Exploring the therapeutic potential of prolinamides as multi-targeted agents for Alzheimer's disease treatment: molecular docking and molecular dynamic simulation studies.

Alzheimer's disease (AD) presents a significant global health challenge, with its prevalence expected to rise sharply in the coming years. Despite extensive research, effective treatments addressing the multifaceted pathophysiology of AD remain elusive. This study investigates the therapeutic potential of twenty-seven prolinamides (P1 - P27), with the focus on their interactions with key proteins implicated in AD pathogenesis. Four of the compounds, namely; 10-((4-nitrophenyl)prolyl)-10 H-phenothiazine (P14), 2-((4-nitrophenyl)prolyl)isoindoline (P19), 1-(4-formylphenyl)-N-(p-tolyl)pyrrolidine-2-carboxamide (P22), and N,1-bis(4-nitrophenyl)pyrrolidine-2-carboxamide (P27) showed promising potential as Alzheimer's drug. In-silico approaches including molecular docking, molecular dynamic (MD) simulation, post md study, physicochemical and drug-likeness parameters were employed to ascertain the potential of these compounds as inhibitors of certain proteins implicated in the pathophysiology of Alzheimer's disease. Molecular docking and dynamics simulations demonstrated that P14, P19, P22 and P27 exhibited promising binding affinities towards crucial AD-associated proteins, including Beta-Secretase 1 (BACE1), Butyrylcholinesterase (BuChE), and Tau-tubulin kinase 2 (TTBK2). Structural stability analyses revealed that prolinamides, particularly P22 and P27 for BACE1 and P14 and P19 for BuChE, exhibited greater stability than their reference ligands, indicated by lower RMSD, RoG, and RMSF values. For BuChE, Rivastigmine had a docking score of -7.0 kcal/mol, a binding free energy (ΔGbind) of -22.19 ± 2.44 kcal/mol, RMSD of 1.361 ± 0.162 Å, RMSF of 9.357 ± 3.212 Å, and RoG of 22.919 ± 0.064 Å, whereas P19 exhibited a superior docking score of -10.3 kcal/mol, a significantly better ΔGbind of -33.74 ± 2.84 kcal/mol, RMSD of 1.347 ± 0.132 Å, RMSF of 8.164 ± 2.748 Å, and RoG of 22.868 ± 0.070 Å. Physicochemical and pharmacokinetic assessments affirmed the drug-likeness and bioavailability of P19 notably capable of penetrating the blood-brain barrier. Compounds P19 and P22, emerged as multi-targeted ligands, offering the potential for simultaneous modulation of multiple AD-related pathways. These findings highlight the possibilities of these compounds to be explored as novel therapeutic agents for AD. They also highlight the need for further experimental validation to confirm their efficacy and safety profiles, advancing them toward clinical application in AD management. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00250-z.

Pharmacokinetics of extended-release clarithromycin in patients with Mycobacterium ulcerans infection.

Clarithromycin extended-release (CLA-ER) was used as companion drug to rifampicin (RIF) for Mycobacterium ulcerans infection in the intervention arm of a WHO drug trial. RIF enhances CYP3A4 metabolism, thereby reducing CLA serum concentrations, and RIF concentrations might be increased by CLA co-administration. We studied the pharmacokinetics of CLA-ER at a daily dose of 15 mg/kg combined with RIF at a dose of 10 mg/kg in a subset of trial participants, and compared these to previously obtained pharmacokinetic data. Serial dried blood spot samples were obtained over a period of ten hours, and analyzed by LC-MS/MS in 30 study participants-20 in the RIF-CLA study arm, and 10 in the RIF-streptomycin study arm. Median CLA Cmax was 0.4 mg/L-and median AUC 3.9 mg*h/L, following 15 mg/kg CLA-ER. Compared to standard CLA dosed at 7.5 mg/kg previously, CLA-ER resulted in a non-significant 58% decrease in Cmax and a non-significant 30% increase in AUC. CLA co-administration did not alter RIF Cmax or AUC. Treatment was successful in all study participants. No effect of CLA co-administration on RIF pharmacokinetics was observed. Based on our serum concentration studies, the benefits CLA-ER over CLA immediate release are unclear.

Non-Cardiac Perioperative Mortality Factors at a Single Urban Veterans Affairs Medical Center.

