Structural proteomics guided annotation of vaccine targets and designing of multi-epitopes vaccine to instigate adaptive immune response against Francisella tularensis.

Francisella tularensis can cause severe disease in humans via the respiratory or cutaneous routes and a case fatality ratio of up to 10% is reported due to lack of proper antibiotic treatment, while F. novicida causes disease in severely immunocompromised individuals. Efforts are needed to develop effective vaccine candidates against Francisella species. Thus, in this study, a systematic computational work frame was used to deeply investigate the whole proteome of Francisella novicida containing 1,728 proteins to develop vaccine against F. tularensis and related species. Whole-proteome analysis revealed that four proteins including (A0Q492) (A0Q7Y4), (A0Q4N4), and (A0Q5D9) are the suitable vaccine targets after the removal of homologous, paralogous and prediction of subcellular localization. These proteins were used to predict the T cell, B cell, and HTL epitopes which were joined together through suitable linkers to construct a multi-epitopes vaccine (MEVC). The MEVC was found to be highly immunogenic and non-allergenic while the physiochemical properties revealed the feasible expression and purification. Moreover, the molecular interaction of MEVC with TLR2, molecular simulation, and binding free energy analyses further validated the immune potential of the construct. According to Jcat analysis, the refined sequence demonstrates GC contents of 41.48% and a CAI value of 1. The in-silico cloning and optimization process ensured compatibility with host codon usage, thereby facilitating efficient expression. Computational immune simulation studies underscored the capacity of MEVC to induce both primary and secondary immune responses. The conservation analysis further revealed that the selected epitopes exhibit 100% conservation across different species and thus provides wider protection against Francisella.

Real-World Outcomes of Faricimab Treatment for Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema.

Purpose: The purpose of this study was to assess preliminary real-world outcomes in neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) treated with intravitreal faricimab. Patients and Methods: This was a retrospective, observational consecutive-case real-world study of patients with nAMD or DME initiated on intravitreal faricimab between November 2022 and April 2023. Treatment-naïve patients and patients previously treated with alternate anti-vascular endothelial growth factor (anti-VEGF) agents were initiated on an intended treatment plan of four monthly faricimab injections as a loading regime. Efficacy was assessed across four treatment groups. Primary outcomes assessed for both cohorts were changes in best corrected visual acuity (BCVA) and central subfield thickness (CST) on optical coherence tomography (OCT). Secondary outcomes were alterations in OCT-defined structural features. Results: From 127 patients, 146 eyes received at least one dose of faricimab. Mean BCVA, measured in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters, from baseline to fifth visit increased from: 59.0±12.8 to 62.2±14.3 in treatment-naïve nAMD; 61.1±17.6 to 63.5±14.8 in previously-treated nAMD; 61.1±13.0 to 72.8±11.5 in treatment-naïve DME; and 60.8±14.6 to 63.3±15.6 in previously-treated DME. Mean CST reduced in all four treatment groups between initiation to final loading dose, from: 442.8±172.0µm to 305.2±117.0µm (p<0.0001) in treatment-naïve nAMD; 355.2±115.1µm to 297.9±92.54µm (p<0.0001) in previously-treated nAMD; 465.8±109.1µm to 343.1±100.3µm (p<0.0001) in treatment-naïve DME; and 492.5±133.1µm to 388.5±131.4µm (p<0.0001) in previously-treated DME. Conclusion: Real-world outcomes showed some improvement in BCVA and CST for nAMD and DME following faricimab administration, including in patients previously treated with other anti-VEGF agents. Further work involving larger cohorts over longer periods is required to determine whether improvement is maintained, and if intervals can be extended to match those observed in clinical trials.

TriClip G4: A game-changer for tricuspid valve regurgitation treatment.

Tricuspid valve regurgitation, or TR, is a difficult-to-manage condition. In addition to EVOQUE, percutaneous annuloplasty, and surgical repair, the TriClip G4 system has been added to the interventional therapeutic choices for TR. Recently, the Food and Drug Administration (FDA) approved the use of the TriClip G4 device to treat patients with symptomatic, severe TR who have received optimal medication therapy but are at intermediate or higher risk of surgery. This review attempts to offer a thorough examination of the procedural features, learning curves, results of the device and compares the TriClip G4 system to other interventional therapies for TR. TriClip G4 has shown to have promising results in pivotal clinical trials, be cost-effective, and improve the quality of life of patients. Furthermore, it has its unique advantages against other conventional techniques and devices.

