Development and content validation of a financial and functional outcomes tool for diabetes-related foot disease in patients undergoing major lower limb amputation: a prospective observational study from Pakistan.

OBJECTIVE: To develop and content validate a questionnaire to assess the financial and functional impact of major lower limb amputation in patients with diabetes-related foot disease. DESIGN: Prospective observational study. SETTING: This study was conducted at a tertiary care centre in Pakistan. PARTICIPANTS: We conducted a thorough literature review and a group interview with 10 participants, resulting in domain identification and item generation. The group included seven patients with diabetes-related foot disease who underwent major lower limb amputation and three caregivers. Subsequently, a focused group discussion was held to assess overlap and duplication among the items, and two rounds of content validation were carried out by five content and five lay experts in both English and Urdu. Question items with a Content Validity Index (CVI) score of >0.79 were retained, items with a CVI score between 0.70 and 0.79 were revised and items with a CVI score of <0.70 were excluded. RESULTS: The initial literature review and group interview resulted in 61 items in the financial and functional domains. After the focused group discussion, the questionnaire was reduced to 37 items. Following two rounds of content validation, the English questionnaire achieved the Scale-Content Validity Index/Average (S-CVI/Ave) of 0.92 and 0.89 on relevance and clarity, respectively. Similarly, the Urdu questionnaire achieved the S-CVI-Ave of 0.92 and 0.95, respectively. CONCLUSION: A 37-item multidimensional questionnaire was developed and rigorously content-validated to assess the financial and functional impact of major lower limb amputation in patients with diabetes-related foot disease. The questionnaire used in this study has shown robust content validity specifically for our population.

High-Pressure Delivery of Oncolytic Viruses via Needle-Free Injection Preserves Therapeutic Activity.

Intratumoural delivery of oncolytic viruses (OVs) to solid tumours is currently performed via multiple percutaneous methods of needle injections (NI). In this study, we investigated the potential use of a novel delivery approach, needle-free injection (NFI), to administer OVs to subcutaneous tumours. The stability and genetic integrity of several RNA and DNA viruses exposed to high-pressure jet injectors were first evaluated in vitro. We demonstrate that replication competence and infectivity of the viruses remained unchanged after NFI, as compared to traditional NI. Using the oncolytic Vesicular Stomatitis Virus expressing luciferase (VSVΔ51-Luc) in the syngeneic CT26 subcutaneous tumour model, we show that NFI administration not only successfully delivers infectious particles but also increases the dissemination of the virus within the tumour tissues when compared to NI. Furthermore, mice treated with VSVΔ51-Luc by NFI delivery showed similar reduction in tumour growth and survival compared to those with needle-administered virus. These results indicate that NFI represents a novel approach to administer and potentially increase the spread of OVs within accessible solid tumours, highlighting its usefulness in virotherapy.

Insight into Structure Activity Relationship of DPP-4 Inhibitors for Development of Antidiabetic Agents.

This article sheds light on the various scaffolds that can be used in the designing and development of novel synthetic compounds to create DPP-4 inhibitors for the treatment of type 2 diabetes mellitus (T2DM). This review highlights a variety of scaffolds with high DPP-4 inhibition activity, such as pyrazolopyrimidine, tetrahydro pyridopyrimidine, uracil-based benzoic acid and esters, triazole-based, fluorophenyl-based, glycinamide, glycolamide, ß-carbonyl 1,2,4-triazole, and quinazoline motifs. The article further explains that the potential of the compounds can be increased by substituting atoms such as fluorine, chlorine, and bromine. Docking of existing drugs like sitagliptin, saxagliptin, and vildagliptin was done using Maestro 12.5, and the interaction with specific residues was studied to gain a better understanding of the active sites of DPP-4. The structural activities of the various scaffolds against DPP-4 were further illustrated by their inhibitory concentration (IC50) values. Additionally, various synthesis schemes were developed to make several commercially available DPP4 inhibitors such as vildagliptin, sitagliptin and omarigliptin. In conclusion, the use of halogenated scaffolds for the development of DPP-4 inhibitors is likely to be an area of increasing interest in the future.

A systematic review of simulation training for lower extremity bypass procedures.