Background: The Veterans affairs (VA) surgical quality improvement program was established to evaluate the quality of VA surgical care to over nine million United States Veterans. Patient demographics vary by region, with urban areas correlating with higher mortality rates. This study attempts to determine the factors associated with 30-day mortality at a single VA medical center in an urban setting. Methods: Patients included in the study were at least 18 years of age and underwent a surgical procedure between January 2013 and June 2023. Baseline demographics included preoperative comorbidities, American Society of Anesthesiology (ASA) class, and preoperative lab values. Clinical outcomes included postoperative mortality within 30 days of the procedure. Chi-square, t-test, ANOVA, and multivariate logistic regressions were used to determine relationships, using P < .05 to determine significance. Results: A total of 11,547 patients with complete data were included, of which 92 patients (0.8%) died within 30 days of surgery. A higher preoperative hematocrit was protective against 30-day mortality. A perioperative transfusion, bleeding disorder, chronic obstructive pulmonary disease (COPD), history of a myocardial infarction, higher ASA class, and an emergency procedure all increased the likelihood of perioperative mortality. Conclusions: Veterans who seek surgical care at Veterans Health Administration centers receive high quality care with a low mortality rate. Identifying risk factors for perioperative mortality provides the opportunity to stratify those veterans at highest risk.

Certified algorithms for equilibrium states of local quantum Hamiltonians.

Predicting observables in equilibrium states is a central yet notoriously hard question in quantum many-body systems. In the physically relevant thermodynamic limit, certain mathematical formulations of this task have even been shown to result in undecidable problems. Using a finite-size scaling of algorithms devised for finite systems often fails due to the lack of certified convergence bounds for this limit. In this work, we design certified algorithms for computing expectation values of observables in the equilibrium states of local quantum Hamiltonians, both at zero and positive temperature. Importantly, our algorithms output rigorous lower and upper bounds on these values. This allows us to show that expectation values of local observables can be approximated in finite time, contrasting related undecidability results. When the Hamiltonian is commuting on a 2-dimensional lattice, we prove fast convergence of the hierarchy at high temperature and as a result for a desired precision ε, local observables can be approximated by a convex optimization program of quasi-polynomial size in 1/ε.

Genome characterization of Rift Valley fever virus isolated from cattle, goats and sheep during interepidemic periods in Kenya.

Rift Valley fever virus (RVFV) is a mosquito-borne RNA virus of the Phlebovirus genus in the phenuviridae family. Its genome is trisegmented with small (S), medium (M) and large (L) fragments. In nature, the virus exists as a single serotype that is responsible for outbreaks of Rift Valley fever (RVF), a zoonotic disease that often occurs in Africa and the Middle East. RVFV genomes are thought to undergo both recombination and reassortment and investigations of these events is important for monitoring the emergence of virulent strains and understanding the evolutionary characteristics of this virus. The aim of this study was to characterize the genomes of RVFV isolates from cattle, sheep, and goats collected during an interepidemic period in Kenya between June 2016 and November 2021. A total of 691 serum samples from cattle (n = 144), goats (n = 185) and sheep (n = 362) were analysed at the Central Veterinary Laboratories. The competitive IgM-capture ELISA, was used to screen the samples; 205 samples (29.67%) tested positive for RVFV. Of the 205 positive samples, 42 (20.5%) were from cattle, 57 (27.8%) from goats, and 106 (51.7%) from sheep. All the IgM-positive samples were further analyzed by qPCR, and 24 (11.71%) tested positive with Ct values ranging from 14.788 to 38.286. Two samples, 201808HABDVS from sheep and 201810CML3DVS from cattle, had Ct values of less than 20.0 and yielded whole genome sequences with 96.8 and 96.4 coverage, respectively. There was no statistically significant evidence of recombination in any of the three segments and also phylogenetic analysis showed no evidence of reassortment in the two isolated RVFV segments when compared with other isolates of different lineages from previous outbreaks whose genomes are deposited in the GenBank. No evidence of reassortment leaves room for other factors to be the most probable contributors of change in virulence, pathogenicity and emergence of highly virulent strains of the RVFV.

Topical Tranexamic Acid (TXA) Decreases Time to Drain Removal, Wound Healing Complications, and Postoperative Blood Loss in Autologous Breast Reconstruction: A Retrospective Study.

Introduction: Drain placement is commonplace after many plastic surgery procedures to evacuate excess blood and fluid. Tranexamic acid (TXA) is an antifibrinolytic that has been shown to decrease bleeding and fluid production at surgical sites and can be administered orally, intravenously, and topically. The purpose of this study is to evaluate the effect of topical TXA on drain removal in abdominally based autologous breast reconstruction (ABABR). Methods: A retrospective chart review was performed on patients who underwent ABABR from August 2018 to November 2019. In 1 cohort, a 2.5% TXA solution was topically applied to the abdominal wall prior to closure. Drains were removed when output was less than 30 mL/day for 2 consecutive days. The primary outcome was days to drain removal. Secondary outcomes include daily inpatient drain output, postoperative hemoglobin levels, blood transfusions, and complications within 30 days postoperatively. Results: Eighty-three patients were included, with 47 in the control group and 36 in the TXA group. Drains were removed significantly earlier in patients who received TXA (16 days vs 23 days, P = .02). Additionally, significantly fewer patients required postoperative blood transfusions in the TXA group (2 vs 14, P = .005). Abdominal complications were fewer in the TXA group with significantly less wound healing complications (22% vs 49%, P = .01). There was no difference in flap loss or systemic thromboembolic events. Conclusion: Topical TXA use in ABABR results in earlier abdominal drain removal, less blood transfusions, and lower abdominal wound complications without an increased risk of flap loss or adverse patient outcomes.

