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To obtain a more recent and comprehensive insight into the prevalence of glomerular diseases in our patient population, medical records of 200 patients with biopsy proven glomerulonephritis (GN), between January 1994 and June 1999, at the King Khalid University Hospital, Riyadh, Saudi Arabia were analyzed. Primary glomerular disease was found to be the most prevalent, accounting for 63.5% of all glomerular diseases. Among primary glomerular diseases, focal and segmental glomerulosclerosis (FSGS) was the most common histological lesion (34.6%) and was associated with a high prevalence of hypertension (86.4%), nephrotic syndrome (68.18%), hematuria (63.6%) and renal functional impairment (27.3%). Mesangioproliferative GN was the second most common lesion (25.1%) followed by mesangiocapillary GN (15.7%), IgA nephropathy (10.2%), and minimal change disease (8.5%). Amongst secondary glomerular diseases, lupus nephritis was the most prevalent (24.5%). In conclusion, primary glomerular diseases constituted the commonest group encountered and the prevalence of FSGS was quite high with male sex and young adults predominating. FSGS was also associated with a high prevalence of end-stage renal disease. Further collaborative studies are necessary to explore the predisposing factors and associations of glomerular disease, especially FSGS.

Abstract The study by Mwatenga et al. found a tuberculosis (TB) prevalence of 10.2% and an HIV prevalence of 19.1% among inmates, with all TB cases co-infected with HIV. Education level, smoking history, and substance use are key predictors of coinfections. Although informative, its single-centred design and reliance on sputum samples may be insufficient for some patient groups, potentially compromising diagnostic accuracy. Expanding the study to include several jails and employing more diagnostic procedures may increase reliability and the ability to generalize. The report also notes the lack of debate on broader socioeconomic variables and structural barriers to healthcare in jails, which are crucial to understanding inmates' health challenges. Overcrowding, malnutrition, and a poor healthcare system are examples of environmental factors that probably contribute to the spread of tuberculosis and make managing HIV more difficult. Additionally, not enough is known about the dietary habits of prisoners and other health conditions like diabetes or mental health, which may have an impact on the course of HIV and TB. Future studies should take these extra characteristics into account to create more comprehensive approaches to controlling HIV coinfections and TB in prison populations. This will help build more effective therapies.

ObjectiveThis study aims to clinically and genetically assess 30 unrelated consanguineous Pakistani families from various ethnic backgrounds, all exhibiting features of neurodevelopmental disorders (NDDs).MethodsWe conducted clinical, genetic, biochemical, and molecular analyses on 30 consanguineous families with NDDs enrolled from various regions of Pakistan. The likely molecular causes of primary microcephaly and NDDs were identified. Detailed clinical investigations and molecular diagnoses were performed using whole exome sequencing (WES) of the proband, followed by Sanger sequencing for validation and segregation in the available family members of the affected families.ResultsWES identified likely disease-causing homozygous variants in 30 unrelated consanguineous families. Six families presented newly described variants in known NDD-related genes: ABAT (c.1439 T > G; p.Phe480Cys) [OMIM613163], SLC12A6 (c.2865_2865insT; p.Glu955Asnfs*5) [OMIM 218000], SHANK3 (c.1305-3_1,305-2delTT; p.Gln29-_Gly305del) [OMIM 606232], BCKDK (c.356_356insC; p.Gly119Alafs*24) [OMIM 614923], DDHD2 (c.2065G > T; p.Asp689Tyr) [OMIM 615033], ERCC2 (c.1255G > A; p.Glu419Lys) [OMIM 610756]. Additionally, 12 families had previously reported disease-causing variants associated with different types of NDDs: ATRX (c.109C > T; p.Arg37*) [OMIM 309580], GPR56 [ADGRG1] (c.1423C > T; p.Arg475*) [OMIM 606854], NAGLU (c.1694G > A; p.Arg565Gln) [OMIM 252920], DOLK (c.3G > A; p.Met1Ile) [OMIM 610768], GPT2 (c.815C > T; p.Ser272Leu) [OMIM 616281], DYNC1I2 (c.607 + 1G > A; p.?) [OMIM 618492], FBXL3 (c.885delT; p.Leu295Phefs25*) [OMIM 606220], LINGO1 (c.869G > A; p.Arg290His) [OMIM 618103], and ASPM (c.3978G > A; Trp1326*, c.9557C > G; p.Ser3186*, c.6994C > T; p.Arg2332*) [OMIM 608716]. All the identified variants showed segregation compatible with autosomal recessive inheritance.ConclusionIn the present study, we observed a high frequency of ASPM variants in the genetic analysis of 30 consanguineous families exhibiting features of NDDs, particularly those associated with autosomal recessive primary microcephaly. These findings contribute to studies on genotype–phenotype correlation, genetic counseling for families, and a deeper understanding of human brain function and development.