OBJECTIVES: Simulation is used across surgical specialties for skill enhancement. The choice and assessment method of a simulator varies across literature. In the age of endovascular approach, trainees have limited exposure to open lower limb bypass procedures which needs attention. This review aims to assess the utility of simulation training in lower limb bypass surgery using Kirkpatrick's model. METHODS: Using PRISMA statement, we included all the studies done on simulators in lower limb bypass surgical procedures for this systematic review. The primary outcome was to assess the effectiveness of different types of simulation used for lower limb bypass surgery using the Kirkpatrick's model for training evaluation. RESULTS: An initial search identified 295 articles out of which 7 articles were found to be eligible for this systematic review. A variety of simulators were used including cadavers and synthetic models. Most studies (n=5) found the use of simulation as an effective tool in achieving technical competence. All the five studies we found at level 2 on Kirpatrick's model evaluation. CONCLUSION: Most of the existing studies are at level 2 of Kirkpatrick's model which reflects learning changes in trainees after simulation. Feedback mechanism needs to be evolved where the improvement after simulation training can be gauged by its replication in clinical practice and improved patient care practices corresponding to the highest level of Kirkpatrick's model.

Axillary synovial sarcoma recurrence involving brachial plexus, a rare case report from Pakistan.

INTRODUCTION: Synovial sarcomas are rare tumors, and the incidence of axillary synovial sarcoma involving the brachial plexus has been reported as 2.9 % among all axillary soft tissue tumors. However, the recurrence of axillary synovial sarcomas has not been reported in literature. CASE PRESENTATION: A 36-years-old Afghan female presented in Karachi, Pakistan with a history of persistently increasing, recurrent, right axillary mass for 6 months. Initially diagnosed as a spindle-cell tumor on excision in Afghanistan, she had received ifosfamide and doxorubicin, but the lesion recurred. On examination, it was a 5 × 6 cm, hard mass palpable in right axilla. After radiological work-up and a multidisciplinary team discussion, she underwent complete excision of the tumor with successful preservation of brachial plexus. The final diagnosis was reported as monophasic synovial sarcoma FNCLCC Grade 3. DISCUSSION: Our patient presented with a recurrent right axillary synovial sarcoma that was involving the axillary neurovascular bundle and brachial plexus, which was initially diagnosed as a spindle cell sarcoma. Pre-operative core-needle biopsy was unable to provide a definitive diagnosis. MRI scan was useful in delineating the proximity of the neurovascular structures. Re-excision of the tumor was performed which is the mainstay of treatment for axillary synovial sarcomas, combined with radiotherapy depending on the disease grading, staging and patient factors. CONCLUSION: Axillary synovial sarcoma recurrence with involvement of the brachial plexus is an extremely rare presentation. Our patient was successfully managed through a multidisciplinary approach with complete surgical excision and preservation of the brachial plexus followed by adjuvant radiotherapy.

Hybrid Steel/NSM/GFRP System versus GFRP Wrapping for Upgrading RC Wall-like Columns.

Reinforced concrete (RC) wall-like columns are commonly employed in structures in Saudi Arabia. These columns are preferred by architects owing to their minimum projection in the usable space. However, they often need strengthening due to several reasons, such as the addition of more stories and increasing the live load as a result of changing the usage of the building. This research aimed to obtain the best scheme for the axial strengthening of RC wall-like columns. The challenge in this research is to develop strengthening schemes for RC wall-like columns, which are favored by architects. Accordingly, these schemes were designed so that the dimensions of the column cross-section are not increased. In this regard, six wall-like columns were experimentally examined in the event of axial compression with zero eccentricity. Two specimens were not retrofitted to be used as control columns, whereas four specimens were retrofitted with four schemes. The first scheme incorporated traditional glass fiber-reinforced polymer (GFRP) wrapping, while the second one utilized GFRP wrapping combined with steel plates. The last two schemes involved the addition of near-surface mounted (NSM) steel bars combined with GFRP wrapping and steel plates. The strengthened specimens were compared with regard to axial stiffness, maximum load, and dissipated energy. Besides column testing, two analytical approaches were suggested for computing the axial capacity of tested columns. Moreover, finite element (FE) analysis was performed for evaluating the axial load versus displacement response of tested columns. As an outcome of the study, the best strengthening scheme was proposed to be used by practicing engineers for axial upgrading of wall-like columns.

Autologous vein graft repair of mycotic innominate artery aneurysm: A case report.