Introduction : La mise en place d'un drain est habituelle après de nombreuses procédures de chirurgie plastique pour l'évacuation des excès de sang et de liquide. L'acide tranexamique (TXA) est un agent antifibrinolytique qui a une efficacité démontrée sur la réduction des saignements et de la production de fluides au niveau des sites chirurgicaux; il peut être administré par voie orale, par voie intraveineuse ou en application locale. L'objectif de cette étude était d'évaluer l'effet du TXA topique sur le retrait du drain après reconstruction mammaire autologue à base abdominale (ABABR). Méthodes : Un examen rétrospectif des dossiers des patients ayant subi une ABABR entre août 2018 et novembre 2019 a été effectué. Dans une cohorte, une solution de TXA à 2,5 % a été appliquée localement sur la paroi abdominale avant sa fermeture. Les drains ont été retirés quand la production est devenue inférieure à 30 mL/jour pendant 2 jours consécutifs. Le critère d'évaluation principal était le nombre de jours jusqu'au retrait du drain. Les critères de jugement secondaires étaient notamment : la production quotidienne du drain chez les patients hospitalisés, les taux d'hémoglobine postopératoires, les transfusions sanguines et les complications survenues dans les 30 jours postopératoires. Résultats : Quatre-vingt-trois patients ont été inclus, dont 47 dans le groupe contrôle et 36 dans le groupe TXA. Les drains ont été retirés significativement plus tôt chez les patients qui avaient reçu du TXA (16 jours contre 23 jours, P = 0,02). De plus, un nombre significativement inférieur de patients a nécessité des transfusions sanguines postopératoires dans le groupe TXA (2 contre 14, P = 0,005). Les complications abdominales ont été moins nombreuses dans le groupe TXA avec significativement moins de complications de cicatrisation (22 % contre 49 %, P = 0,01). Il n'y a pas eu de différence concernant la perte du lambeau cutané ou les événements thromboemboliques systémiques. Conclusion : L'utilisation topique de TXA dans l'ABABR permet un retrait plus précoce du drain abdominal, moins de transfusions sanguines et moins de complications de la plaie abdominale inférieure sans augmentation du risque de perte du lambeau cutané ou d'événements indésirables pour le patient.

Evaluation of Morphometric Measurements on Preoperative CT Angiograms to Determine Risk of Abdominal Donor Site Complications-A Retrospective Review of 174 Patients.

Introduction: Autologous breast reconstruction remains a popular surgical option following mastectomy; however, it is not without complications. Preoperative CT angiograms (CTAs) are often obtained for surgical planning, and morphometric data such as fat and muscle distribution can be measured. This study aimed to assess if CTA morphometric data predicts abdominal donor site complications in patients undergoing abdominally based autologous breast reconstruction. Methods: A retrospective cohort study was performed for patients who underwent abdominally based autologous breast reconstruction from 2013 to 2018. Along with population and operative characteristics, preoperative morphometric variables were assessed for the following: subcutaneous adipose tissue, visceral adipose tissue, skeletal muscle area and index, rectus and psoas cross-sectional area, and bone density. Statistical comparison to abdominal donor site complications was performed using logistic regression analysis for every 100-unit change. Results: A total of 174 patients were included in this study. Visceral adipose tissue was significantly associated with the development of infection (P = .005), epidermolysis (P = .031), and seroma (P = .04). Subcutaneous adipose tissue, skeletal muscle index, cross-sectional muscle area, and bone density were not associated with abdominal donor site complications. Obesity (P = .024), history of smoking (P = .049), and the number of perforators harvested (P = .035) significantly increased the likelihood of delayed abdominal healing. Conclusions: This study demonstrates that increased visceral adipose tissue, as measured by CTA, is significantly associated with an increased risk of abdominal donor site complications. CTA morphometric data and identifying high-risk patient characteristics can help guide preoperative counseling and better inform surgical risks.