Risk of infection with arboviruses in a healthy population in Pakistan based on seroprevalence.

Infectious diseases caused by arboviruses are a public health concern in Pakistan. However, studies on data prevalence and threats posed by arboviruses are limited. This study investigated the seroprevalence of arboviruses in a healthy population in Pakistan, including severe fever with thrombocytopenia syndrome virus (SFTSV), Crimean-Congo hemorrhagic fever virus (CCHFV), Tamdy virus (TAMV), and Karshi virus (KSIV) based on a newly established luciferase immunoprecipitation system (LIPS) assays, and Zika virus (ZIKV) by enzyme-linked immunosorbent assays (ELISA). Neutralizing activities against these arboviruses were further examined from the antibody positive samples. The results showed that the seroprevalence of SFTSV, CCHFV, TAMV, KSIV, and ZIKV was 17.37%, 7.58%, 4.41%, 1.10%, and 6.48%, respectively, and neutralizing to SFTSV (1.79%), CCHFV (2.62%), and ZIKV (0.69%) were identified, as well as to the SFTSV-related Guertu virus (GTV, 0.83%). Risk factors associated with the incidence of exposure and levels of antibody response were analyzed. Moreover, co-exposure to different arboviruses was demonstrated, as thirty-seven individuals were having antibodies against multiple viruses and thirteen showed neutralizing activity. Males, individuals aged ≤40 years, and outdoor workers had a high risk of exposure to arboviruses. All these results reveal the substantial risks of infection with arboviruses in Pakistan, and indicate the threat from co-exposure to multiple arboviruses. The findings raise the need for further epidemiologic investigation in expanded regions and populations and the necessity to improve health surveillance in Pakistan.

Investigating the role of functional mutations in leucine binding to Sestrin2 in aging and age-associated degenerative pathologies using structural and molecular simulation approaches.

Leucine is the native known ligand of Sestrin2 (Sesn2) and its interaction with Sesn2 is particularly important, as it influences the activity of mTOR in aging and its associated pathologies. It is important to find out how leucine interacts with Sesn2 and how mutations in the binding pocket of leucine affect the binding of leucine. Therefore, this study was committed to investigating the impact of non-synonymous mutations by incorporating a broad spectrum of simulation techniques, from molecular dynamics to free energy calculations. Our study was designed to model the atomic-scale interactions between leucine and mutant forms of Sesn2. Our results demonstrated that the interaction paradigm for the mutants has been altered thus showing a significant decline in the hydrogen bonding network. Moreover, these mutations compromised the dynamic stability by altering the conformational flexibility, sampling time, and leucine-induced structural constraints that consequently caused variation in the binding and structural stability. Molecular dynamics-based flexibility analysis revealed that the regions 217-339 and 371-380 demonstrated a higher fluctuation. Noteworthy, these regions correspond to a linker (217-339) and a loop (371-380) that cover the leucine binding cavity that is critical for the 'latch' mechanism in the N-terminal, which is essential for leucine binding. Further validation of reduced binding and modified internal motions caused by the mutants was obtained through binding free energy calculations, principal components analysis (PCA), and free energy landscape (FEL) analysis. By unraveling the molecular intricacies of Sesn2-leucine interactions and their mutations, we hope to pave the way for innovative strategies to combat the inevitable tide of aging and its associated diseases.Communicated by Ramaswamy H. Sarma.

Multiple integrated computational approach to analyse wound healing potential of Symplocos racemosa bark as Matrix metalloproteinase inhibitors.

