Background: Cerebellopontine angle (CPA) tumors present surgical challenges due to their proxim-ity to the facial nerve. Despite preservation efforts, facial nerve paresis is a major issue. This study aims to identify key factors affecting facial nerve preservation during microsurgical resection of large CPA tumors in a low- and middle-income countries (LMIC) setting. Methods: This retrospective cross-sectional study, conducted at Aga Khan University, includedpatients who underwent microsurgical resection of large (>3 cm) CPA tumors with House-Brackmann (HB) grades 1–4. Postoperative facial nerve function was assessed using the HB grading system. Data was extracted from medical records and analyzed using SPSS 22. Results: This study analyzed 95 patients (M:F=1:1.16, mean age 44.24±13.71 years) withCPA tumors who underwent microsurgical resection. Common presenting complaints included a complete hearing loss (57.9%), headache (52.6%), and abnormal gait (40%). Preoperative facial nerve function was normal (HB grade I) in 75%, with 19%, 7%, and 2% having HB grades II, III, and IV, respectively. Schwannoma (69.5%), meningioma (16.8%), and epidermoid cyst (10.5%) were the most common diagnoses. Postoperative preservation of facial nerve function was achieved in 73.7% of patients. At six months, HB grades I and II were observed in 64% and 11.5%, respectively, while none had complete facial nerve palsy. On univariate analysis, larger tumor size and higher HB grade correlated with worse facial nerve outcomes (p=0.02). Complications were more frequent in patients with worsened outcomes (72% vs. 38.6%, p=0.004). However, in multivariate analysis, only preoperative HB grade was identified as a predictor. Conclusion Facial nerve preservation during CPA tumor resection is influenced by intrinsic tumorcharacteristics, surgical complexity, and patient-specific factors. Detailed preoperative counseling is crucial to set realistic expectations.

A new generation of smart nanocarriers offers excellent safety, efficiency, and targeted drug delivery for cancer immunotherapy. Conventional cancer treatments, such as radiation and chemotherapy, are often associated with severe systemic toxicity and extensive collateral damage to healthy tissues. In contrast, the enhanced permeability and retention effect and active targeting mechanisms of certain nanocarriers, such as liposomes, dendrimers, polymeric nanoparticles, and lipid-based systems, enable precise drug delivery. Therapeutic agents can be encapsulated within nanoscale delivery systems, protected from early degradation, and released in response to specific signals within the tumor microenvironment, such as changes in pH or enzyme concentrations. Targeting accuracy is further improved through surface modifications, including ligands, antibodies, or aptamers, which facilitate intracellular uptake and mitigate off-target effects. Additionally, the wide variety of nanocarrier structures available—from polymersomes and micelles to nanospheres and nanocapsules—allows customized applications tailored to different cancer types and stages. Current research highlights the potential for immunomodulatory drugs loaded into nanocarriers to enhance antitumor immunity and overcome mechanisms of immunoresistance. This review discusses the classification, processes, and biological applications of smart nanocarriers, with particular emphasis on how they can advance cancer immunotherapy by addressing challenges related to drug loading, targeted delivery, and biocompatibility.

Major depressive disorder (MDD) affects people all over the world, and yet, its etiology is complex and remains incompletely understood. In this review, we aim to assess recent advances in understanding depression and its regulation, as well as its interaction with circadian rhythms. Circadian rhythms are internalized representations of the periodic daily light and dark cycles. Accumulating evidence has shown that MDD and the related mental disorders are associated with disrupted circadian rhythms. In particular, depression has often been linked to abnormalities in circadian rhythms because dysregulation of the circadian system increases susceptibility to MDD. The fact that several rhythms are disrupted in depressed patients suggests that these disruptions are not restricted to any one rhythm but rather involve the molecular circadian clock core machinery. The sleep-wake cycle is one rhythm that is often disrupted in depression, which often leads to disturbances in other rhythms. The circadian disruptions manifested in depressed patients and the effectiveness and fast action of chronobiologically based treatments highlight the circadian system as a key therapeutic target in the treatment of depression. This review assesses the evidence on rising depression rates and examines their contributing factors, including circadian misalignment. We discuss key hypotheses underlying depression pathogenesis, potential etiology, and relevant animal models, and underscore potential mechanisms driving depression's growing burden and how understanding these factors is critical for improving prevention and treatment strategies.
Humans ; Circadian Rhythm/physiology* ; Depressive Disorder, Major/therapy* ; Animals ; Sleep/physiology* ; Depression/therapy*

