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Resistance to platinum-based chemotherapy is a major clinical challenge in ovarian cancer, contributing to the high mortality-to-incidence ratio. Management of the platinum-resistant disease has been difficult due to diverse underlying molecular mechanisms. Over the past several years, research has revealed several novel molecular targets that are being explored as biomarkers for treatment planning and monitoring of response. The therapeutic landscape of ovarian cancer is also rapidly evolving, and alternative therapies are becoming available for the recurrent platinum-resistant disease. This review provides a snapshot of platinum resistance mechanisms and discusses liquid-based biomarkers and their potential utility in effective management of platinum-resistant ovarian cancer.

Purpose The purpose of this paper is to discover the main reasons for change, why change is necessary and how library professionals can adapt to change. Academic institutions are rapidly changing around the world where libraries are facing similar challenges and adapting change is a demand for growth and improvement. Library administrators need a clear vision and strategic plan to meet the upcoming challenges, they must have self-confidence, ability to work with diversity. Library professionals need to show flexibility and a willingness to develop new skills, they also need to adopt new ways of working and dealing with the academic community. Design/methodology/approach The literature review is built on resources from offline and online full-text databases such as ProQuest, EBSCO, Emerald, Library Literature and Information Science databases. This paper is based on a systematic literature review method which includes 50 research articles and 5 print books. A total of 109 articles were collected at the beginning stage but after their analysis in detail, they were reduced to 50 articles as the rest of the articles did not exactly focus on adapting to change in academic libraries. Basic keyword and advanced searching options have been used to retrieve the relevant literature on the topic from peer-reviewed and scholarly resources. Findings Changes are the result of organizational restructuring, user expectations and accessibility to a growing range of digital content, so library professionals are under pressure to adopt change in academic libraries and introduce new services and technology. Library professionals need to change traditional ways of working and boost their knowledge and skills, collaborative attitude, redesign and policies and procedures and create a willingness to adapt to the change. Challenges can be managed if an individual has a keen interest and eagerness to keep up to date with the current knowledge and emerging trends in academic libraries. Research limitations/implications Appropriate literature on the topic was reviewed systematically, not all publications were included. Literature on this topic is relatively limited so more research and publications are needed to deal with current and future scenarios of academic libraries. Practical implications This paper offers a useful overview of the ways and approaches used to adopting change by library professionals and the approaches that can be used in the current and future settings of academic libraries. Suggestions and recommendations can be used in the field of LIS, as well as library professionals may apply in the academic and research libraries to effectively change. Originality/value This paper focuses on the concept of adapting to change in academic libraries, rather than responding to change. This piece of opinion contributes to library science in the area of how to manage and implement change, suggests ways and frameworks which can be used to adopting change by library professionals.

Late diagnosis, unreliable prognostic assessment, and poorly-guided therapeutic planning result in dismal survival of ovarian cancer (OC) patients. Therefore, identifying novel functional biomarker(s) is highly desired for improved clinical management. MYB is an oncogenic transcription factor with emerging functional significance in OC. Here we examined its clinicopathologic significance by immunohistochemistry and TCGA/GTex data analyses. Aberrant MYB expression was detected in 94% of OC cases (n = 373), but not in the normal ovarian tissues (n = 23). MYB was overexpressed in all major epithelial OC histological subtypes exhibiting the highest incidence (~ 97%) and overall expression in serous and mucinous carcinomas. MYB expression correlated positively with tumor grades and stages. Moreover, MYB exhibited race-specific prognostic association. Moderate-to-high MYB levels were significantly associated with both poor overall- (p = 0.02) and progression-free (p = 0.02) survival in African American (AA), but not in the Caucasian American (CA) patients. Consistent with immunohistochemistry data, we observed significantly higher MYB transcripts in OC cases (n = 426) than normal ovary (n = 88). MYB transcripts were significantly higher in all epithelial OC subtypes, compared to normal, and its greater levels predicted poor survival in AA OC, but not CA OC, patients. Thus, MYB appears to be a useful clinical biomarker for prognostication, especially in AA patients.

Purpose This paper aims to discover the key challenges and identifies reasons for the changing behavior of academic libraries and the role of library professionals, and how can they manage those challenges in a time of change. The paper reveals the most important competencies in a reshaping environment of libraries and the best ways of dealing with change. Library professionals are struggling to reform their traditional ways of working and trying to boost their knowledge and skills as current demand for higher education. Organizations can play an important role to develop willingness for accepting change and reduce stress among employees and prepare them to accept new systems and reality by creating collaborative and supporting environments that provide opportunities for growth and improvement. All library professionals must have the eagerness to keep up with the emerging trends and prepare themselves to accept changes that would have a direct impact on the libraries and the role of library professionals. Academic libraries have similar issues and challenges around the world, those are outcomes of technological advancement, digital resources, innovative services and diversity in higher education; therefore, the role of library professionals is changing. Design/methodology/approach The research method is built on literature reviews from offline and online. The systematic literature review method is used to review full-text databases such as EBSCO, ProQuest, Library Literature and Information Science databases. Basic search options for keyword searching and advanced searching options have been used to retrieve the relevant papers on the right topic. A total of 113 papers were collected at the initial stage, but after their analysis in detail, they were reduced to 52 scholarly and peer-reviewed papers because the rest of the papers did not exactly express relevant content on the topic. Findings Library professionals are struggling to keep up with the new competencies and adopt the innovative system and reality because diversity is rapidly changing. The best ways of dealing with change include reform the traditional ways to new ways of working and create collaboration at all levels. Librarians are under pressure to develop new skills to deal with the current scenarios that are affecting the role of library professionals. Academic libraries have similar challenges in a rapidly reshaping environment that are needed to address by researchers and library professionals for the present and future of academic libraries. Research limitations/implications This paper is a piece of opinion, 52 appropriate papers on the topic have been reviewed from the peer-reviewed journals, not all publications were included. The existing literature described that there is a need for growth and improvement of academic libraries and workforce in financial crises because they play fundamental roles in society by offering services and information resources, so library professionals need to be very aware of these implications. Originality/value The literature on this particular topic is relatively limited. Therefore, this paper is the first to offer a systematic literature review on the changing behavior of academic libraries and the role of library professionals. This paper provides insights into the concept of adopting change and dealing with challenges in a time of change. It adds value to the library and information sciences literature and delivers outlines for the library professionals.