INTRODUCTION: Innominate artery aneurysm (IAA) is an extremely rare fatal condition with an overall prevalence of less than 3 % of all supra-aortic artery aneurysms. These infrequent lesions usually present as an emergency and require challenging surgical procedures. CASE PRESENTATION: We report an interesting case of mycotic IAA in a 25 years old male patient. He was a known intravenous drug abuser having mycotic aneurysm arising from brachiocephalic artery with eccentric thrombus causing adjacent mass effect over the trachea. He underwent successful emergent surgical management of aneurysm with autologous vein graft using superficial femoral vein. Unfortunately, he died due to massive upper gastrointestinal bleeding leading to multi-organ failure after a prolonged post-operative course. CLINICAL DISCUSSION: Mycotic aneurysms of the IA are extremely rare with an overall incidence of 1-2.7 % cases of all IAA. Presentation of the IAA can be quite variable from asymptomatic to symptoms exhibiting mass effect over surrounding structures. Rupture of IAA can be fatal and can occur if not treated promptly. There are no current recommendations or guidelines for treatment and interventions in IAA. Surgical management involves complete excision of the aneurysm and then revascularization. CONCLUSION: Infected Innominate artery aneurysm is a rare surgical entity requiring early diagnosis, detailed investigation and prompt surgical management involving multidisciplinary team approach. Our case describes a relatively innovative approach to this scarce condition.

Role of stem cells in arteriovenous access: perspective from Lower Middle Income Countries.

Adequately created well functional haemodialysis access is an important part for the physical and mental wellbeing of renal failure patients. Every effort should be made to enhance the patency of these accesses. Recently, stem cell treatment modalities have opened new avenues in the better patency of arteriovenous fistula. Use of mesenchymal stromal cells (MSC) to prevent venous neointimal hyperplasia have been studied with good success rates. Adopting such costly treatment modalities in low middle income class country like Pakistan is associated with significant challenges. This short report discusses the current role of stem cells in arteriovenous access and how this exciting modality can be utilized in our country.

Pyrazole scaffold-based derivatives: A glimpse of α-glucosidase inhibitory activity, SAR, and route of synthesis.

The α-glucosidase is a validated target to develop drugs for treating type 2 diabetes mellitus. The existing α-glucosidase inhibitors have certain shortcomings related to side effects and route of synthesis. Accordingly, it is inevitable to develop new chemical templates as α-glucosidase inhibitors. Pyrazole derivatives have a special place in medicinal chemistry because of various biological activities. Recently, pyrazole-based heterocyclic compounds have emerged as a promising scaffold to develop α-glucosidase inhibitors. This study focuses on the recently reported pyrazole-based α-glucosidase inhibitors, including their biological activity (in vivo, in vitro, and in silico), structure-activity relationship, and ways of synthesis. The literature revealed the development of several promising pyrazole-based α-glucosidase inhibitors and new synthetic routes for their preparation. The encouraging α-glucosidase inhibitory results of the pyrazole-based heterocyclic compounds make them an attractive target for further research. The authors also foresee the arrival of the pyrazole-based α-glucosidase inhibitors in clinical practice.

Identification of novel pyrazole containing ɑ-glucosidase inhibitors: insight into pharmacophore, 3D-QSAR, virtual screening, and molecular dynamics study.

Pharmacophore modelling, 3 D QSAR modelling, virtual screening, and molecular dynamics study, all-in-one combination were employed successfully design and develop an alpha-glucosidase inhibitor. To explain the structural prerequisites of biologically active components, 3 D-QSAR models were generated using the selected best hypothesis (AARRR) for compounds 55 included in the model C. The selection of 3 D-QSAR models showed that the Gaussian steric characteristic is crucial to alpha glucosidase's inhibitory potential. The alpha-glucosidase inhibitory potency of the compound is enhanced by other components, including Gaussian hydrophobic groups, Gaussian hydrogen bond acceptor or donor groups, Gaussian electrostatic characteristics, and a Gaussian steric feature. An identification of structure-activity relationships can be obtained from the developed 3 D-QSAR, C model, with R2 = 0.77 and SD = 0.02 for training set, and Q2 = 0.66, RMSE 0.02, and Pearson R = 0.81 for testing set, corresponding to elevated predictive ability. Additionally, docking and MM/GBSA experiments on 1146023 showed that it interacts with critical amino acids in the binding site when coupled with acarbose. Further, five compounds that display a high affinity for alpha-glucosidase were found, and these compounds may serve as potent leads for alpha-glucosidase inhibitor development. Biological activity will be tested for these compounds in the future.Communicated by Ramaswamy H. Sarma.