Atrial fibrillation (AF) is a prevalent cardiac arrhythmia affecting millions of individuals worldwide and posing significant challenges to healthcare systems. The growing body of research has uncovered sex-related differences in AF pathophysiology, including the role of fatty acid-binding protein 4 (FABP4) and leptin as potential biomarkers. FABP4 and leptin, key adipokines involved in cardiovascular health, have been linked to inflammation, oxidative stress, and endothelial dysfunction, all of which may contribute to AF development. These adipokines exhibit sex-specific differences in their concentrations, with females generally showing higher FABP4 levels and males displaying distinct leptin profiles. Furthermore, hormonal influences, particularly estrogen, and testosterone, play significant roles in shaping AF risk and atrial remodeling. Estrogen is associated with cardioprotective effects, while testosterone may exert proarrhythmic effects. Understanding these sex-specific mechanisms could lead to more tailored and effective clinical management of AF. The future of AF research holds promise for precision medicine, novel therapeutic targets, artificial intelligence integration, and personalized care approaches. Emphasizing patient-centered care, telemedicine, and multidisciplinary collaboration can further enhance AF management and improve patient outcomes. In conclusion, recognizing and addressing sex-related factors in AF pathophysiology offer opportunities for gender-responsive interventions and advancements in AF management. Implementing these insights may pave the way for targeted therapies and improved quality of life for individuals affected by AF.

Purpose: Limited data exist regarding outcome and morbidity associated with portosystemic shunts in the pediatric transplant population. Our study assesses the outcomes of pediatric patients who underwent a portosystemic shunt procedure, both with and without liver transplantation (LT). Methods: This study retrospectively reviewed the medical records of pediatric patients aged 0–19 years who underwent shunt placement between 2003 and 2017 at a tertiary care center.The analysis included cases of shunt placement with or without LT. Results: A total of 13 pediatric patients were included in the study with median age of 8.8 years. Among the cases, 11 out of 13 (84.6%) underwent splenorenal shunt, 1 (7.7%) underwent a mesocaval shunt, and another 1 (7.7%) underwent a Modified Rex (mesoportal) shunt. Additionally, 5 out of 13 (38.5%) patients had LT, with 4 out of 5 (80.0%) receiving the transplant before shunt placement, and 1 out of 5 (20.0%) receiving it after shunt placement.Gastrointestinal bleeding resulting from portal hypertension was the indication in all cases.A total of 10 complications were reported in 5 patients; the most common complication was anemia in 3 (23.1%) patients. At the most recent follow-up visit, the shunts were functional without encephalopathy, and no deaths were reported. Conclusion Shunt placement plays a crucial role in the management of patients with portal hypertension. Our study demonstrates favorable long-term outcomes in pediatric patients who underwent shunt placement. Long term shunt outcomes were similar and unremarkable in patients with LT and without LT.

OBJECTIVE: To explore potential natural products against severe acute respiratory syndrome coronavirus (SARS-CoV-2) via the study of structural and non-structural proteins of human coronaviruses. METHODS: In this study, we performed an in-silico survey of 25 potential natural compounds acting against SARS-CoV-2. Molecular docking studies were carried out using compounds against 3-chymotrypsin-like protease (3CL^PRO), papain-like protease (PL^PRO), RNA-dependent RNA polymerase (RdRp), non-structural protein (nsp), human angiotensin converting enzyme 2 receptor (hACE2R), spike glycoprotein (S protein), abelson murine leukemia viral oncogene homolog 1 (ABL1), calcineurin-nuclear factor of activated T-cells (NFAT) and transmembrane protease serine 2. RESULTS: Among the screened compounds, amentoflavone showed the best binding affinity with the 3CL^PRO, RdRp, nsp13, nsp15, hACE2R. ABL1 and calcineurin-NFAT; berbamine with hACE2R and ABL1; cepharanthine with nsp10, nsp14, nsp16, S protein and ABL1; glucogallin with nsp15; and papyriflavonol A with PL^PRO protein. Other good interacting compounds were juglanin, betulinic acid, betulonic acid, broussooflavan A, tomentin A, B and E, 7-methoxycryptopleurine, aloe emodin, quercetin, tanshinone I, tylophorine and furruginol, which also showed excellent binding affinity towards a number of target proteins. Most of these compounds showed better binding affinities towards the target proteins than the standard drugs used in this study. CONCLUSION Natural products or their derivatives may be one of the potential targets to fight against SARS-CoV-2.
Animals ; Antiviral Agents/therapeutic use* ; Biological Products/pharmacology* ; COVID-19/drug therapy* ; Humans ; Mice ; Molecular Docking Simulation ; SARS-CoV-2