Vegetable cultivation offers a unique opportunity for hill farmers of Uttarakhand due to the favourable climatic conditions. Consequently, vegetable cultivation in Uttarakhand hills, even in off-season, has picked up on quite a large scale. Although it has become quite remunerative but farmers are reportedly facing lots of marketing and production constraints. The present study was conducted in Kumaon region of Uttarakhand to study the production and marketing constraints faced by the vegetable growers. Study sample comprised of 200 farmers selected purposively from eight villages spread across four blocks and two districts in Kumaon division of Uttarakhand. The data was collected using a pre-tested structured interview schedule. The study findings revealed that major marketing constraints reported by vegetable growers were: long chain of intermediaries, inadequate transportation facilities, high transportation charges, inadequate storage facilities, low price / lack of remunerative price and non-availability of market information. Further, some production related constraints reported by the respondents were high cost of seeds/ fertilizers, lack of information about planting material/ production inputs, lack of knowledge about grading and standardization of vegetable, non-availability of farm labour and lack of packaging material. These findings will be helpful to the State government for developing a policy framework and relevant guidelines for promoting vegetable production in the state.

Metastasis-associated in colon cancer-1 (MACC-1) is a newly identified tumor marker, found to express in various normal and cancerous tissue. This study is conducted to evaluate the serum MACC-1 level as a diagnostic marker for breast cancer (BC). Sixty new BC patients were included in this study. Patients who received neoadjuvant chemotherapy or with metastatic disease were excluded. Eighty patients of benign disease were taken as control group. All the patients were females with the mean age of 46.7 ± 10.6 years in study group and 40.2 ± 8.4 years in control group (p = 0.0001). The mean serum MACC-1 level in BC patients was 3.46 ± 1.3 ng/ml which was significantly higher than control mean serum MACC-1 level (1.90 ± 0.2 ng/ml) (p < 0.0001). On ROC analysis, the AUC was 0.98 (p ≤ 0.0001; 95% CI = 0.97-1.0) i.e., a good predictor for breast cancer. At the cut-off value of 2.12 ng/ml, the sensitivity and the specificity of serum MACC-1 were 96.7% and 92.5%, respectively. This study showed that serum MACC-1 can be a potential biomarker for diagnosis and tumor progression in patients with breast cancer.

Objectives: The objective of our study was to find diagnostic accuracy of APACHE-II score to predict mortality in poly trauma patients within first 24 hours of hospitalization. Study Design: Cross Sectional study. Setting: Department of Emergency Lahore General Hospital. Period: 25 March, 2016 to 25 September, 2016. Material & Methods: A total of 230 patients who fulfilled inclusion criteria were enrolled in the study from emergency department of Lahore General Hospital, informed consent was taken from all patients or their attendants to take their demographic profile (name, age, gender and contact no) and other necessary clinical data. To calculate APACHE-II score, vital signs, blood / serum profile, GCS, age and prolong health problems were measured on patients’ arrival. Patients were classified as per their APACHE-II score. After calculating APACHE-II score patients were managed according to trauma severity and followed up till 24 hours to note the in- hospital mortality. All the data was recorded on a Performa. Statistical analysis was carried out using SPSS 20. Results: Out of 230 patients, 147 (63.91%) were male and 83(36.09%) were female; mean age was 38.53 ± 11.67 years. Out of 230 cases, in hospital mortality occurred in 84(36.5%) while other 146(63.5%) were alive within 24 hours of admission. According to APACHE-II score, 84(36.5%) cases had > 11.5 score and rests of 146(63.5%) had APACHE-II ≤ 11.5. The sensitivity, specificity, PPV, NPV and diagnostic accuracy of APACHE-II was 89.16%, 93.2%, 88.1%, 93.84% and 91.74% respectively. Conclusion: According to the findings of this study, we found APACHE-II highly accurate for indicating in-hospital mortality. Using APACHE-II in future we can devise an efficient treatment plan for poly trauma patients to reduce the probability of hospital mortality.

Objectives: To determine the management of open diaphyseal fracture of tibia with plaster of Paris (pop) cast vs external fixator in orthopedic ward PUMHSW Hospital Nawabshah. Study Design: Cross-Sectional Comparative study. Setting: Orthopedic Department, Peoples University of Medical And Health Science Shaheed Benazirabad. Period: 18 months from January 2017 to June 2018. Material & Methods: The data was analyzed in SPSS Version 22.0. Results: Out of 50 patients with tibial diaphyseal fractures, there were 34 males compared to females 16 (2.1:1) (68% vs 32%) with an average age of 41 years. Patients with external fixator applied yielded decreased rates of infection; shorter duration of hospital stay and early union compared to patients with plaster of Paris (pop) cast application. However, the difference reached statistical significant value. Conclusion: Open Tibial diaphyseal fractures should be managed with external fixation that yields better results. A plaster cast is the initial treatment of modality in patients with open tibial diaphyseal fractures.

Objectives: To compare the external fixator and unreamed interlocking nail in treating Gustilo type II, type IIIA, and type IIIB tibial diaphyseal fractures regarding complications. Study Design: Cross-Sectional and Comparative Study. Setting: Department of Orthopaedic Surgery and Traumatology (DOST) Liaquat University of Medical and Health Sciences Jamshoro/Hyderabad. Period: Two years February 2016 to January 2018. Material & Methods: 40 cases of open tibia fractures in Patients of Gustilo type II, type IIIA, and type IIIB tibial diaphyseal fractures were included. The data were analyzed using the statistical program SPSS version 16.0. Results: A total of 23 cases were treated by external fixator and 22 cases were treated by unreamed solid interlocking nail. A total of 14 cases, that is, 31% showed delayed union. Type II injury 3/15 = 20%; Type IIIA injury 6/22 = 27.3%; Type IIIB injury it is -5/8 = 12.5%. For cases treated with unreamed nail, it was 22.7%; external fixator was 39.1% among 45 cases, 05 cases showed nonunion. For cases treated with unreamed nail, it was 13.6%; external fixation was 8.7%. The overall rate of eep infection is 11.1%. The rate in interlocking nail was 13.6%, and external fixation was 8.7%. Reoperation in the form of dynamization and bone graft application after 20 weeks in unreamed nail was 36.4%, whereas in external fixation the rate was high, almost 48%. The average time of union with unreamed interlocking was about 25.4 weeks, wherein external fixation it was 28.6 weeks. Conclusion: External fixators are a good and reliable method of stabilization of Gustilo type II, type IIIA, and type IIIB tibial diaphyseal fractures, unreamed interlocking intramedullary nail yields better results in treating Gustilo type II and type IIIA tibial shaft fractures.