The Use of Formative Assessment in Postgraduate Urology Training: A Systematic Review.

Formative assessment is an essential component of surgical training. However, it is not usually a mandatory component in postgraduate curricula. The purpose of this study is to identify and evaluate how formative assessments are integrated into postgraduate urology training in programs across the globe. This study consisted of a systemic review to see how formative assessments are being implemented in various urology programs globally. A total of 427 articles were identified for the literature review. Of these, only 10 were included and critically appraised. These studies explored various techniques for exploration of formative assessments in urology training programs, which included established tools, such as portfolio reviews, and direct observations of procedure skills (DOPS); novel tools, including the Dutch urology practical skills (D-UPS) program and Ottawa surgical competency operating room evaluation (O-SCORE); and curricular models. Nine of the 10 articles favored their potential utility in formative assessments. Current literature involving formative assessments in postgraduate urology programs is scarce, and available resources have a high heterogeneity between them. More structured formative assessments need to be incorporated into surgical training programs, and affiliated training institutions should be encouraged to integrate them into their curricula.

Training and Assessment in Urology: Perspective From a Third World Country.

Formative assessments are an essential yet often overlooked aspect of postgraduate surgical training. This report explores the strategies by which formative assessments are integrated into postgraduate surgical training in Pakistan (using urology as an example), by comparing the regional recommendations and infrastructures offered by local governing bodies to that of a more structured system, as offered by the General Medical Council (GMC). The College of Physicians and Surgeons Pakistan (CPSP) serves as the de facto local accrediting body for postgraduate surgical training and makes a conscious effort in maintaining the standard of training throughout the country. However, although formative assessment activities are encouraged in its roster, they are rarely monitored as strictly as summative outcomes. This is a far cry from how the structured format is exemplified by the GMC's various guidelines and protocols. It must be emphasized that in order to improve the overall quality of training, measures need to be made to improve the ways in which feedback and formative activities are implemented and monitored.

Perception and Validity of Online Formative Oral Assessment in Surgical Trainees: A Cross-Sectional Study.

BACKGROUND: Online oral assessments have been poorly studied in medical education. This study aims to assess the perception of the online oral assessment strategy for formative purposes. OBJECTIVE: To explore the perception of trainees and examiners on their experience of online oral assessment. METHODS: Online oral assessments were conducted using the Zoom platform (Zoom Video Communications, Inc., San Jose, California, United States) over a period of six days. Each candidate was examined by two examiners and formative feedback was provided at the same time. At the end of the course, participants were asked to fill out an online questionnaire regarding their perception of this online platform for oral assessment.  Results: A total of 192 participants were included in this study as examiners (n=48), candidates (n=53), and observers (n=91). The overall impression of the organization and accessibility of the model was found favorable with a generally lower degree of perceived anxiety in this format. Major limitations faced by participants included technical difficulties (n=84), linguistic issues (n=37), and failure to observe body language (n=38). Using the Joughin matrix, this model of online oral assessment was found as a fair and valid assessment tool with relatively low reliability. CONCLUSIONS: The online oral assessment model has been found to be a reliable and valid method of formative assessment. Further work could be done on this model to assess its potential for summative purposes.

How do plants remember drought?

MAIN CONCLUSION: Plants develop both short-term and transgenerational memory of drought stress through epigenetic regulation of transcription for a better response to subsequent exposure. Recurrent spells of droughts are more common than a single drought, with intermittent moist recovery intervals. While the detrimental effects of the first drought on plant structure and physiology are unavoidable, if survived, plants can memorize the first drought to present a more robust response to the following droughts. This includes a partial stomatal opening in the watered recovery interval, higher levels of osmoprotectants and ABA, and attenuation of photosynthesis in the subsequent exposure. Short-term drought memory is regulated by ABA and other phytohormone signaling with transcriptional memory behavior in various genes. High levels of methylated histones are deposited at the drought-tolerance genes. During the recovery interval, the RNA polymerase is stalled to be activated by a pause-breaking factor in the subsequent drought. Drought leads to DNA demethylation near drought-response genes, with genetic control of the process. Progenies of the drought-exposed plants can better adapt to drought owing to the inheritance of particular methylation patterns. However, a prolonged watered recovery interval leads to loss of drought memory, mediated by certain demethylases and chromatin accessibility factors. Small RNAs act as critical regulators of drought memory by altering transcript levels of drought-responsive target genes. Further studies in the future will throw more light on the genetic control of drought memory and the interplay of genetic and epigenetic factors in its inheritance. Plants from extreme environments can give queues to understanding robust memory responses at the ecosystem level.