Video forgery detection is a critical aspect of digital forensics, addressing the challenges posed by the manipulation of video content. This paper presents a novel approach for video forgery detection using Deep Convolutional Neural Networks (DCNN). Leveraging the power of deep learning, our method aims to improve the accuracy and efficiency of object-based forgery detection in advanced video sequences. In the proposed approach, we build upon the foundation of an existing method, which utilizes Convolutional Neural Networks, and introduce innovative modifications to the DCNN architecture. These modifications include data preprocessing, network architecture, and training strategies that enhance the model’s ability to detect tampered objects in video frames. We conduct experiments on the SYSU-OBJFORG dataset, the largest object-based forged video dataset to date, with advanced video encoding standards. Our DCNN-based approach is compared with the existing method, demonstrating superior performance. The results show increased accuracy and robustness in detecting object-based video forgery. This paper not only contributes to the field of video forgery detection but also underscores the potential of deep learning, particularly DCNN, in addressing the evolving challenges of digital video manipulation. The findings open avenues for future research in the localization of forged regions and the application of DCNN in lower bitrate or lower resolution video sequences.

Here we present the detection of ultralow concentrations of biomolecules in a device made from a polycarbonate membrane containing a network of gold nanowires and using a 'contactless' impedance tomoscopy technique. The sensor comprises a thin dielectric layer with two parallel band electrodes on the one side and a micro-channel containing gold nanowires onto which the adsorption of antibodies occurs. Upon applying a high-frequency ac voltage between the two electrodes, the adsorption process occurring at the surface of the gold nanowires can be followed through contactless impedance measurements. The configuration allows the real-time detection of biomolecules with a bulk concentration in the picomolar range.

Pakistan's Emergency Medical Services (EMS) are a critical component of its healthcare system, providing pre-hospital emergency care across a nation with over 220 million people. This article explores the evolutionary journey of Pakistan's EMS, highlighting both the challenges it faces and the strides it has made, with a specific emphasis on patients experiencing out-of-hospital cardiac arrest (OHCA). To extract relevant information, we searched MEDLINE & Embase data bases using MeSH terms “Emergency Medical Services” OR “EMS” AND “Out-of-Hospital-Cardiac-Arrest” OR “OHCA” AND “Pakistan”. In addition, we also retrieved information from the EMS leadership in Pakistan through e-mails. We delve into the significance of key performance indicators for OHCA, advocate for the establishment of OHCA registries to improve patient outcomes, address regional disparities in pre-hospital care, and acknowledge the gradual progress of the EMS system.

Abstract DNA can be folded into rationally designed, unique, and functional materials. To fully realise the potential of these DNA materials, a fundamental understanding of their structure and dynamics is necessary, both in simple solvents as well as more complex and diverse anisotropic environments. Here we analyse an archetypal six-duplex DNA nanoarchitecture with single-particle cryo-electron microscopy and molecular dynamics simulations in solvents of tunable ionic strength and within the anisotropic environment of biological membranes. Outside lipid bilayers, the six-duplex bundle lacks the designed symmetrical barrel-type architecture. Rather, duplexes are arranged in non-hexagonal fashion and are disorted to form a wider, less elongated structure. Insertion into lipid membranes, however, restores the anticipated barrel shape due to lateral duplex compression by the bilayer. The salt concentration has a drastic impact on the stability of the inserted barrel-shaped DNA nanopore given the tunable electrostatic repulsion between the negatively charged duplexes. By synergistically combining experiments and simulations, we increase fundamental understanding into the environment-dependent structural dynamics of a widely used nanoarchitecture. This insight will pave the way for future engineering and biosensing applications.

Abstract Sweet potato feathery mottle virus (SPFMV) and Sweet potato mild mottle virus (SPMMV) are members of the genera Potyvirus and Ipomovirus, family Potyviridae, sharing Ipomoea batatas as common host, but transmitted, respectively, by aphids and whiteflies. Virions of family members consist of flexuous rods with multiple copies of a single coat protein (CP) surrounding the RNA genome. Here we report the generation of virus-like particles (VLPs) by transient expression of the CPs of SPFMV and SPMMV in the presence of a replicating RNA in Nicotiana benthamiana. Analysis of the purified VLPs by cryo-electron microscopy, gave structures with resolutions of 2.6 and 3.0 Å, respectively, showing a similar left-handed helical arrangement of 8.8 CP subunits per turn with the C-terminus at the inner surface and a binding pocket for the encapsidated ssRNA. Despite their similar architecture, thermal stability studies reveal that SPMMV VLPs are more stable than those of SPFMV.