The healing of wounds is the flagging concern in chronic wound cases especially when accompanied by pathogenic, diabetic comorbidities. Matrix metalloproteinases are associated with widespread pathological ailments, and the selective inhibitors for metalloproteinases can be of great interest in wound healing strategies. In the present research study, six constituents of Symplocos racemosa Roxb were evaluated for the docking aptitudes on human matrix metalloproteinase MMP 2 (PDB ID: 1QIB) and MMP 9 (PDB ID: 4H1Q) utilising Autodock Vina followed by the visualisation using Discovery studio (DS). The Pymol was used to generate the poses and the best binding pose was chosen for the docking aptitudes. 2D interactions and the 3D poses of the docked complex were accomplished using DS and LigPlot + software respectively. Working on SWISS ADME and OSIRIS software accomplished the physicochemical characteristics, absorption, distribution, metabolism, excretion, molecular properties, bioactivity score, and toxicity predictions. The molecule's physiochemical investigations discovered that all of the ligands comply with Lipinski's rule of five except compound 6, which deviated with two violations. Docking studies against 4H1Q revealed that compounds 1, 3, 5 and 6 exhibited maximum interactions with the target protein, with the free binding energies of -8.3 kJ Mol-1, -9.3 kJ Mol-1, -7.2 kJ Mol-1 and -11.0 kJ Mol-1 respectively. In case of the 1QIB target, compounds 1, 3 and 6 displayed remarkable binding energies of -8.7 kJ mol-1, -9.0 kJ mol-1 and -8.8 kJ mol-1. Bioactivity prediction study revealed that all of the selected Phytoconstituents displayed incredible Bioactivity scores. None of the selected chemical compounds was found to be irritant to the skin as discovered by toxicity studies. The contacts of the ligand-protein complex during the simulation studies revealed that the H-bond interactions of the ligands with LEU188, ALA189, GLN402, ARG420, MET422, PRO421, and ARG424 of 4H1Q were stable for more than 30% of the simulation time. It was thus concluded that the tested compounds predominantly compounds 1, 5 and 6 might rank among the vital supplementary lead drugs in chronic wounds and healing complexities. It is also worth noting the potential aptitude of the compound 3, however, its toxicity concern must be considered.

Structure-guided engineering and molecular simulations to design a potent monoclonal antibody to target aP2 antigen for adaptive immune response instigation against type 2 diabetes.

Introduction: Diabetes mellitus (DM) is recognized as one of the oldest chronic diseases and has become a significant public health issue, necessitating innovative therapeutic strategies to enhance patient outcomes. Traditional treatments have provided limited success, highlighting the need for novel approaches in managing this complex disease. Methods: In our study, we employed graph signature-based methodologies in conjunction with molecular simulation and free energy calculations. The objective was to engineer the CA33 monoclonal antibody for effective targeting of the aP2 antigen, aiming to elicit a potent immune response. This approach involved screening a mutational landscape comprising 57 mutants to identify modifications that yield significant enhancements in binding efficacy and stability. Results: Analysis of the mutational landscape revealed that only five substitutions resulted in noteworthy improvements. Among these, mutations T94M, A96E, A96Q, and T94W were identified through molecular docking experiments to exhibit higher docking scores compared to the wild-type. Further validation was provided by calculating the dissociation constant (KD), which showed a similar trend in favor of these mutations. Molecular simulation analyses highlighted T94M as the most stable complex, with reduced internal fluctuations upon binding. Principal components analysis (PCA) indicated that both the wild-type and T94M mutant displayed similar patterns of constrained and restricted motion across principal components. The free energy landscape analysis underscored a single metastable state for all complexes, indicating limited structural variability and potential for high therapeutic efficacy against aP2. Total binding free energy (TBE) calculations further supported the superior performance of the T94M mutation, with TBE values demonstrating the enhanced binding affinity of selected mutants over the wild-type. Discussion: Our findings suggest that the T94M substitution, along with other identified mutations, significantly enhances the therapeutic potential of the CA33 antibody against DM by improving its binding affinity and stability. These results not only contribute to a deeper understanding of antibody-antigen interactions in the context of DM but also provide a valuable framework for the rational design of antibodies aimed at targeting this disease more effectively.

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.

Inoculation of heavy metal resistant bacteria alleviated heavy metal-induced oxidative stress biomarkers in spinach (Spinacia oleracea L.).

