details of the pathway. The endoplasmic reticulum (ER) is the primary source of lipids and proteins for the newly-formed peroxisomes. More recently, an intricate sorting process functioning at the ER has been proposed, that segregates specific PMPs first to peroxisome-specific ER domains (pER) and then assembles PMPs selectively into distinct pre-peroxisomal vesicles (ppVs) that later fuse to form import-competent peroxisomes. In addition, plausible roles of the three key peroxins Pex3, Pex16 and Pex19, which are also central to the growth and division pathway, have been suggested in the de novo process. In this review, we discuss key developments and highlight the unexplored avenues in de novo peroxisome biogenesis.

Cell-free sorting of peroxisomal membrane proteins from the endoplasmic reticulum.

Several yeast and mammalian peroxisomal membrane proteins (PMPs) are delivered to peroxisomes via the endoplasmic reticulum (ER). Fluorescence microscopy showed a focused assembly of PMPs in a specialized domain of the ER, referred to as the preperoxisomal ER. It is proposed that preperoxisomal vesicles containing PMPs bud from this domain to either fuse with preexisting peroxisomes or to mature into functional peroxisomes by uptake of peroxisomal membrane and matrix proteins. However, such vesicular entities are not identified nor are the biochemical requirements for the budding process known. We developed an in vitro cell-free ER-budding assay using Pichia pastoris and followed two endogenous PMPs, Pex11p and Pex3p during their ER exit. Both the PMPs were copackaged in the ER-budded vesicles that float on a Nycodenz gradient. PMP budding from the ER was dependent on ATP, temperature, cytosol, and Pex19p and generated preperoxisomal vesicles with an incomplete complement of PMPs. Surprisingly, Pex11p budding was independent of Pex3p; however, the budded vesicles were devoid of most of the PMPs otherwise present in the wild-type vesicles and might represent peroxisomal remnants. Our findings provide a biochemical platform to uncover the mechanism of PMP budding from the ER.

Scanning electron microscopic analysis to compare the cleaning efficiency of three different irrigation systems at different root canal levels: an in vitro study.

AIM: This study compared the efficacy of conventional, endovac and ultrasonic irrigation system for the removal of debris from root canal walls, using scanning electron microscopy (SEM) at cervical, middle and apical 3rd. MATERIALS AND METHODS: A total of 30 freshly extracted human mandibular premolars with complete root formation were selected and divided into group 1 endovac, group 2 conventional and group 3 ultrasonic. After instrumentation and irrigation, the teeth were sectioned in buccolingual direction and analyzed by SEM and the results were analyzed statistically by students unpaired 't' test. RESULTS: There was significant difference between mean values of cervical (CV), middle (M), and apical (A) when endovac compared with conventional and conventional compared with ultrasonic group (i.e. < 0.05) and no significant difference between mean values at CV, M and A when endovac compared with ultrasonic group. CONCLUSION: Among all groups ultrasonic and endovac group showed cleaner canal walls and less amount of debris than conventional group. CLINICAL SIGNIFICANCE: Application of ultrasonic and endovac can be used effectively for irrigation of canals leading to least debris and better prognosis.

Mycobacterium avium ssp. paratuberculosis and Crohn's Disease-Diagnostic Microbiological Investigations Can Inform New Therapeutic Approaches.

Mycobacterium avium ssp. paratuberculosis (MAP) is the cause of Johne's disease (JD), which is a chronic infectious gastrointestinal disease of ruminants and is often fatal. In humans, MAP has been associated with Crohn's disease (CD) for over a century, without conclusive evidence of pathogenicity. Numerous researchers have contributed to the subject, but there is still a need for evidence of the causation of CD by MAP. An infectious aetiology in CD that is attributable to MAP can only be proven by bacteriological investigations. There is an urgency in resolving this question due to the rising global incidence rates of CD. Recent papers have indicated the "therapeutic ceiling" may be close in the development of new biologics. Clinical trial outcomes have demonstrated mild or inconsistent improvements in therapeutic interventions over the last decades when compared with placebo. The necessity to revisit therapeutic options for CD is becoming more urgent and a renewed focus on causation is essential for progress in identifying new treatment options. This manuscript discusses newer interventions, such as vaccination, FMT, dietary remediation and gut microbiome regulation, that will become more relevant as existing therapeutic options expire. Revisiting the MAP theory as a potential infectious cause of CD, rather than the prevailing concept of an "aberrant immune response" will require expanding the current therapeutic programme to include potential new alternatives, and combinations of existing treatments. To advance research on MAP in humans, it is essential for microbiologists and medical scientists to microscopically detect CWDM and to biologically amplify the growth by directed culture.

Fecal microbiota transplantation: indications, methods, evidence, and future directions.

Fecal microbiota transplantation (FMT) has attracted great interest in recent years, largely due to the global Clostridium difficile infection (CDI) epidemic and major advances in metagenomic sequencing of the gastrointestinal (GI) microbiota, with growing understanding of its structure and function. FMT is now recommended as the most effective therapy for relapsing CDI and, with further refinement, may even be used in "first-time" CDI. There is interest also in other conditions related to GI dysbiosis--for example, inflammatory bowel disease, irritable bowel syndrome, obesity, and diabetes mellitus--although quality evidence is at present lacking. A few trials are now underway in FMT for ulcerative colitis. Many unanswered questions remain, including FMT methodology--for example, optimal route of administration, what makes a "good donor," safety issues, and long-term effects of FMT.

Ethics and Morality.