COVID-19/virology* ; Cities ; Environmental Monitoring ; Genome, Viral ; Humans ; Infection Control/methods* ; Pakistan ; RNA, Viral/genetics* ; SARS-CoV-2/genetics* ; Sewage/virology*

Networks of synaptically connected neurons underlie all brain functions. Various cell-cell signaling and extrinsic molecules influence synapse assembly at the synaptic site. Calcium ions play a significant role in signal transduction pathways that control various neuronal functions. Multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMK II) is an important mediator of calcium signaling in neurons, it plays an essential role in controlling synaptic strength and plasticity, and it is highly expressed in the cytosol of developing neurons, especially in presynaptic neurons. However, the precise role of CaMKII in synapse formation and synaptic transmission has not yet been determined. We hypothesized that CaMKII activity could be necessary for synapse formation and synaptic transmission. To test whether CaMKII activity is required for the synapse formation and synaptic transmission, the identified neurons visceral dorsal 4 (VD4 – presynaptic) and its postsynaptic partner left pedal dorsal 1 (LPeD1) from the freshwater snail Lymnaea stagnalis were paired in soma-soma configuration in cell culture. The soma-soma paired cells recapitulated their excitatory connections in vitro. To test the possible role of CaMKII in synapse formation and synaptic transmission, the in vitro paired neurons were exposed to a CaMKII-specific inhibitor KN-93 and its inactive analog KN-92. The incidence of synapse formation and efficacy of synaptic transmission was tested electrophysiologically.

Background: There are limited studies comparing the risk of osteoporosis and fractures between different direct oral anticoagulants (DOACs) and vitamin K antagonists (VKA) in non-valvular atrial fibrillation (AF). Using a network meta-analysis (NMA), we compared osteoporotic fractures among 5 different treatment arms, viz. dabigatran, rivaroxaban, apixaban, edoxaban, and VKA. Methods: Ten studies, including 5 randomized control trials and 5 population-based studies, with a total of 321,844 patients (148,751 and 173,093 in the VKA and DOAC group, respectively) with a median follow-up of 2 years, were included. A Bayesian random-effects NMA model comparing fractures among the treatment arms was performed using MetInsight V3. Sensitivity analysis excluded studies with the highest residual deviances from the NMA model. Results: The mean age of the patients was 70 years. The meta-analysis favored DOACs over VKA with significantly lower osteoporotic fracture (odds ratio [OR], 0.77; 95% credible interval [CrI], 0.70-0.86). The NMA demonstrated that fractures were significantly lower with apixaban compared with dabigatran (OR, 0.64; 95% CrI, 0.44-0.95); however, fractures were statistically similar between apixaban and rivaroxaban (OR, 0.84; 95% CrI, 0.58-1.24) and dabigatran and rivaroxaban (OR, 1.32; 95% CrI, 0.90-1.87). Based on the Bayesian model of NMA, the probability of osteoporotic fracture was highest with VKA and lowest with apixaban, followed by rivaroxaban, edoxaban, and dabigatran. Conclusions The decision to prescribe anticoagulants in elderly patients with AF should be made not only based on thrombotic and bleeding risks but also on the risk of osteoporotic fracture; these factors should be considered and incorporated in contemporary cardiology practice.