Introduction : La reconstruction mammaire autologue reste une option chirurgicale appréciée après une mastectomie. Toutefois, elle ne va pas sans complications. Des angio-TDM préopératoires sont souvent effectués dans le cadre de la planification chirurgicale et les données morphométriques (comme la répartition du tissu adipeux et musculaire) peuvent être mesurées. Cette étude a eu pour but d'évaluer si les données morphométriques de la TDM prédisent les complications abdominales au site donneur chez les patientes subissant une reconstruction mammaire autologue à partir de tissus abdominaux. Méthodes : Une étude de cohorte rétrospective a été effectuée avec des patients ayant subi une reconstruction mammaire autologue à base abdominale entre 2013 et 2018. Parallèlement aux caractéristiques opératoires et de la population, les variables morphométriques préopératoires suivantes ont été évaluées : tissu adipeux sous-cutané, tissu adipeux viscéral, surface de muscle squelettique et surface transversale index, du grand droit et du psoas, densité osseuse. Une comparaison statistique aux complications du site donneur abdominal a été réalisée au moyen d'une analyse de régression logistique pour chaque changement de 100 unités. Résultats: Cent-soixante-quatorze patientes ont été incluses dans l'étude. Le tissu adipeux viscéral a été associé de manière significative avec le développement d'une infection (P = 0005), d'une épidermolyse (P = 0031 et d'un sérome (P = 0,04). Le tissu adipeux sous-cutané, l'indice de muscle squelettique, la surface musculaire transversale et la densité osseuse n'ont pas été associées à des complications abdominales du site donneur. L'obésité (P = 0024), les antécédents de tabagisme (P = 0049) et le nombre de perforantes collectées (P = 0035) ont significativement augmenté la probabilité du retard de guérison abdominales. Conclusions: Cette étude démontre que l'augmentation de tissu adipeux viscéral, mesurée par angio-TDM, est significativement associée à une augmentation du risque de complications abdominales au site donneur. Les données morphométriques de l'angio-TDM et l'identification des caractéristiques des patients à risque élevé peuvent aider à orienter les conseils préopératoires et à mieux renseigner sur les risques chirurgicaux.

Enhancing siRNA efficacy in vivo with extended nucleic acid backbones.

Therapeutic small interfering RNA (siRNA) requires sugar and backbone modifications to inhibit nuclease degradation. However, metabolic stabilization by phosphorothioate (PS), the only backbone chemistry used clinically, may be insufficient for targeting extrahepatic tissues. To improve oligonucleotide stabilization, we report the discovery, synthesis and characterization of extended nucleic acid (exNA) consisting of a methylene insertion between the 5'-C and 5'-OH of a nucleoside. exNA incorporation is compatible with common oligonucleotide synthetic protocols and the PS backbone, provides stabilization against 3' and 5' exonucleases and is tolerated at multiple oligonucleotide positions. A combined exNA-PS backbone enhances resistance to 3' exonuclease by ~32-fold over the conventional PS backbone and by >1,000-fold over the natural phosphodiester backbone, improving tissue exposure, tissue accumulation and efficacy in mice, both systemically and in the brain. The improved efficacy and durability imparted by exNA may enable therapeutic interventions in extrahepatic tissues, both with siRNA and with other oligonucleotides such as CRISPR guide RNA, antisense oligonucleotides, mRNA and tRNA.

Development of a diagnostic predictive model for determining child stunting in Malawi: a comparative analysis of variable selection approaches.

BACKGROUND: Childhood stunting is a major indicator of child malnutrition and a focus area of Global Nutrition Targets for 2025 and Sustainable Development Goals. Risk factors for childhood stunting are well studied and well known and could be used in a risk prediction model for assessing whether a child is stunted or not. However, the selection of child stunting predictor variables is a critical step in the development and performance of any such prediction model. This paper compares the performance of child stunting diagnostic predictive models based on predictor variables selected using a set of variable selection methods. METHODS: Firstly, we conducted a subjective review of the literature to identify determinants of child stunting in Sub-Saharan Africa. Secondly, a multivariate logistic regression model of child stunting was fitted using the identified predictors on stunting data among children aged 0-59 months in the Malawi Demographic Health Survey (MDHS 2015-16) data. Thirdly, several reduced multivariable logistic regression models were fitted depending on the predictor variables selected using seven variable selection algorithms, namely backward, forward, stepwise, random forest, Least Absolute Shrinkage and Selection Operator (LASSO), and judgmental. Lastly, for each reduced model, a diagnostic predictive model for the childhood stunting risk score, defined as the child propensity score based on derived coefficients, was calculated for each child. The prediction risk models were assessed using discrimination measures, including area under-receiver operator curve (AUROC), sensitivity and specificity. RESULTS: The review identified 68 predictor variables of child stunting, of which 27 were available in the MDHS 2016-16 data. The common risk factors selected by all the variable selection models include household wealth index, age of the child, household size, type of birth (singleton/multiple births), and birth weight. The best cut-off point on the child stunting risk prediction model was 0.37 based on risk factors determined by the judgmental variable selection method. The model's accuracy was estimated with an AUROC value of 64% (95% CI: 60%-67%) in the test data. For children residing in urban areas, the corresponding AUROC was AUC = 67% (95% CI: 58-76%), as opposed to those in rural areas, AUC = 63% (95% CI: 59-67%). CONCLUSION: The derived child stunting diagnostic prediction model could be useful as a first screening tool to identify children more likely to be stunted. The identified children could then receive necessary nutritional interventions.