The evolving role of digital media in medical education.

Within the last decade, social media has progressed from a form of mere entertainment to a medium for solution of complex issues in our daily lives. During the last few years, social media has gained value in medical education and the diversity in the use of digital media has given new dimensions to medical education while facing the Covid pandemic. Digital media helps in creating virtual communities which not only bring more harmony between teachers and students but has also shown to have reduced anxiety and stress among students. Common social media platforms such as Facebook and WhatsApp have recently gained popularity as platforms which are being actively used in various ways to enhance learning. Social media in medical education is also utilised to enhance communication skills, professionalism and better patient care, but this should be addressed with caution as violation of patient's privacy and confidentiality remains a threat.

Availability of Operative Surgical Experience and Supervision for Competency-Based Education: A Review of A General Surgery Program at A Tertiary Care Teaching Hospital in Pakistan.

BACKGROUND: In view of importance for competency-based education (CBE), we undertook a self-study to elicit the available operative surgical workload and supervision for residents in the general surgical residency program at the teaching hospital in Karachi. METHODOLOGY: This was a cross-sectional study spanning a 5-year period between January 2015 and December 2019. The numbers of surgical residents during this period were identified. Five procedures were selected as core general surgical procedures: incision and drainage of superficial abscess, laparoscopic appendectomy, laparoscopic cholecystectomy, open inguinal hernia repair, and perianal procedures. Trends of the number of residents per year and the numbers of procedures per year were determined. The mean number of core procedures per eligible resident during their entire training was calculated to represent potential operative surgical experience and were benchmarked. The ratio of the average number of residents rotating in general surgery per year to the number of attending surgeons was determined as a measure of available supervision. RESULT: The mean total number of general surgical residents per year was 31.2 (range 28-35). The numbers of core general surgical procedures were consistent over the years of study. Potential exposure of eligible residents to each core procedure during their entire training was: 19.5 cases for incision and drainage of superficial abscess; 89 cases for laparoscopic appendectomy; 113.6 for inguinal hernia repair, 267.5 for laparoscopic cholecystectomy and 64.5 for perianal procedures. The average yearly residents to full-time attending surgeons' ratio was 2.5. The workload of core general surgical procedures at AKUH was higher than the Accreditation Council for Graduate Medical Education (ACGME) recommended volumes for operative surgical experience for residents in the US. CONCLUSION: This method of assessing the potential of a surgical program for transitioning to CBE appears practical and can be generalized.

Clinicians as Leaders: Impact and Challenges.

Healthcare has always been a complex system phenomenon which needs accountability from the leading clinical and management roles. Adequate and competent leadership is recognized as a driving point for a successful healthcare division. Medical professionals taking charge for quality improvement are well placed yet the style to deliver their leadership qualities bears a massive significance. While exceptional clinical prowess is of tremendous importance, harmonious teamwork, inefficiency reduction and patient communication and safety lead to noteworthy health management outcomes. Explores not explains the importance of leadership, qualities and styles of a leader, various leadership theories, the impact of leadership in medical education and the current issues related to medical leadership.

Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure.

Hepatokines, secretory proteins from the liver, mediate inter-organ communication to maintain a metabolic balance between food intake and energy expenditure. However, molecular mechanisms by which hepatokine levels are rapidly adjusted following stimuli are largely unknown. Here, we unravel how CNOT6L deadenylase switches off hepatokine expression after responding to stimuli (e.g., exercise and food) to orchestrate energy intake and expenditure. Mechanistically, CNOT6L inhibition stabilizes hepatic Gdf15 and Fgf21 mRNAs, increasing corresponding serum protein levels. The resulting upregulation of GDF15 stimulates the hindbrain to suppress appetite, while increased FGF21 affects the liver and adipose tissues to induce energy expenditure and lipid consumption. Despite the potential of hepatokines to treat metabolic disorders, their administration therapies have been challenging. Using small-molecule screening, we identified a CNOT6L inhibitor enhancing GDF15 and FGF21 hepatokine levels, which dramatically improves diet-induced metabolic syndrome. Our discovery, therefore, lays the foundation for an unprecedented strategy to treat metabolic syndrome.