Sweating is a physiological phenomenon to eliminate the waste as well as excess matter from the body. Importance of sweating was discussed thousands of years back in Greek Arab system of medicine under the heading of Tareeq or Arq. In this system of medicine, abundant literature is available regarding sweating and its significance. Regime and diaphoretic drugs used to induce therapeutic sweating are described. Actually physis of body works continuously to manage everything. Ancient Greek Arab scholars explained that the sweating occurs for cleansing of blood or to reduce the workload of other excretory organs. They also described the importance of sweating as a regime in different diseases. Literature related to sweating is in scattered manner in classical books. Present paper is an effort to compile the relevant literature.

Purpose A prospective observational study was conducted to assess sterile compounding time and workforce requirements in a hospital pharmacy, resulting in development of staff benchmarking metrics. Methods The study was conducted in the IV room of a quaternary hospital over 2 periods totalling 7 weeks. Compounding was directly observed and timing data collected for each compounded sterile preparation (CSP). The primary objective was to assess CSP workload, compounding time requirements, and workforce requirements to enable development of a data-driven staffing benchmark. Results A total of 320 sterile product preparations were directly observed during the study. Overall, the average time to compound 1 CSP (including small- and large-volume parenteral solutions, chemotherapy CSPs, batched CSPs, and syringes) was 3.25 minutes. Chemotherapy CSPs had the longest average preparation time (17.74 minutes); batched CSPs had the shortest preparation time, at 1.90 minutes per unit. A safe workload analysis indicated that in an 8-hour shift, 1 pharmacy technician can safely prepare 253 batched CSPs; 148 preparations of SVP solutions, LVP solutions, and syringes combined; 31 parenteral nutrition solutions prepared using an automated device; or 29 chemotherapy preparations. Through extrapolation of these results, it was calculated that a hospital with a capacity of 100 beds would require 1.4 pharmacist full-time equivalents (FTEs) and 2.7 technician FTEs to meet its sterile compounding needs, with proportionate increases in those estimates for a 300-bed hospital. Conclusion Organizations wishing to use external benchmarking information need to understand data characterization, pharmacy services offered, automation, workflows, and workload before utilizing that information for workforce planning.

Cholecystectomy is one of the commonest general surgical procedures performed all over India. The risk of bile duct injury (BDI) during laparoscopic cholecystectomy is two to three times higher than during open cholecystectomy. The worldwide incidence of bile duct injury is 0.5% or 1 in 200 cases. BDI and its consequences result in significant morbidity and may even cause mortality. BDI increases the cost of treatment and is a common reason for a medicolegal suit against the surgeons. To minimize the incidence of BDI and to manage it timely and appropriately, a set of guidelines was deemed necessary by a group of senior surgeons during a Society of Endoscopic and Laparoscopic Surgeons of India (SELSI) meeting in 2016. Guidelines for “Safe Laparoscopic Cholecystectomy” and bile duct injury management formulated by other international societies are already available. The applicability of these guidelines to Indian subjects especially in small peripheral centers was limited. Hence, a decision was taken to form a set of guidelines for general surgeons with basic laparoscopic skills with little or no advanced laparoscopic skills. Those working in a solo practice, nursing homes, and small private hospitals at talukas or districts should have “Safe Cholecystectomy” guidelines and management of BDI suitable to their situation. These guidelines were formed after three consensus meetings and have been approved by a SELSI Expert Group.

Information needs to be expressed by farmers have often been understood as extension needs. However, the mandate of extension services is more than just providing information about agri-inputs and its supply chain. The present study was undertaken to determine the extension needs of vegetable growers. The study sample comprised of 160 vegetable growers spread across four villages in two districts of Kumaon region of Uttarakhand. The data was collected through personal interviews using a pre-tested structured interview schedule. The study findings revealed that a large majority of the vegetable growers expressed high extension needs. Certain attributes of farmers such as age, education, farming experience, information-seeking behaviour, media exposure and income were found to have a significant relationship with the extension needs of vegetable growers. The study findings will help policymakers, technology developers, extension scientists and field extension agents learn about the extension needs of the vegetable growers and help in designing and developing appropriate extension strategies according to their extension need and convenience of the farmers so that they could get the maximum benefit out of it.

Negotiating meaning and form has an important role in the development of a language. At the same time, written and audio output may also vary, which can lead to the generation of a variety of discourse functions and materialize in teaching methodologies and academic content used in the language teaching process. Since technology is increasingly becoming an indispensable and integral educational tool across the world, Saudi Arabia being no exception, language teachers are encouraged to integrate new technologies into their teaching methodology and practice to ensure they meet learners’ needs. WhatsApp Messenger, as a messaging and Voice over IP (VoIP) service that allows users to, among others, send text and voice messages and make voice and video calls, is investigated as a real-time language learning in this research. The current paper was conceived out of the researcher’s consistent observation of the positive impact of synchronous audio and written mobile-mediated communication tools, in particular WhatsApp, and the nature of negotiating meaning and form on the development of English as a foreign language for ESL and EFL learners. There has been previous similar research on WhatsApp as an educational tool but, in these studies, the language outcomes have largely been neglected. By analyzing audio and text negotiations and interactions conducted over WhatsApp, and comparing them with equivalent asynchronous computer-based exchanges, this study aims to investigate different types of discourse functions that are used in the negotiation of meaning via synchronous mobile-mediated communication. On a micro level, we compare Synchronous Audio Mobile-Mediated Communication (SAMMC) and Synchronous Written Mobile-Mediated Communication (SWMMC) modes of interaction, when applying discourse functions, to determine which mode offers a greater range of innovative language output. The language output of forty undergraduate EFL learners was studied over a five-week period and it was concluded that SAMMC outperformed SWMMC in terms of the scope of meaning and form.