Most vegetable crops are severely affected by the uptake of heavy metals from the soil. Heavy metals in vegetable bodies generate reactive oxygen species (ROS) that unbalance the antioxidant defense system. This study was initiated to determine the physiological and biochemical characteristics of spinach plants grown on soil contaminated with heavy metals and responding to Bacillus cereus and Bacillus aerius were isolated from soil contaminated with heavy metals. Heavy metal contamination led to a significant reduction in seed germination, seedling biomass, protein, and total nitrogen content of spinach plants grown in contaminated soils compared to control soils. In contrast, a significant increase in the content of metallothioneins and antioxidant enzymes was observed. Plants inoculated with B. cereus and B. aerius significantly reduced the oxidative stress induced by heavy metals by improving seed germination (%), seedling growth, nitrogen, and protein content. The content of metallothioneins and the activities of antioxidant enzymes were reduced in spinach plants grown from seeds inoculated with bacterial strains. In addition, plants inoculated with, B. cereus and B. aerius showed greater stomata opening than plants grown on soil contaminated with heavy metals, whose stomata were almost closed. These results suggested that both bacterial strains enhanced plant growth by reducing oxidative stress caused by metals.

Breeding for water-use efficiency in wheat: progress, challenges and prospects.

Drought poses a significant challenge to wheat production globally, leading to substantial yield losses and affecting various agronomic and physiological traits. The genetic route offers potential solutions to improve water-use efficiency (WUE) in wheat and mitigate the negative impacts of drought stress. Breeding for drought tolerance involves selecting desirable plants such as efficient water usage, deep root systems, delayed senescence, and late wilting point. Biomarkers, automated and high-throughput techniques, and QTL genes are crucial in enhancing breeding strategies and developing wheat varieties with improved resilience to water scarcity. Moreover, the role of root system architecture (RSA) in water-use efficiency is vital, as roots play a key role in nutrient and water uptake. Genetic engineering techniques offer promising avenues to introduce desirable RSA traits in wheat to enhance drought tolerance. These technologies enable targeted modifications in DNA sequences, facilitating the development of drought-tolerant wheat germplasm. The article highlighted the techniques that could play a role in mitigating drought stress in wheat.

Human antigen R: Exploring its inflammatory response impact and significance in cardiometabolic disorders.

RNA-binding proteins (RBPs) play a crucial role in the regulation of posttranscriptional RNA networks, which can undergo dysregulation in many pathological conditions. Human antigen R (HuR) is a highly researched RBP that plays a crucial role as a posttranscriptional regulator. HuR plays a crucial role in the amplification of inflammatory signals by stabilizing the messenger RNA of diverse inflammatory mediators and key molecular players. The noteworthy correlations between HuR and its target molecules, coupled with the remarkable impacts reported on the pathogenesis and advancement of multiple diseases, position HuR as a promising candidate for therapeutic intervention in diverse inflammatory conditions. This review article examines the significance of HuR as a member of the RBP family, its regulatory mechanisms, and its implications in the pathophysiology of inflammation and cardiometabolic illnesses. Our objective is to illuminate potential directions for future research and drug development by conducting a comprehensive analysis of the existing body of research on HuR.

Genotypic analysis of hepatitis E virus (HEV) from sporadic symptomatic cases in Pakistan.

Pakistan is the fifth most populous nation in the world and faces several challenges, including devastating floods, sub-optimal sanitary conditions, clustered accommodations, and unregulated cross-border movements. These drastic population shifts make it vulnerable to the efficient spread of the Hepatitis E virus (HEV). The current study analyzed the genotypic characteristics and variants of the Hepatitis E virus circulating in the population of Pakistan. A total of 75 ELISA-IgM positive samples were collected from three metropolitan cities: Lahore, Peshawar, and Karachi, and subjected to viral RNA extraction. The amplification of the HEV RNA-dependent RNA polymerase (RdRp) region was done using Nested PCR and degenerate primers. Out of the total, 40% of the samples were positive for HEV RNA. Sequencing and phylogenetic analysis identified the new HEV isolates as Subtype 1 g, a subtype within an existing HEV genotype 1. This shift warrants investigation into its impact on clinical manifestation and disease severity. Importantly, this study marks the first HEV subtype analysis in Pakistan, contributing valuable insights into subtype diversity and prevalence in the region.