In the underlying work, the problems faced during message dissemination in the conventional Vehicular Energy Networks (VENs) like lack of security, breach of personal identities, absence of trust between vehicle owners, etc., are tackled. In this study, a Blockchain (BC) based announcement system is proposed for VENs to ensure secure and reliable announcement dissemination in the proposed network. The proposed system is a three-layered system comprising message dissemination layer, storage layer and BC layer. In the first layer, all the vehicles are registered through a Certificate Authority (CA), which ensures only the legitimate vehicles become part of the proposed network and interact with each other. Later, in the second layer, the data sent by the vehicles is stored at the artificial intelligence based Interplanetary File System (IPFS), which is incorporated with the Road Side Units (RSUs). This ensures reduction in storage cost and data availability. Besides, vehicle owners’ privacy is ensured by concealing the real identities of the vehicles. Moreover, the hashes of the data stored in the IPFS are stored in BC in the third layer. Also, lightweight trustworthiness verification of the vehicles, reputation based incentivization and concealing predictable trends in vehicles’ reputation scores are performed in the same layer. Overall, the novelty of the proposed work lies in the fact that the proposed system efficiently tackles different problems encountered in the existing systems simultaneously. Through extensive simulations, it is inferred that the computational time is reduced by 15–18% and the storage overhead is reduced by 80–85%, respectively when storing hash of data on the BC network as compared to storing actual data on the network.

AIM: To investigate the genetic basis of autosomal recessive retinitis pigmentosa (arRP) in two consanguineous/ endogamous Pakistani families. METHODS: Whole exome sequencing (WES) was performed on genomic DNA samples of patients with arRP to identify disease causing mutations. Sanger sequencing was performed to confirm familial segregation of identified mutations, and potential pathogenicity was determined by predictions of the mutations' functions. RESULTS: A novel homozygous frameshift mutation [NM_000440.2:c.1054delG, p. (Gln352Argfs*4); Chr5:g.149286886del (GRCh37)] in the PDE6A gene in an endogamous family and a novel homozygous splice site mutation [NM_033100.3:c.1168-1G>A, Chr10:g.85968484G>A (GRCh37)] in the CDHR1 gene in a consanguineous family were identified. The PDE6A variant p. (Gln352Argfs*4) was predicted to be deleterious or pathogenic, whilst the CDHR1 variant c.1168-1G>A was predicted to result in potential alteration of splicing. CONCLUSION: This study expands the spectrum of genetic variants for arRP in Pakistani families.

Replicative hexameric helicases are fundamental components of replisomes. Here the authors resolve a cryo-EM structure of the E1 helicase from papillomavirus bound to a DNA replication fork, providing insights into the mechanism of DNA unwinding by these hexameric enzymes.

BACKGROUND: Although tyrosine kinase inhibitors (TKIs) are the gold standard in clinical management of chronic myeloid leukemia, it is not feasible to use these drugs in at least some cases when patients are resistance to all available TKIs due to compound BCR-ABL mutations, due to patient safety profile or due to the nonavailability of drugs in developing countries on account of cost or logistic issues. We reported earlier that interferon alpha can eradicate compound BCR-ABL mutations and induce stable responses. Here, we report a follow-up of this study. PATIENTS AND METHODS: Some chronic myeloid leukemia (CML) patients did not get TKIs directly because of very high cost of imatinib and were given interferon alpha (experimental group) until the provision of imatinib free of cost through GLIVEC® International Patient Assistance Program while the other groups of patients (control group) were directly given imatinib. A very sensitive allele-specific polymerase chain reaction was employed to detect BCR-ABL compound mutations before treatment and confirmation of mutations was carried out using reliable molecular assays. Mutations were reinvestigated at all important time points during the long-term follow-up studies. RESULTS: The use of interferon-alpha for 6 months prior to TKIs eradicated compound BCR-ABL mutations (Phe311Val/Met351Thr and Thr315Ile/Phe311Val/Met351Thr) and provided deep molecular responses without any progression or mortality in CML patients (experimental group) as compared with patients who did not use interferon and was directly given TKIs (control group). CONCLUSIONS: Interferon alpha can eradicate highly resistant BCR-ABL mutations and lead to durable deep molecular responses to TKIs in CML. Therefore, interferon-alpha is recommended for CML patients with compound mutations resistant to TKIs, specifically in those scenarios where some TKIs are not available or not safe to use for CML patients. Our long-term follow-up study is well supported by recently published literature.