Purpose The purpose of this study is to explore the key challenges of academic libraries in times of changing nature of higher education system and how library leaders can manage the challenges when effective leadership is highly required for academic libraries today. As the time is changing, the kinds of challenges that library leaders face have also changed. Author of this study explores the methods and approaches, which are more effective ways of managing challenges in the reshaping environment of academic libraries. At the same time, change has become a permanent part of academic libraries and they need leaders who are able to lead and manage change efficiently, bring theories into practices, find innovative solutions to challenges, creative thinkers, effective communicators, collaborative mindset and self-motivators. Design/methodology/approach The selective publications have been reviewed to find the best ways to leading changes and managing challenges in academic libraries. The approaches and methods in this study are based on personal experiences of author as director of the university libraries and experiences of library leadership worldwide are conversed. Findings Academic libraries are facing similar challenges around the world. The author found that academic library leadership needs innovative skills and competencies, effective communication abilities and a new way of thinking to deal with challenges and create willingness to adapt the changes. Kotter’s leadership manage change model may apply for creating and implementing organizational change in academic libraries. Originality/value Literature on this topic is comparatively limited. Consequently, this manuscript adds value to the publications of library and information sciences and offers the literature in the field of leadership challenges and manage change in the academic libraries. It also provides guidelines to academic library leadership universally, and how can leaders work with change effectively.

Plants are very potential & vital source for human health and also used therapeutically in the various kidney disorders due to presence of phytochemical constituents. There are numerous herbs existing that have more pharmacological activities including with nephroprotective activity. Now a days herbal drugs are verified & proved as nephroprotective agents and used for improving renal health, even reverse renal damages. The current review is targeted to explain the Unani & modern concept of kidney disorders, nephrotoxicity and the list of scientifically proved medicinal plants having nephroprotective activity medicinal plants which used in the treatment of renal disorders. Keywords: Nephroprotection, Unani Medicine, Kidney disorders

Two Water Supply Systems (WSSs) have been operating and providing drinking water services to two discrete districts, namely, Second Ayno Maina (AM-WSS), District 10, owned and managed by a private sector: AFCO Corporation, and Central Kandahar (CK-WSS), Share-Naw, District 2, owned and managed by government entity: Department of Kandahar Water Supply and Sewerage, for four and ten years respectively. Both the WSSs use groundwater as source of drinking water, and due to overpopulation and urbanization, they tend to expand their services and improve their performances, despite the fact that the primary step to do so is the performance assessment of the existing systems, lacking at the moment and needs a careful consideration. Therefore, the research study is aimed at assisting the responsible authorities of the performances being carried by their existing systems and satisfaction level of their customers against the services provided, along with their international comparisons, with similar-typed associated water supply schemes. Two sets of primary data were collected, including service-provider-driven and customer-driven, from relevant authorities and districts respectively. More specifically, for consumer-driven data collection, 66 and 75 questionnaires were distributed to the consumers of (AM-WSS) and (CK-WSS) respectively. Both the data set was classified as the input and output performance indicators (PIs), and was analyzed using SPSS, DEAP and Ms. Excel softwares, in compliance with Data Envelopment Analysis (DEA) methodology. The findings showed that (AM-WSS) had a relative technical efficiency, te of 1 (100 %), whereas CK-WSS had a te of 0.545. As a result, CK-WSS was the only System considered and recommended for amendments. Furthermore, the analysis of the findings showed that CK-WSS needed to focus on decreasing the staff size and total expenditure by 45 % to comply with optimization. The team recommends to train their personnel and reduce the number by 45 %, and additionally recommends to collect, keep and register all the necessary data of the schemes in an organized manner for future demands, plans, rehabilitation, performance, and improvements of the corresponding components of their systems.

The year 2020 started with the emergence of novel coronavirus, severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), which causes COVID‐19 infection. Soon after the first evidence was reported in Wuhan, China, the World Health Organization declared global public health emergency and imminent need to understand the pathogenicity of the virus was required in limited time. Once the genome sequence of the virus was delineated, scientists across the world started working on the development of vaccines. Although, some laboratories have been using previously developed vaccine platforms from severe acute respiratory syndrome coronavirus (SARS) and middle east respiratory syndrome‐related coronavirus and apply them in COVID‐19 vaccines due to genetic similarities between coronaviruses. We have conducted a literature review to assess the background and current status of COVID‐19 vaccines. The worldwide implementation and strategies for COVID‐19 vaccine development are summarized from studies reported in years 2015–2020. While discussing the vaccine candidates, we have also explained interpretative immune responses of SARS‐CoV‐2 infection. There are several vaccine candidates at preclinical and clinical stages; however, only 42 vaccines are under clinical trials. Therefore, more industry collaborations and financial supports to COVID‐19 studies are needed for mass‐scale vaccine development. To develop effective vaccine platforms against SARS‐CoV‐2, the genetic resemblance with other coronaviruses are being evaluated which may further promote fast‐track trials on previously developed SARS‐CoV vaccines., Flow diagram to illustrate selection criteria for the systematic review on COVID‐19 vaccines.

Background This study aimed to assess the effectiveness and safety of percutaneous needle aspiration (PNA) and percutaneous catheter drainage (PCD) in the treatment of liver abscess. Methods A prospective randomized study was conducted in the Department of Surgery, JN Medical College, Aligarh Muslim University, Aligarh, UP, India, between February 2018 and August 2019, after getting approval from the institutional ethics committee. A total of 543 patients with liver abscess were randomized into two groups using computer-generated randomization method. Appropriate details regarding patients' clinico-demographic profile and investigations were also collected. The effectiveness of either treatment was measured in terms of duration of intravenous antibiotic, clinical improvement, reduction in the size of cavity, treatment success rate, duration of hospital stay including long-term outcomes such as sonographic resolution of cavity and recurrence rate at 6 months post-treatment. Results The PCD group had statistically significant rate of duration of antibiotics need, days for clinical improvement and time for 50% reduction in abscess cavity and treatment success rate with comparable long-term outcomes. Conclusion PCD is more efficient than PNA and can be used primarily in the treatment of both amoebic and pyogenic liver abscesses along with systemic antibiotics. However, PNA can serve as a safe alternative when PCD is not available.