Harnessing root exudates for plant microbiome engineering and stress resistance in plants.

A wide range of abiotic and biotic stresses adversely affect plant's growth and production. Under stress, one of the main responses of plants is the modulation of exudates excreted in the rhizosphere, which consequently leads to alterations in the resident microbiota. Thus, the exudates discharged into the rhizospheric environment play a preponderant role in the association and formation of plant-microbe interactions. In this review, we aimed to provide a synthesis of the latest and most pertinent literature on the diverse biochemical and structural compositions of plant root exudates. Also, this work investigates into their multifaceted role in microbial nutrition and intricate signaling processes within the rhizosphere, which includes quorum-sensing molecules. Specifically, it explores the contributions of low molecular weight compounds, such as carbohydrates, phenolics, organic acids, amino acids, and secondary metabolites, as well as the significance of high molecular weight compounds, including proteins and polysaccharides. It also discusses the state-of-the-art omics strategies that unveil the vital role of root exudates in plant-microbiome interactions, including defense against pathogens like nematodes and fungi. We propose multiple challenges and perspectives, including exploiting plant root exudates for host-mediated microbiome engineering. In this discourse, root exudates and their derived interactions with the rhizospheric microbiota should receive greater attention due to their positive influence on plant health and stress mitigation.

Study Comparing Topical Ivermectin Versus Topical Permethrin in the Treatment of Scabies.

Introduction Scabies is a highly contagious skin disease caused by an ectoparasite mite called Sarcoptes scabiei. Ivermectin and permethrin have been commonly used for the treatment of scabies. However, topical ivermectin has been compared to other treatment modalities to a lesser extent. Objective This study aimed to compare the efficacy of topical ivermectin versus topical permethrin in the treatment of uncomplicated scabies. Methods 354 patients with scabies attending the dermatology outpatient department of Pak Emirates Military Hospital Rawalpindi were enrolled. Patients were divided into two groups randomly. The first group and their family contacts received 1% ivermectin lotion whereas the other received 5% permethrin lotion. Patients were evaluated at the end of the second and the fourth week. Results At the end of the second week, initial follow-up showed that 97 out of 159 patients (61.0%) in the ivermectin 1% group, and 107 out of 159 patients (67.3%) in the permethrin 5% group had achieved clinical cure (P=0.24). On the final follow-up at the end of Week 4, the cure rate amounted to 85.5% (136 of 159 patients) in the ivermectin group and 89.9% (143 of 159 patients) in the permethrin group. Differences among both groups remained statistically insignificant (P=0.23). Conclusions The use of ivermectin 1% versus permethrin 5% as topical therapy showed almost identical results for the treatment of uncomplicated scabies. Side effects were minimal and there were no significant differences observed in patients with regard to compliance among both the groups.

Estimating access to surgical care: A community centered national household survey from Pakistan.

Pakistan is a lower middle-income country in South Asia with a population of 225 million. No estimate for surgical care access exists for the country. We postulate the estimated access to surgical care is less than the minimum 80% to be achieved by 2030. We conducted a randomized, stratified two-stage cluster household survey. A sample of 770 households was selected using 2017 census frames from the Pakistan Bureau of Statistics. Data was collected on choice of hospital and travel time to the chosen hospital for C-section, laparotomy, open fracture repair (OFR), and specialized surgery. Analysis was conducted using Stata 14. Access to all Bellwether surgeries (C-section, laparotomy, and open fracture repair) in Pakistan is estimated to be 74.8%. However, estimated access in rural areas and the provinces of Balochistan, Khyber Pakhtunkhwa (KP) and Sindh is far less than in urban areas and in Punjab and Islamabad. Estimated access to C-sections is more compared to OFR, laparotomy, and specialized surgery. Health system strengthening efforts should focus on improving surgical care access in rural areas and in Balochistan, KP, and Sindh. More focus is required on standardizing the availability and quality of surgical services in secondary-level hospitals.

Plant breeding for harmony between sustainable agriculture, the environment, and global food security: an era of genomics-assisted breeding.