TAZ downregulated ANXA1 expression to modulate myeloma cell interactions with bone marrow mesenchymal stromal cells.

We and others have previously shown that TAZ plays a tumor suppressive role in multiple myeloma. However, recent reports suggest that molecular crosstalk between the myeloma cells and bone marrow stromal components contributes to the myeloma cell survival and drug resistance. These reports further point to reciprocal interaction via adhesion molecules as the most prominent mechanism of intercellular crosstalk between myeloma cells and bone marrow mesenchymal stromal cells (BM-MSCs). YAP/TAZ silencing/expression has been shown to correlate across all cancers with a set of adhesion/extracellular matrix proteins. Therefore, we hypothesized that TAZ may regulate myeloma cell interaction with BM stromal cells by influencing the expression of distinct cell adhesion signatures. We used previously established TAZ myeloma cell line models, including DELTA47-pLENTI or TAZ knockout DELTA47 cells cocultured with or without BM-MSCs, as our study models. Using RNA sequencing analysis, we performed the first comprehensive screen for cell adhesion-related transcriptional targets of TAZ in multiple myeloma (MM). In doing so, we uncovered an enrichment of cell adhesion-related genes in TAZ knockout DELTA47 cells relatively to pLENTI-DELTA47 cells, including 11 genes with log2 fold change > 2 (p < 0.05), namely, ANXA1, ADGRL2, NCAM1, NCAM2, ADGRL3, CXADR, ALCAM, JAM2, KIRREL1, KIRREL2, and ADGRG7, suggesting possible relationship with TAZ. We validated ANXA1 as a bona fide target of TAZ in MM. We show that TAZ represses myeloma cell migration and interaction with BM-MSCs by transcriptionally downregulating ANXA1 expression via TEAD-dependent mechanism. Our data provide new insights into the understanding of the role of TAZ in the intercellular communication signals between myeloma cells and BM-MSCs. Our findings also suggest that ANXA1 represents a putative cell adhesion target to attenuate BM-MSC driven, tumor-promoting interaction with myeloma cells.

A landscape review of malaria vaccine candidates in the pipeline.

BACKGROUND: Globally, malaria continues to pose a major health challenge, with approximately 247 million cases of the illness and 627,000 deaths reported in 2021. However, the threat is particularly pronounced in sub-Saharan African countries, where pregnant women and children under the age of five face heightened vulnerability to the disease. As a result, the imperative to develop malaria vaccines especially for these vulnerable populations, remains crucial in the pursuit of malaria eradication. However, despite decades of research, effective vaccine development faces technical challenges, including the rapid spread of drug-resistant parasite strains, the complex parasite lifecycle, the development of liver hypnozoites with potential for relapse, and evasion of the host immune system. This review aims to discuss the different malaria vaccine candidates in the pipeline, highlighting different approaches used for adjuvating these candidates, their benefits, and outcomes, and summarizing the progress of these vaccine candidates under development. METHOD: A comprehensive web-based search for peer-reviewed journal articles published in SCOPUS, MEDLINE (via PubMed), Science Direct, WHO, and Advanced Google Scholar databases was conducted from 1990 to May 2022. Context-specific keywords such as "Malaria", "Malaria Vaccine", "Malaria Vaccine Candidates", "Vaccine Development", "Vaccine Safety", "Clinical Trials", "mRNA Vaccines", "Viral Vector Vaccines", "Protein-based Vaccines", "Subunit Vaccines", "Vaccine Adjuvants", "Vaccine-induced Immune Responses", and "Immunogenicity" were emphatically considered. Articles not directly related to malaria vaccine candidates in preclinical and clinical stages of development were excluded. RESULTS: Various approaches have been studied for malaria vaccine development, targeting different parasite lifecycle stages, including the pre-erythrocytic, erythrocytic, and sexual stages. The RTS, S/AS01 vaccine, the first human parasite vaccine reaching WHO-listed authority maturity level 4, has demonstrated efficacy in preventing clinical malaria in African children. However, progress was slow in introducing other safe, and feasible malaria vaccines through clinical trials . Recent studies highlight the potential effectiveness of combining pre-erythrocytic and blood-stage vaccines, along with the advantages of mRNA vaccines for prophylaxis and treatment, and nonstructural vaccines for large-scale production. CONCLUSION: Malaria vaccine candidates targeting different lifecycle stages of the parasite range from chemoprophylaxis vaccination to cross-species immune protection. The use of a multi-antigen, multi-stage combinational vaccine is therefore essential in the context of global health. This demands careful understanding and critical consideration of the long-term multi-faceted interplay of immune interference, co-dominance, complementary immune response, molecular targets, and adjuvants affecting the overall vaccine-induced immune response. Despite challenges, advancements in clinical trials and vaccination technology offer promising possibilities for novel approaches in malaria vaccine development.