The development of cancer is not just the growth and proliferation of a single transformed cell, but its surrounding environment also coevolves with it. Indeed, successful cancer progression depends on the ability of the tumor cells to develop a supportive tumor microenvironment consisting of various types of stromal cells. The interactions between the tumor and stromal cells are bidirectional and mediated through a variety of growth factors, cytokines, metabolites, and other biomolecules secreted by these cells. Tumor-stromal crosstalk creates optimal conditions for the tumor growth, metastasis, evasion of immune surveillance, and therapy resistance, and its targeting is being explored for clinical management of cancer. Natural agents from plants and marine life have been at the forefront of traditional medicine. Numerous epidemiological studies have reported the health benefits imparted on the consumption of certain fruits, vegetables, and their derived products. Indeed, a significant majority of anti-cancer drugs in clinical use are either naturally occurring compounds or their derivatives. In this review, we describe fundamental cellular and non-cellular components of the tumor microenvironment and discuss the significance of natural compounds in their targeting. Existing literature provides hope that novel prevention and therapeutic approaches will emerge from ongoing scientific efforts leading to the reduced tumor burden and improve clinical outcomes in cancer patients.

Greco Arab physicians have explained diseases as well as their signs and symptoms. They have documented the importance of urinary Symptomatology in diagnosis of disease and other conditions of body. They have classified the symptoms on the basis of time period, temporary or permanent etc. They discussed the factors affecting the urine presentation related to urinary tract condition. Symptomatology related to urine available in the Greco Arab classical books were being surveyed. After extensive review of literature, it was found that; Unani physicians were very much familiar to diseases of urinary tract and their signs and symptoms. Urine Symptomatology is very important aspect of medical science; every physician must know the presentation of diseases to make good differential diagnosis, right diagnosis and treatment. Peer Review History: Received 31 December 2019; Revised 22 January; Accepted 3 March, Available online 15 March 2020 UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency. Received file Average Peer review marks at initial stage: 4.5/10 Average Peer review marks at publication stage: 7.0/10 Reviewer(s) detail: Name: Dr. Adebayo Gege Grace Iyabo Affiliation: University of Ibadan, Nigeria E-mail: funbimbola@gmail.com Name: Dr. George Zhu Affiliation: Tehran University of Medical Sciences, Tehran, Iran E-mail: sansan4240732@163.com Comments of reviewer(s): Similar Articles: BIOFILM FORMATION AND ANTIBIOTIC SUSCEPTIBILITY OF UROPATHOGENS IN PATIENTS WITH CATHETER ASSOCIATED URINARY TRACT INFECTIONS IN IBB CITY -YEMEN

ICP in Saudi institutions of higher education is a university preparation course based on an academic curriculum aimed to hone the school leavers’ intellectual skills to succeed in the challenge of higher education. Universities all over the world, and especially in the west, offer similar programs, rather they mandate prospective international students whose mother tongue is other than English to opt for such programmes. These are popularly known as ESL (English as Second Language) intensive courses. In the KSA these are limited to the period at the very start of the academic session. However, in the west, students can opt for longer and more frequent programmes with the choice of sitting for these during the vacation periods. In this sense, they are more flexible to suit student needs. The aim is similar as that in KSA: To set the non-English speaking student at a language pedestal where he/she has a fair a chance to pursue higher education as the English-speaking one. Seen from this vantage, this is a bridge course to select incumbents for the English courses offered by the universities. Pilot studies in the KSA on the success of ICP failed to yield conclusive results amidst rising agreement to scrap the programme as tangible learning outcomes were not visible. However, before doing so it would have been worthwhile to find correlations. If any, between attrition rates and course shortcomings. This aim motivated the current study across three campuses in the departments of English at Qassim University Colleges of Sciences and Arts in Methnab, Al-Asyah, and Buraidah. The study collected all enrolment and follow up data for the three departments and interviewed fifteen subjects each from among those who completed the course but decided against pursuing higher education, those who dropped out before course completion, and those who enrolled for higher education after undertaking the ICP. Our greater concern was with those who dropped out during the course as they neither pursued higher education nor benefitted as they would have on completing the programme.

Background: Worldwide, intestinal parasitic infections are major causeof human mortality and morbidity especially among developing countries wherein publichealth standards are not much better like developed countries. Intestinal parasiticinfections are linked with poor sanitation, lack of safe drinking water, inadequate dietaryand cultural habits and climate conditions. Objective: To assess the frequency, riskfactors and clinical manifestations related to intestinal parasite infections in patients withgastrointestinal disorders. Study Design: Cross-sectional multi-centre study. Setting:Department of Medicines, Chandka Medical College Larkana and Civil Hospital, KhairpurMirs. Period: 1st January 2017 to 31st December 2017. Method: 260 patients, the patientswith gastrointestinal disorders presenting one or more symptoms (e.g. diarrhea, dysentery,abdominal pain, nausea and vomiting, cramping and constipation) were included.Results: Frequency of intestinal parasites was 32.3%. The most common parasites wereEntamoeba histolytica (10.4%), Giardia lamblia (8.5%) and Hymenolepis nana (6.9%). Age,education, monthly income and contact with animal were significantly associated withintestinal parasite infections. Concerning symptoms, the presence of intestinal parasitesinfection was significantly associated with diarrhea and dysentery. Conclusion: Studyconcluded that most prevalent parasites were Entamoeba histolytica, Giardia lambliaand Hymenolepis nana. Significant association was found in age, education and monthlyincome.