Introduction: Ethics and morality are a branch of philosophy dealing with moral principles. Morals conceptualise the tenets of human character or behaviour as good or bad, right or wrong. However, morals are an individual and subjective concept which vary across individuals, cultures and time. Intentions, decisions and actions which may be considered moral by one individual or society may be considered amoral by another. The need for an organised system of guidelines, which can be universally applicable to all members of a society and against which all moral or immoral actions can be judged is the driving factor behind foundation of ethics. History of Ethics: A study of ancient Mesopotamian, Greek and Indian cultures over the millennia give a unique insight into ethics as a structural foundation of civilised society. The historical aspect of ethics and ethical systems helps guide present and future generations towards a harmonious and secure society across regional, organizational and global stages. Study of Ethics: A study of moral philosophy endeavours to classify ethical systems based on various schools of thought which act as the guiding principle on which an ethical system is structured. The major branches of ethical philosophy include descriptive ethics which studies the prevalent ethical and moral standards, normative ethics which evaluates the prevalent moral norms and their interpretation and application, meta-ethics which reevaluates the prevalent ethical systems and applied ethics dealing with ethical considerations specific to a particular field. Importance in Life and Clinical Orthopaedics: In this chapter, the authors have attempted to outline the importance of a structured ethical system in various walks of life, including personal, professional and social. A sound ethical system clearly outlines moral versus amoral behaviour, provides an objective means for judging the morality of decisions and actions, provides aids to teaching moral behaviour to new members of a society, defines behaviour of individuals professionally and personally, guides individuals in making decisions over issues of moral conflict or ambiguity and helps maintain structure and order in society so as to achieve the greatest good for the greatest number. The authors also discuss the essential role played by ethics in the life and practice of the modern-day Clinical Orthopaedician.

Electrospun Nanofiber-Based Drug Carrier to Manage Inflammation.

Significance: Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most widely prescribed drugs to treat inflammation and related ailments. In recent years, loading these drugs onto nanodevices like nanoparticles, nanofibers, etc. as a drug delivery system has gained momentum due to its desirable properties and advantages. The purpose of this review is to examine the existing research on the potential and novel use of nanofiber-assisted delivery of NSAIDs. Recent Advances: Electrospun nanofibers have recently garnered considerable attention from researchers in a variety of sectors. They have proved to be promising vehicles for drug delivery systems because of their exceptional and favorable features like prolonged drug release, controllable porosity, and high surface area. In this article, various polymers and even combinations of polymers loaded with single or multiple drugs were analyzed to achieve the desired drug release rates (burst, sustained, and biphasic) from the electrospun nanofibers. Critical Issues: The administration of these medications can induce major adverse effects, causing patients discomfort. Thus, encapsulating these drugs within electrospun nanofibers helps to reduce the severity of side effects while also providing additional benefits such as targeted and controlled drug release, reduced toxicity, and long-lasting effects of the drug with lower amounts of administration. Future Directions: This review covers previous research on the delivery of NSAIDs using electrospun nanofibers as the matrix. Also, this study intends to aid in the development of enhanced drug delivery systems for the treatment of inflammation and related issues.

Osteoporosis and Vertebral Column.

Background: Osteoporosis is an age-related metabolic disease which has a significant impact on bone health and overall quality of life. It is gaining importance as a major medical consideration with the rapid increase in geriatric population globally. It increases the risk of vertebral fractures, progressive spinal deformities and neurological complications, contributing significantly to morbidity and mortality. Increase in life expectancy and advancement of medical technology has led to an increase in the proportion of geriatric patients undergoing orthopaedic procedures. It is becoming vital to adequately evaluate, investigate and treat osteoporosis before planning spinal surgery, especially spinal fusions and instrumentation. Content: Historically, osteoporosis was considered a contraindication to spine surgery adding to the burden of Disability Adjusted Life Years (DALYs) and mortality. Conversely, osteoporotic patients who underwent spine surgery were not adequately optimized, leading to an increase in failure and complication rates. Better understanding of the pathophysiology of osteoporosis and the biomechanics of an osteoporotic spine with knowledge of current standards of treatment of osteoporosis facilitate the timely and adequate management of this disease. Advances in surgical and anaesthetic techniques facilitate successful surgeries on high-risk elderly and osteoporotic patients with multiple comorbidities allowing for a significantly high predictability for long-term positive outcomes.This article discusses the biomechanics of the osteoporotic spine, the diagnosis and management of osteoporotic patients with spinal disease, and the new treatments, recommendations, surgical indications, strategies and advances in instrumentation in patients with osteoporosis who require spinal surgery. Implications: In this article, the authors aim to provide a generalized overview for better understanding of the pathophysiological processes underlying osteoporosis in the vertebral column. This review provides a comprehensive set of guidelines for overall health and management of spine patients with pathologies, either caused by or compounded with osteoporosis. An overview of current techniques, strategies and technologies designed to address the challenges associated with spine surgery in osteoporotic patients is also outlined. Sources: Content for this article has been sourced from routinely cited articles available via PubMed, from National Institute of Health consensus development conference, from the recommendations by World Health Organization technical report series, from previous articles by the authors and from the protocols established by the authors in their clinical practice based on experience and detailed case reviews.

How Not To Fix a Tibial Fracture: A Case Report on Treatment By a Quack.

Quackery in the orthopaedic profession has existed for quite a long time. Due to the shortage of orthopaedic healthcare staff in public hospitals and the high costs in private facilities, members of disadvantaged communities turn to unlicensed and unskilled practitioners (quacks). The main factors responsible for the increased number of quacks performing orthopaedic treatment are illiteracy, high treatment cost, mismatch in the orthopaedic surgeon-to-population ratio, especially in rural areas, and the absence of any form of health insurance. Moreover, their easy availability and offer of low-cost treatment draw innocent and illiterate patients to them, even though these quacks perform orthopaedic treatment in the most unhygienic, unsterilized, and unconventional manner. The government should intervene and take measures to make orthopaedic treatment more affordable and accessible, especially to the rural population.