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*

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.

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.

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.

Soil transmitted helminth (STH) infection is a major public health concern among the indigenous children of Malaysia. Precarious living conditions at home including unavailability of water, drinking of contaminated water, poor sanitation and livestock presence, are known risk factors for the infection. In order to provide better living conditions, these children are enrolled in boarding schools. This study was conducted to determine whether boarding schools is a solution in reducing soil transmitted helminth infection among Orang Asli children in Sg Siput, Perak, Malaysia. An analytical cross-sectional study was conducted among 204 schoolchildren aged 7-17 years from three boarding schools in Sungai Siput, Perak from January to March 2017. Stool samples were collected and examined using direct smear and Kato-Katz technique. Information on sociodemographic and environmental conditions were collected using a modified Demographic Health Survey (DHS) questionnaire. Data analysis was done using IBM SPSS Statistics Processor 20.0.Out of a total of 204 children, only 48% (n= 97) were infected with at least one type of STH species which showed a reduced prevalence as compared to previous studies conducted among home dwelling schoolchildren with overall prevalence of 78-97%. Majority of the children had monoparasitism (31%; n=63) with moderate intensity by T trichuira (n=51, 25%). Univariate analysis shows that unavailability of water at home has a statistically significant association with STH infection among boarding school children (OR=0.73; 95% CI= 0.56-0.95 p=0.021). Multivariate analysis proves children who had unavailability of water at home has 2.1 times more likelihood of getting an STH infection (OR= 2.08; 95%CI= 1.07-4.07; p= 0.032).This study demonstrates a reduced STH prevalence among Orang Asli boarding school children as better living condition there limits the spread of STH infection among them.