Introduction: Ischaemic stroke is a heterogeneous multifactorial disorder characterized by acute focal neurological deficit due to cerebrovascular disease. Considering the clinical evidence of dyslipidaemia as a risk factor for ischaemic stroke, there is a need to know the magnitude of dyslipidaemia in patients. Aim of the study was to determine the frequency of dyslipidaemia in patients of ischaemic stroke at a tertiary care teaching hospital in Larkana, Pakistan. Methods: A cross-sectional study was conducted at the Department of Medicine, Shaheed Mohtarma Benazir Bhutto Medical University Hospital Larkana, Pakistan during the period of six months (July-December 2016). All patients between 18-75 years of age of either gender suffering from ischaemic stroke were included. All patients with intracranial haemorrhage, CNS tumour, epilepsy, multiple sclerosis, familial lipid disorders, endocrine disorders, chronic diseases, and on anti-lipid medications, cocaine or alcohol addicts were excluded. The statistical analysis was conducted by using Stata Statistical Software 14. Results: Mean age of enrolled participants was 46.3 (SD=15.2) years. Of 85 enrolled participants, 73 (85.9%) were males and 12 (14.1%) were females, with male to female ratio of 6:1. The frequency of dyslipidaemia was 28 (32.9%), with mean LDL 100.7 (SD=18.4) mg/dl and HDL 42 (SD=11.7) mg/dl and total cholesterol 166.3 (SD=34.3) mg/dl. Conclusions & Recommendations: Dyslipidaemia, with low HDL 13 (15.3%) was found to be the most common risk factor we observed in our patients with stroke. The importance of preventive measures for a disease which has modifiable risk factors (diabetes and hypertension) should be emphasized to reduce the burden of stroke in the country.

Purpose The purpose of this paper is to reflect on major issues and trends of academic libraries and leadership in the changing nature of higher education. Changing environment of academic libraries has impacted significantly on the knowledge, skills requirement and role of the library leaders, and how organizations can maintain and manage the changing nature of academic libraries as well as leadership while effective leadership is extremely required for the library leaders and organizations are concern about future scenarios. The primary objective is to identify the key challenges in libraries, leadership skills and approaches of the leaders, their effective leadership traits and future perceptions are discussed. Design/methodology/approach The aim of this paper is to facilitate as how to develop effective and successful leadership for the academic libraries during the changing nature of higher education. The findings and recommendations in the paper are based on personal experience of leadership positions in an academic library as well as experience of library leaders across the world. Findings Academic libraries are facing similar challenges and issues across the world. This paper identifies that library leaders need to be effective communicators, strategic thinkers, visionary, and able to examine the new ways of working. Originality/value This paper discusses why academic library leaders need a set of new skills and how can they develop leadership skills and competencies in the changing nature of academic libraries.

The high optical gain of InGaAs/GaAsSb/InAlAs nano-scale heterostructure has motivated us for its further study under variable temperature and electric field. The presented work is devoted to show the impact of variable temperature and electric field on optical gain characteristics of InGaAs/GaAsSb/InAlAs nano-scale heterostructure which has been assumed to grow on lattice matched GaAs substrate. A six band k.p approach has been utilized to optimize the heterostructure in terms of carrier's wavefunctions, local carriers' density in conduction and valence band and dispersion curves followed by calculating momentum matrix elements and the optical gain spectra. According to the calculation results, the increasing range of temperature (having range of 100–300 K at the interval of 50 K) can control the peak gain significantly (6070 cm−1 to 4470 cm−1) with the red shift in wavelength; while enhanced order of electric field at room temperature can control the gain slightly (4470 cm−1 to ~4150 cm−1) with fine red shift in wavelength. The results achieved in this work will definitely prove the method of controlling the gain characteristics as excellent; and the heterostructure studied will be suitable in design of tunable NIR (near infrared) light sources.

Background and Aims: The organophosphate (OP) poisoning is one of the important preventable public health problems in developing countries. It is estimated that OP pesticide self-poisoning kills around 200,000 people every year. The aim of the study was to determine the frequency of electrocardiographic (ECG) changes in acute OP poisoning at tertiary care hospital Larkana, Pakistan.Methods: It was an observational retrospective study of the patients who were diagnosed with acute OP poisoning during the period of four years January 2012 to December 2015 at medical emergency department, Shaheed Mohtarma Benzir Bhutto Medical University Hospital Larkana, Pakistan. A sample of 223 patients between 16-45 years with definite history of OP ingestion, were included in study. Patients with the history of cardiac disease, diabetes mellitus, hypertension, chronic renal failure and electrolyte imbalance were excluded.Results: Mean age was 29.61 ± 8.656 years with range of 16-45 years. Duration of OP ingestion ranged from 30 to 300 minutes with mean of 167.53 ± 45.26 minutes. Sixty five percent patients were in their 3rd and 4th decades of life. Males were 122 (54.71%) while 101 (45.29%) were females. ECG changes found in 145 (65.02%) with tachycardia and bradycardia was 85 (38.1%) and 60 (26.9%) respectively. The ST elevation was noted in 59 (26.5%), depression in 50 (22.4%), T wave changes observed in 51 (22.9%) patients. QTc interval was prolonged in 129 (57.85%).Conclusion: ECG changes are frequent in OP patients. QTc interval followed by sinus arrhythmias were most common changes observed. ECG should be done in all the patients who present with OP poisoning.Nepalese Heart Journal 2017; Vol 14(2), 5-8

Pakistan is facing multiple challenges for harnessing the indigenous energy resources and devise rational energy policies. The country is believed to have abundant energy resources, however, coping substantial electricity supply gap of over 5000 MW. This paper analyses country’s energy and power planning studies conducted since its independence in 1947 and policies announced so far. It is found that water resources management attained more emphasis in early decades of post-independence rather than energy concerns. The first energy and power planning study was conducted in late 1960s and since then various studies were undertaken to supplement five yearly medium term development plans of government. However, it is pertinent to mention that formal energy and power policies were only announced from 1994 onwards owing to growing electricity demand and progressing industrialization. Beside this, the focus of these policies is not only varied but were conceived without undertaking integrated energy planning using energy modeling tools e.g. MARKAL/TIMES; LEAP, ENPEP BALANCE, MESSAGE and EnergyPLAN. It is despite the fact that these tools are successfully applied globally for devising the energy policies and address the complexities of energy system by assisting effective policy formulation. This study recommends that integrated energy planning using energy modeling tools will be helpful to develop sustainable energy policies in Pakistan to eradicate electricity crises.