System-agnostic prediction of pharmaceutical excipient miscibility via computing-as-a-service and experimental validation.

We applied computing-as-a-service to the unattended system-agnostic miscibility prediction of the pharmaceutical surfactants, Vitamin E TPGS and Tween 80, with Copovidone VA64 polymer at temperature relevant for the pharmaceutical hot melt extrusion process. The computations were performed in lieu of running exhaustive hot melt extrusion experiments to identify surfactant-polymer miscibility limits. The computing scheme involved a massively parallelized architecture for molecular dynamics and free energy perturbation from which binodal, spinodal, and mechanical mixture critical points were detected on molar Gibbs free energy profiles at 180 °C. We established tight agreement between the computed stability (miscibility) limits of 9.0 and 10.0 wt% vs. the experimental 7 and 9 wt% for the Vitamin E TPGS and Tween 80 systems, respectively, and identified different destabilizing mechanisms applicable to each system. This paradigm supports that computational stability prediction may serve as a physically meaningful, resource-efficient, and operationally sensible digital twin to experimental screening tests of pharmaceutical systems. This approach is also relevant to amorphous solid dispersion drug delivery systems, as it can identify critical stability points of active pharmaceutical ingredient/excipient mixtures.

Unmatched. What's Next? Is a Preliminary Year of Residency or Research Fellowship Better for Reapplicants to Plastic Surgery?

Background: Plastic and reconstructive surgery is one of the most competitive residency programs, and given the increased number of applicants for a relatively fixed number of positions, successfully matching is a challenge. Match rates have declined since 2018, with a match rate of ~55% in 2022. Two common options before reapplying are a preliminary year of residency (preliminary year) or a research fellowship. This study investigated which option is more beneficial for reapplicants seeking a successful match. Methods: This retrospective study included all applicants to an integrated plastic and reconstructive surgery residency from 2015 to 2023. Two cohorts based on reapplication strategy (research fellowship or preliminary year) were created. Demographic, applicant, and match data were collected. Pearson chi-squared, Fisher exact, and Wilcoxon rank sum testing were performed. Results: In total, 125 reapplicants were included. Seventy-one (56.8%) reapplicants pursued a preliminary year, and 29 (23.2%) completed a research fellowship. Research fellowship reapplicants had a greater mean number of first author publications (8.8 versus 3.2, P < 0.001), non-first author publications (11.3 versus 5.9, P = 0.021), poster presentations (9.7 versus 6.0, P = 0.028), and oral presentations (11.8 versus 6.4, P < 0.001). Research fellowship reapplicants were more likely to match into plastic and reconstructive surgery (PRS) than preliminary year reapplicants, with 72.4% (n = 21) of research fellowship reapplicants matching into PRS compared with 39.4% (n = 28) of preliminary year reapplicants (P = 0.003). Conclusions: Research fellowship reapplicants demonstrated greater research productivity and were almost twice as likely to match into PRS compared with preliminary reapplicants.

Preclinical antidiabetic and antioxidant effects of Erythrophleum africanum (benth.) harms in streptozotocin-induced diabetic nephropathy.

OBJECTIVES: This study investigated the antidiabetic effects of the methanolic extract of E. africanum (MEEA) stem bark on streptozotocin (STZ)-induced diabetic nephropathy (DN) in Wistar rats. METHODS: The in vitro enzyme (α-amylase) inhibitory activity of MEEA was measured using a standard procedure. Diabetic rats with fasting blood glucose above 250 mg/dL were considered diabetic and were divided into the following groups: control (distilled water-treated), diabetic-control, diabetic metformin (100 mg/kg), diabetes + MEEA (150 mg/kg), and diabetes + MEEA (300 mg/kg) via oral gavage once daily for 14 days. At the end of the experimental period, kidney tissues were collected for biochemical and histological analyses. Kidney apoptosis and marker gene expression were measured by real-time quantitative PCR. RESULTS: MEEA exhibited α-amylase inhibitory effects. MEEA significantly (p<0.05) reduced the STZ-induced increases in blood glucose, serum urea, serum creatinine, uric acid, alanine aminotransferase, alkaline phosphatase, and malondialdehyde and increased the STZ-induced decreases in superoxide dismutase, catalase, and reduced glutathione. In addition, MEEA protects against DN by significantly downregulating the mRNA expression of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP-response binding protein (CREB), and cFOS and upregulating B-cell lymphoma 2 (Bcl-2), suggesting that the nephroprotective ability of MEEA is due to the modulation of the cAMP/PKA/CREB/cFOS signaling pathway. Furthermore, MEEA treatment protected against histopathological alterations observed in diabetic rats. CONCLUSIONS: The data from this study suggest that MEEA modulates glucose homeostasis and inhibits redox imbalance in DN rats.