MAIN CONCLUSION: Genomics-assisted breeding represents a crucial frontier in enhancing the balance between sustainable agriculture, environmental preservation, and global food security. Its precision and efficiency hold the promise of developing resilient crops, reducing resource utilization, and safeguarding biodiversity, ultimately fostering a more sustainable and secure food production system. Agriculture has been seriously threatened over the last 40 years by climate changes that menace global nutrition and food security. Changes in environmental factors like drought, salt concentration, heavy rainfalls, and extremely low or high temperatures can have a detrimental effects on plant development, growth, and yield. Extreme poverty and increasing food demand necessitate the need to break the existing production barriers in several crops. The first decade of twenty-first century marks the rapid development in the discovery of new plant breeding technologies. In contrast, in the second decade, the focus turned to extracting information from massive genomic frameworks, speculating gene-to-phenotype associations, and producing resilient crops. In this review, we will encompass the causes, effects of abiotic stresses and how they can be addressed using plant breeding technologies. Both conventional and modern breeding technologies will be highlighted. Moreover, the challenges like the commercialization of biotechnological products faced by proponents and developers will also be accentuated. The crux of this review is to mention the available breeding technologies that can deliver crops with high nutrition and climate resilience for sustainable agriculture.

Pneumatic Retinopexy: An Experience of 12 Years at a Tertiary Care Hospital.

Purpose The purpose of this study is to retrospectively analyze single-operation success (SOS) rates of pneumatic retinopexy (PR) for the treatment of rhegmatogenous retinal detachment (RRD) and to identify the predictors of treatment outcomes. Methods Sixty-one eyes of 61 patients who underwent PR for RRD during a period of 12 years were included in this study. Patient demographics along with pre-treatment clinical characteristics were recorded. Treatment outcomes in terms of best-corrected visual acuity (BCVA) and anatomical characteristics were reported including any post-operative complications. Visual outcomes were compared according to pre-treatment characteristics and between groups of the eyes achieving SOS and those requiring additional surgery. Results SOS was achieved in 37 (61%) eyes. Twenty-four (39%) eyes required one (36%) or two (3%) additional procedures. There was no significant association between pre-treatment characteristics and treatment failure. SOS eyes had significantly better visual outcomes (P=0.002), and so did those with macula-on status (P=0.003). New/missed breaks (9.8%) and proliferative vitreoretinopathy (PVR) (4.9%) were the most common causes of failure. Conclusions We found PR to be a beneficial technique for the treatment of RRD in this cohort. PR remains the least invasive treatment modality, and as a cost-effective technique, it is especially useful in low/middle-income countries such as Pakistan.

Use of big data and machine learning algorithms to extract possible treatment targets in neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs) impact multiple aspects of an individual's functioning, including social interactions, communication, and behaviors. The underlying biological mechanisms of NDDs are not yet fully understood, and pharmacological treatments have been limited in their effectiveness, in part due to the complex nature of these disorders and the heterogeneity of symptoms across individuals. Identifying genetic loci associated with NDDs can help in understanding biological mechanisms and potentially lead to the development of new treatments. However, the polygenic nature of these complex disorders has made identifying new treatment targets from genome-wide association studies (GWAS) challenging. Recent advances in the fields of big data and high-throughput tools have provided radically new insights into the underlying biological mechanism of NDDs. This paper reviews various big data approaches, including classical and more recent techniques like deep learning, which can identify potential treatment targets from GWAS and other omics data, with a particular emphasis on NDDs. We also emphasize the increasing importance of explainable and causal machine learning (ML) methods that can aid in identifying genes, molecular pathways, and more complex biological processes that may be future targets of intervention in these disorders. We conclude that these new developments in genetics and ML hold promise for advancing our understanding of NDDs and identifying novel treatment targets.

Rise in the Number of Complex Skin Cancers Necessitates Establishing Mohs Micrographic Surgery Fellowships in Pakistan.

As more and more patients seek treatment for increasingly complicated and cosmetically challenging skin cancers, Mohs Micrographic Surgery (MMS) is now exceedingly in demand. Training in MMS could help dermatologists improve patient outcomes allowing them to handle complex lesions safely and efficiently and hence, provide the best possible care. As a result, there is an urgent need to train additional dermatologists in Mohs Surgery in order to meet the huge demand for dermatologists with imperative expertise, specifically in this field.