The CCS (Carbon Capture and Storage) is one of the significant solutions to reduce CO_2 emissions from fossil fuelled electricity generation plants and minimize the effect of global warming. Economic analysis of CCS technology is, therefore, essential for the feasibility appraisal towards CO_2 reduction. In this paper LCOE (Levelized Cost of Electricity Generation) has been estimated with and without CCS technology for fossil fuel based power plants of Pakistan and also further compared with computed LCOE of WE (Wind Energy) based power plants of the Pakistan. The results of this study suggest that the electricity generation costs of the fossil fuel power plants increase more than 44% with CCS technology as compared to without CCS technology. The generation costs are also found to be 10% further on higher side when considering efficiency penalty owing to installation of CCS technology. In addition, the CO_2 avoided costs from natural gas plant are found to be 40 and 10% higher than the local coal and imported coal plants respectively. As such, the electricity generation cost of 5.09 Rs/kWh from WE plants is found to be competitive even when fossil fuel based plants are without CCS technology, with lowest cost of 5.9 Rs./kWh of CCNG (Combined Cycle Natural Gas) plant. Based on analysis of results of this study and anticipated future development of efficient and cheap WE technologies, it is concluded that WE based electricity generation would be most appropriate option for CO_2 reduction for Pakistan.

The adaptation of maximum power point tracking algorithm for photovoltaic systems is of immense importance. In this paper, solar photovoltaic system is developed using MATLAB/SIMULINK which is connected to utility, artificial neural network (ANN) is used as maximum power point tracking (MPPT) algorithm for generation of maximum power by the system. Proportional-Integral (PI) controller that supports the information provided by ANN and generates boost converter duty-cycle helps in improving overall system stability. MPPT is evolved from a highly efficient boost converter where artificial neural network (ANN) with Levenberg-Marquardt (LM) algorithm is used for generating reference voltage for MPPT using feed forward back propagation training algorithm; error calculation is done by using the concept of mean square error algorithm. The developed system is verified under different test conditions and its control strategy shows exceptional performance having tracking efficiency exceeding 94.5%. Developed MATLAB/SIMULINK model offers control strategy and tool for the optimization of solar PV system connected to utility.

The British exit from the European Union (Brexit) referendum conducted in the United Kingdom (UK) about remaining in the European Union (EU) has had a profound effect on the world economy. Stock markets across the globe bore the brunt and pound sterling weakened sharply on this announcement. However, not all the economies were affected in the same way and the effect ranged from no impact to high impact. Economies which had considerable exposure to the UK, were affected. Though Malaysia does not have highly significant trade connections with the UK, the construction sector has moderate exposure to UK investments. In this study, construction companies’ stock price movement during the Brexit announcement was analyzed using the Event Study Methodology. Ten publicly traded construction companies were randomly selected and their stock returns were compared with the KCI Market Index returns. The returns were very volatile and showed a negative trend during the first few days around the Brexit announcement indicating that there was an insignificant short-term impact. However, the shock was quickly absorbed and the stock returns stabilized in a few days implying that the Brexit announcement did not have a significant long-term impact on construction company stocks in Malaysia. Keywords: brexit, event study, bursa Malaysia, Malaysian construction industry

Electricity demand in Pakistan has consistently increased in the past two decades. However, this demand is so far partially met due to insufficient supply, inefficient power plants, high transmission and distribution system losses, lack of effective planning efforts and due coordination. The existing electricity generation also largely depends on the imported fossil fuels, which is a huge burden on the national economy alongside causing colossal loss to the environment. It is also evident from existing government plans that electricity generation from low-cost coal fuels in the near future will further increase the emissions. As such, in this study, following the government&rsquo, s electricity demand forecast, four supply side scenarios for the study period (2013&ndash, 2035) have been developed using Long-range Energy Alternatives Planning System (LEAP) software tool. These scenarios are Reference scenario (REF) based on the government&rsquo, s power expansion plans, and three alternative scenarios, which include, More Renewable (MRR), More Hydro (MRH), and More Hydro Nuclear (MRHN). Furthermore, the associated gaseous emissions (CO2, SO2, NOX, CH4, N2O) are projected under each of these scenarios. The results of this study reveal that the alternative scenarios are more environmentally friendly than the REF scenario where penetration of planned coal-based power generation plants would be the major sources of emissions. It is, therefore, recommended that the government, apart from implementing the existing plans, should consider harnessing the renewable energy sources as indispensable energy sources in the future energy mix for electricity generation to reduce the fossil-fuel import bill and to contain the emissions.

Background: Branchial cleft cyst is rare congenital anomaly and most common cause of head and neck pathology in children. Second branchial cyst accounts 95 % of the all brnchial anomalies. It mostly manifest in 2nd and 3rd decade of life. Early diagnosis, controlling the infection status and complete excision without nerve injury is mainstay of treatment. Recurrence rates is very low after complete surgical excision. Study Design: Retrospective study. Setting: Department of Otolaryngology, Head and Neck Surgery, Benazir Bhutto Hospital Rawalpindi. Period: 02 year from August 2016 to July 2018. Methods: 04 cases of branchial anomalies. Age, sex, and duration of symptoms were noted from the case records. The side and site of the lesion and the site of opening of sinuses and fistula were noted. The cystic lesions were investigated with ultrasound and CT scan. Surgical excision of cyst and sinus done. Results: The structure of the studied group was as follows: the ratio men/women was of approximately 3/1; the ratio branchial cysts/branchial sinuses/branchial fistulae = 2/2/0. Age ranged from 16 to 27 years. Two patients presented with left neck swelling and one patient presented with right neck swelling and one with right sided discharging sinus. Complete surgical excision was done in all cases and no complication occured. Conclusion: Branchial cysts are commonly misdiagnosed and rarely included in the differential diagnosis. Physician should suspect in any patient with a swelling in the lateral part of the neck.

Prostate cancer incidence and mortality rates are remarkably higher in African-American men as compared to their European-Americans counterparts. Despite these recognitions, precise causes underlying such prevalent racial disparities remain poorly understood. Although socioeconomic factors could account for such differences up to a certain extent, it is now being increasingly realized that such disparity has a molecular basis. Indeed, several differences, including genetic polymorphism, gene mutations, epigenetic modifications, miRNAs alterations, etc., have been reported in malignant prostate tissues from patients of diverse racial backgrounds. Here, we attempt to provide a molecular perspective on prostate cancer racial disparities by gathering available information on these associated factors and discussing their potential significance in disproportionate incidence and clinical outcomes.