Hemophilic pseudotumor in the bilateral forearms: a unique case report.

Hemophilic pseudotumor (HP) is a rarely encountered cystic mass that forms as a result of repeated bleeding from extra-articular soft tissues. HP cases have been previously documented in several locations in the body, most commonly in the femur and pelvis. To date, no upper extremity case involving the bilateral forearms has been reported. The current case involves an adult male with uncontrolled hemophilia who presented with diffuse enlargement of the bilateral forearms with associated pain. Radiographs and magnetic resonance imaging (MRI) were subsequently performed revealing variable aged hemorrhagic, expansile, lytic intramedullary lesions. In keeping with the history, a subsequent radiologic diagnosis of HP was favored, among other differentials, including benign and malignant processes with biopsy confirming the diagnosis. The hemorrhagic masses were surgically excised after initial management with factor VIII replacement. This case details a unique presentation of this pathology in the bilateral forearms and highlights the diagnostic value of radiographs and MRI in diagnosis and management.

Altitude-dependent agro-ecologies impact the microbiome diversity of scavenging indigenous chicken in Ethiopia.

BACKGROUND: Scavenging indigenous village chickens play a vital role in sub-Saharan Africa, sustaining the livelihood of millions of farmers. These chickens are exposed to vastly different environments and feeds compared to commercial chickens. In this study, we analysed the caecal microbiota of 243 Ethiopian village chickens living in different altitude-dependent agro-ecologies. RESULTS: Differences in bacterial diversity were significantly correlated with differences in specific climate factors, topsoil characteristics, and supplemental diets provided by farmers. Microbiota clustered into three enterotypes, with one particularly enriched at high altitudes. We assembled 9977 taxonomically and functionally diverse metagenome-assembled genomes. The vast majority of these were not found in a dataset of previously published chicken microbes or in the Genome Taxonomy Database. CONCLUSIONS: The wide functional and taxonomic diversity of these microbes highlights their importance in the local adaptation of indigenous poultry, and the significant impacts of environmental factors on the microbiota argue for further discoveries in other agro-ecologies. Video Abstract.

Genomic Epidemiology of Rift Valley Fever Virus Involved in the 2018 and 2022 Outbreaks in Livestock in Rwanda.

Rift Valley fever (RVF), a mosquito-borne transboundary zoonosis, was first confirmed in Rwanda's livestock in 2012 and since then sporadic cases have been reported almost every year. In 2018, the country experienced its first large outbreak, which was followed by a second one in 2022. To determine the circulating virus lineages and their ancestral origin, two genome sequences from the 2018 outbreak, and thirty-six, forty-one, and thirty-eight sequences of small (S), medium (M), and large (L) genome segments, respectively, from the 2022 outbreak were generated. All of the samples from the 2022 outbreak were collected from slaughterhouses. Both maximum likelihood and Bayesian-based phylogenetic analyses were performed. The findings showed that RVF viruses belonging to a single lineage, C, were circulating during the two outbreaks, and shared a recent common ancestor with RVF viruses isolated in Uganda between 2016 and 2019, and were also linked to the 2006/2007 largest East Africa RVF outbreak reported in Kenya, Tanzania, and Somalia. Alongside the wild-type viruses, genetic evidence of the RVFV Clone 13 vaccine strain was found in slaughterhouse animals, demonstrating a possible occupational risk of exposure with unknown outcome for people working in meat-related industry. These results provide additional evidence of the ongoing wide spread of RVFV lineage C in Africa and emphasize the need for an effective national and international One Health-based collaborative approach in responding to RVF emergencies.

Knowledge, Attitudes, and Practices of Antibiotic Use among Small-, Medium-, and Large-Scale Fish Farmers of the Stratum II of the Volta Lake of Ghana.