IntroductionA subset of individuals with COVID-19 can suffer from a severe form of the disease requiring breathing support for respiratory failure and even death due to disease complications. COVID-19 disease severity can be attributed to numerous factors, where several studies have associated changes in the expression of serum pro-inflammatory cytokines with disease severity. However, very few studies have associated the changes in expression of pro-inflammatory changes in the nasopharyngeal milieu with disease severity. Therefore, in the current study, we performed differential gene expression analysis of various pro-inflammatory cytokines in the nasopharyngeal milieu of mild & severe COVID-19 cases.Material and methodFor this retrospective, cross-sectional study, a total of 118 nasopharyngeal swab samples, previously collected from mild and severe (based on the WHO criteria) COVID-19 patients were used. A real-time qPCR was performed to determine the viral loads and also evaluate the mRNA expression of eight cytokines (IL-1, IL-2, IL-4, IL-6, IL-10, IFN-γ, TGF-β1, and TNF-α). Subsequently, an unpaired T-test was applied to compare the statistical difference in mean expression of viral loads and each cytokine between the mild and severe groups, while the Pearson correlation test was applied to establish a correlation between disease severity, viral load, and cytokines expression. Similarly, a multivariable logistic regression analysis was performed to assess the relationship between different variables from the data and disease severity.ResultsOut of 118 samples, 71 were mild, while 47 were severe. The mean viral load between the mild and severe groups was comparable (mild group: 27.07± 5.22; severe group: 26.37 ±7.89). The mRNA expression of cytokines IL-2, IL-6, IFN- γ, and TNF-α was significantly different in the two groups (pConclusionThis decreased expression of certain cytokines (IL-2, IL-6, TNF-α, and IFN-γ) in the nasopharyngeal milieu may be considered early biomarkers for disease severity in COVID-19 patients.

Ampullary cancers are rare accounting for 0.2% of all gastrointestinal cancers. Signet ring is a rare variant of adenocarcinoma, characterized by having more than 50% of mucin secreting cells and clinically having a worse prognosis. We present the case of a teenage girl with this tumor, the youngest ever reported in medical literature. An 18 years old girl with no significant past medical history presented to our clinic with symptoms of upper abdominal pain and jaundice. Her upper GI endoscopy showed an ampullary lesion which was biopsied—diagnosing it as adenocarcinoma. She underwent a pancreato-duodenectomy (Whipple’s procedure) with Child’s reconstruction and a feeding jejunostomy. Her final histopathology report was documented as infiltrating adenocarcinoma of Signet Ring variety arising from the Ampulla of Vater. Being such a rare entity, there is a lack of randomized trials advising the optimum treatment for such cases. Till then anecdotal experiences will drive the optimum management of this rare disease.

Abstract Background Parathyroid cancer is a rare cause of primary hyperparathyroidism. It presents a diagnostic and therapeutic challenge that may not be recognized preoperatively, and is often not conclusively identified during the operation. We present the case of a lady with backache and hypercalcemia, but with inadequate work-up for her condition for several years. Case presentation A middle aged lady of Asian descent presented with backache. Initial work up revealed mild hypercalcemia, negative work up for multiple myeloma, negative sestamibi scan for parathyroid pathology. A phenomenally elevated parathormone (PTH) level—2105 pg/mL (16–87 pg/mL), and rising serum calcium, 15.1 mg/dL, (8.6–10.5 mg/dL), ordered years later prompted a repeat sestamibi scan and ultrasonography of neck. Based on these investigations, a diagnosis of primary hyperparathyroidism, with high suspicion of parathyroid cancer was made. The patient underwent surgical tumour resection, with subsequent histopathological confirmation of diagnosis. Conclusion In the setting of hypercalcemia, PTH level assessment is a must. This helps to differentiate between the parathyroid dependant and independent causes of high serum calcium, thereby encouraging a comprehensive pathway to the work up of the cause of hypercalcemia. The parathyroid cancer is a very rare cause of hypercalcemia, which needs to be considered in the differentials of primary hyperparathyroidism, particularly in the setting of high PTH levels.