ICT equipment generates significant amount of green house gases. Presently, the ICT produces more than 830 million tons of CO2, that is about 2% of global CO2 emissions, and it is expected to double by 2020 (Chan et al., 2012; Pothitou et al., 2017; Park, 2018). There is a need for ICT to standardise, energy consumption and emissions and investigate means to reduce energy consumption. The electricity consumption which dominates direct carbon footprint of the ICT sector can be reduced by using renewable energy sources. The dye-sensitised-solar-cell (DSC) is a renewable energy device that works well inside a built-environment. The transparent characteristic of DSCs makes it suitable for building-integrated-photovoltaic (BIPV) applications such as windows. In this study, we successfully fabricated and assembled a transparent DSC which was used to power ICT products. Such building-integrated DSC systems can potentially power ICT devices in homes and offices.

Prostatic abscess is declining disease because of widespread using of antibiotic in management of early prostatitis and urinary tract infections. Causing pathogenic factors usually gram-negative organisms. In lack of a guidelines, diagnosis and management sometimes is a challenge.

Pancreatic cancer (PC) is the third leading cause of cancer-related death in the United States. It is challenging to treat PC due to the existence of intrinsic and extrinsic chemoresistance mechanisms. We previously reported that honokiol, a phytochemical isolated from Magnolia plant, targets important signaling pathways involved in PC associated with survival, chemoresistance and stromal remodeling, and exhibits significant anti-tumor activity both in vitro and in vivo. However, considering poor bioavailability and tumor uptake as major hurdles in clinical translation, we made efforts to develop an exosomal nanoformulation of honokiol. Mesenchymal cell-derived exosomes are non-immunogenic and express surface markers that could support tumor-targeted delivery. Maximum entrapment of honokiol was achieved when it was used in 1:4 weight ratio with exosomes and subjected to 6 cycles of sonication. Data from dynamic light scattering suggested that key features of exosomes (size, polydispersity and integrity) remained intact post-honokiol encapsulation. The comparative half maximal inhibitory concentration (IC50) data suggested 4 to 5 times greater therapeutic efficacy of exosomal honokiol as compared to that of free honokiol. Similarly, exosomal-honokiol had significantly superior effect on cell cycle progression, apoptosis and expression of cell cycle- and survival-associated proteins than that observed in PC cells treated with equivalent doses of free honokiol. We also found that the cellular uptake of honokiol was significantly greater for exosomal-honokiol as compared to its free form. Together, our work is the first demonstration of exosomal encapsulation of honokiol and its improved anti-tumor efficacy against pancreatic cancer. Citation Format: Mohammad Aslam Khan, Rajashekhar Kanchanapally, Sachin Kumar Deshmukh, Sanjeev K. Srivastava, Seema Singh, Ajay P. Singh. Exosomal formulation escalates cellular uptake of honokiol leading to enhanced antitumor efficacy in pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6259.

Rab proteins form the largest subfamily of small GTPases and play an indispensable role in the regulation of vesicle trafficking. They control a wide variety of endocytic, transcytic and exocytic transport pathways and thus play important roles in cellular growth and behavior. Altered expression and functions of Rab proteins have been reported in various malignancies and implicated in tumorigenic processes. Pancreatic cancer (PC) is a highly lethal malignancy and molecular mechanisms associated with its pathobiology are relatively less understood. Here we mined The Cancer Genome Atlas (TCGA) Database for differential expression and clinicopathological association of RAB genes in pancreatic cancer. Out of the 62 RAB genes analyzed, 5 (RAB3A, RAB26, RAB25, RAB21, and RAB22A) were found to have significant upregulation in cancer, while 5 (RAB6B, RAB8B, RABL2A, RABL2B and RAB32) exhibited significant downregulation. Racially disparate expression was also reported for some RABs. RAB3A and RAB26 had significantly higher and lower expression, respectively, in African American (AA) and Asian PC as compared to Caucasian Americans (CA) PC, whereas RAB25 was significantly higher in Asian PC than CA PC. No clear trend of altered expression was observed with increasing stage and grade, although stage- and grade-specific differences were recorded for some RABs. RAB21, RAB22A, and RAB8B showed significantly higher expression in PC from middle-aged patients (41-60 years) compared to older age groups, but no gender-associated differential expression was observed. PC from occasional drinkers had significantly higher expression of RAB21 compared to daily or weekly drinker, whereas RAB25 expression was significantly higher in social drinkers, compared to occasional ones. Expression of RABL2A was significantly reduced in PC of diabetic patients whereas RAB26 was significantly down in pancreatitis patients. Most importantly, a significant association of high expression of RAB21, RAB22A and RAB25, and low expression of RAB6B, RABL2A, and RABL2B was observed with poorer survival of PC patients. Together, our study is suggestive of potential diagnostic and prognostic significance of RABs in PC and warrants further investigations to define their functional and mechanistic significance. Citation Format: Shashi Anand, Haseeb Zubair, Mohammad Aslam Khan, Seema Singh, Ajay P. Singh. Expression and clinicopathological association of RABs in pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2601.

RAB proteins (RABs) represent the largest subfamily of Ras-like small GTPases that regulate a wide variety of endosomal membrane transport pathways. Their aberrant expression has been demonstrated in various malignancies and implicated in pathogenesis. Using The Cancer Genome Atlas (TCGA) database, we analyzed the differential expression and clinicopathological association of RAB genes in pancreatic ductal adenocarcinoma (PDAC). Of the 62 RAB genes analyzed, five (RAB3A, RAB26, RAB25, RAB21, and RAB22A) exhibited statistically significant upregulation, while five (RAB6B, RAB8B, RABL2A, RABL2B, and RAB32) were downregulated in PDAC as compared to the normal pancreas. Racially disparate expression was also reported for RAB3A, RAB25, and RAB26. However, no clear trend of altered expression was observed with increasing stage and grade, age, and gender of the patients. PDAC from occasional drinkers had significantly higher expression of RAB21 compared to daily or weekly drinkers, whereas RAB25 expression was significantly higher in social drinkers, compared to occasional ones. The expression of RABL2A was significantly reduced in PDAC from diabetic patients, whereas RAB26 was significantly lower in pancreatitis patients. More importantly, a significant association of high expression of RAB21, RAB22A, and RAB25, and low expression of RAB6B, RABL2A, and RABL2B was observed with poorer survival of PC patients. Together, our study suggests potential diagnostic and prognostic significance of RABs in PDAC, warranting further investigations to define their functional and mechanistic significance.