BACKGROUND: Antibiotic residue in food products and the resulting antibiotic-resistant bacteria represent a significant global public health threat. The misuse of antibiotics is a primary contributor to this issue. This study investigated the knowledge, attitudes, and practices (KAP) regarding antibiotic use among cage fish farmers on Ghana's Volta Lake. METHOD: We conducted a cross-sectional survey with 91 cage fish farmers across three scales: small, medium, and large. A semi-structured questionnaire complemented by personal observations provided comprehensive data. We used several statistical methods for analysis: Pearson Chi-Square and Spearman correlation tests to examine relationships and trends among variables, logistic regression to analyze variable interactions, and Cronbach's alpha to check internal consistency. Additionally, Kendall's coefficient was used to rank challenges, utilizing STATA and SPSS for these calculations. RESULTS: The survey revealed that 58.55% of cage fish farmers earn an average of 10,000 USD annually, with 35.16% having over 16 years of experience. From the survey, all sampled populations admitted to antibiotic applications in their farming operation. Knowledge of antibiotic types was mainly influenced by peers (46.15%), with tetracycline being the most recognized and used. There was a significant reliance on the empirical use of antibiotics, with 52.75% of farmers using them based on personal experience and 40.66% without a prescription. When initial treatments failed, 41.76% of the farmers would change or combine drugs. Older farmers (over 51 years) and those with tertiary education demonstrated significantly better KAP scores regarding antibiotic use. Strong correlations were also found among knowledge, attitudes, and practices in antibiotic usage. CONCLUSIONS: The findings indicate a need for improved education on antibiotic use among fish farmers to reduce misuse and enhance awareness of the potential consequences. This study provides foundational data for designing interventions to address these issues in the context of cage fish farming on Volta Lake.

Clinical presentation and symptomatology of Guillain-Barré syndrome: A literature review.

Guillain-Barré Syndrome (GBS) is a rare but potentially life-threatening neurological disorder characterized by acute onset ascending paralysis and sensory abnormalities. This article provides a comprehensive overview of GBS, covering its epidemiology, etiology, clinical presentation, diagnostic evaluation, management and treatment, prognosis, psychosocial impact, recent advances in research, public health implications, and ethical considerations. Epidemiological data reveal variations in GBS prevalence, incidence rates, and geographical distribution influenced by climate, infectious disease prevalence, and genetic susceptibility. Etiological factors include preceding infections, vaccinations, and autoimmune mechanisms, although the precise pathophysiology remains incomplete. Clinical presentation encompasses prodromal symptoms, motor deficits, sensory abnormalities, autonomic dysfunction, and variants such as Miller-Fisher Syndrome and Bickerstaff brainstem encephalitis. Neurological examination findings include weakness, paralysis, sensory deficits, and reflex changes, while autonomic dysfunction manifests as cardiovascular, respiratory, and gastrointestinal symptoms. Diagnostic evaluation relies on clinical criteria, laboratory tests (e.g., cerebrospinal fluid analysis, nerve conduction studies), and consideration of differential diagnoses. Management strategies encompass supportive care, immunomodulatory therapies (e.g., intravenous immunoglobulin, plasma exchange), and rehabilitation interventions to optimize functional outcomes and promote recovery. Prognosis varies depending on clinical features, treatment response, and complications such as respiratory failure and autonomic instability. Psychosocial impact encompasses psychological effects on patients and caregivers, highlighting the importance of coping strategies and support systems. Recent advances in research focus on emerging treatments, genetic predisposition, and biomarker discovery, offering promise for improving GBS outcomes. Public health implications include vaccination safety concerns and healthcare system considerations for GBS management. Ethical considerations encompass patient autonomy, resource allocation, and end-of-life decision-making.

Iron rescues glucose-mediated photosynthesis repression during lipid accumulation in the green alga Chromochloris zofingiensis.

Energy status and nutrients regulate photosynthetic protein expression. The unicellular green alga Chromochloris zofingiensis switches off photosynthesis in the presence of exogenous glucose (+Glc) in a process that depends on hexokinase (HXK1). Here, we show that this response requires that cells lack sufficient iron (-Fe). Cells grown in -Fe+Glc accumulate triacylglycerol (TAG) while losing photosynthesis and thylakoid membranes. However, cells with an iron supplement (+Fe+Glc) maintain photosynthesis and thylakoids while still accumulating TAG. Proteomic analysis shows that known photosynthetic proteins are most depleted in heterotrophy, alongside hundreds of uncharacterized, conserved proteins. Photosynthesis repression is associated with enzyme and transporter regulation that redirects iron resources to (a) respiratory instead of photosynthetic complexes and (b) a ferredoxin-dependent desaturase pathway supporting TAG accumulation rather than thylakoid lipid synthesis. Combining insights from diverse organisms from green algae to vascular plants, we show how iron and trophic constraints on metabolism aid gene discovery for photosynthesis and biofuel production.