Widespread antibiotic resistance has returned attention to bacteriophages as a means of managing bacterial pathogenesis. Synthetic biology approaches to engineer phages have demonstrated genomic editing to broaden natural host ranges, or to optimise microbicidal action. Gram positive pathogens cause serious pastoral animal and human infections that are especially lethal in newborns. Such pathogens are targeted by the obligate lytic phages of the Salasmaviridae and Guelinviridae families. These phages have relatively small ~20 kb linear protein-capped genomes and their compact organisation, relatively few structural elements, and broad host range, are appealing from a phage-engineering standpoint. In this study, we focus on portal proteins, which are core elements for the assembly of such tailed phages. The structures of dodecameric portal complexes from Salasmaviridae phage GA1, which targets Bacillus pumilus, and Guelinviridae phage phiCPV4 that infects Clostridium perfringens, were determined at resolutions of 3.3 Å and 2.9 Å, respectively. Both are found to closely resemble the related phi29 portal protein fold. However, the portal protein of phiCPV4 exhibits interesting differences in the clip domain. These structures provide new insights on structural diversity in Caudovirales portal proteins and will be essential for considerations in phage structural engineering.

Background: Chronic myeloid leukemia (CML) is initiated in bone marrow due to chromosomal translocation t(9;22) leading to fusion oncogene BCR-ABL. Targeting BCR-ABL by tyrosine kinase inhibitors (TKIs) has changed fatal CML into an almost curable disease. Despite that, TKIs lose their effectiveness due to disease progression. Unfortunately, the mechanism of CML progression is poorly understood and common biomarkers for CML progression are unavailable. This study was conducted to find novel biomarkers of CML progression by employing whole-exome sequencing (WES). Materials and Methods: WES of accelerated phase (AP) and blast crisis (BC) CML patients was carried out, with chronic-phase CML (CP-CML) patients as control. After DNA library preparation and exome enrichment, clustering and sequencing were carried out using Illumina platforms. Statistical analysis was carried out using SAS/STAT software version 9.4, and R package was employed to find mutations shared exclusively by all AP-/BC-CML patients. Confirmation of mutations was carried out using Sanger sequencing and protein structure modeling using I-TASSER followed by mutant generation and visualization using PyMOL. Results: Three novel genes (ANKRD36, ANKRD36B and PRSS3) were mutated exclusively in all AP-/BC-CML patients. Only ANKRD36 gene mutations (c.1183_1184 delGC and c.1187_1185 dupTT) were confirmed by Sanger sequencing. Protein modeling studies showed that mutations induce structural changes in ANKRD36 protein. Conclusions: Our studies show that ANKRD36 is a potential common biomarker and drug target of early CML progression. ANKRD36 is yet uncharacterized in humans. It has the highest expression in bone marrow, specifically myeloid cells. We recommend carrying out further studies to explore the role of ANKRD36 in the biology and progression of CML.

Background: Cervical radiculopathy is a condition of pain and sensorimotor deficits due to cervical nerve root compression. The symptoms may include weakness, tingling, numbness and pain. C6, C7 nerve roots are most involved in cervical radiculopathy. Various modalities and therapeutic interventions are used and recommended for management of cervical radiculopathy including cervical collars, immobilization, manipulation, cervical traction TENS and therapeutic exercises.The aimof this study is to evaluate the efficacy of neurodynamics in comparison to manual traction in the management of cervical radiculopathy. Methods: An Interventional research was performed in the Department of Physiotherapy, Mayo hospital Lahore, Pakistan. 40 subjects aged between 18-60 years participated in the study. They were divided into two groups namely Group A and Group B with 20 subjects in each group. The duration of the study was 4 weeks with 4 sessions per week. GroupA received neurodynamics along with strengthening exercises while Group B received manual traction along with strengthening exercises. Neck Disability Index (NDI) scale was used as an outcome measure andpaired sample t-test was used for statistical analysis. Results: A significant improvement was found in both neurodynamics group and manual traction group for pain and functional status with p value< 0.05. Conclusion: This study concluded that the treatment techniques, neurodynamics and manual traction were effective in alleviating the symptoms associated with cervical radiculopathy in terms of decreasing pain intensity, increasing ranges of motion and improving functional capacity.

A 40-year-old premenopausal female presented with foul-smelling per vaginal discharge for 3 months. Diagnostic work revealed a locally advanced primary malignant melanoma of uterine cervix. The patient declined pelvic surgery and was treated with Dacarbazine. Malignant melanoma is a rare tumour of skin and has been ranked in the top ve cancers of Australia and Sweden. It is a tumour of melanocytes which forms melanin pigment in the skin. In men, the most common site is trunk while in females common site is limbs. However, melanoma can arise from mucosal surfaces where the melanocytes are present. Most common mucosal sites are head and neck followed by female genital tract. Key words: Cervix, dacarbazine, malignant melanoma