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Health Affairs (Project Hope) Jul 2024Global supply chains for active pharmaceutical ingredients (APIs) are highly centralized in certain countries and are susceptible to supply-chain shocks. However, there...
Global supply chains for active pharmaceutical ingredients (APIs) are highly centralized in certain countries and are susceptible to supply-chain shocks. However, there is no systematic monitoring or global coordination to manage risk and ensure equitable supply continuity during public health emergencies. In this study, we applied quasi-experimental methods on shipment-level customs data to determine how prices and export volume for APIs exported from India were affected by the COVID-19 pandemic. We found that API prices for key essential medicines not used for COVID-19 did not change significantly in the year after the World Health Organization pandemic declaration, but volume decreased by 80 percent. Prices for medicines speculatively repurposed for COVID-19, such as hydroxychloroquine and ivermectin, increased by as much as 250 percent compared with prices for nonrepurposed medicines, but only ivermectin saw a decrease in volume. Systematic monitoring of API markets, investments to promote supply diversification, and legal and political reforms to disincentivize price speculation could support supply-chain resilience and safeguard access to medicines.
Topics: Humans; COVID-19; SARS-CoV-2; India; Commerce; COVID-19 Drug Treatment; Global Health; Drugs, Essential; Ivermectin; Pandemics; Internationality; Bulk Drugs
PubMed: 38950300
DOI: 10.1377/hlthaff.2023.00722 -
International Maritime Health 2024The World Health Organization (WHO) reported an estimated 249 million malaria cases globally in 2023, of which 94% were reported from Africa. Tanzania, a Sub-Saharan...
BACKGROUND
The World Health Organization (WHO) reported an estimated 249 million malaria cases globally in 2023, of which 94% were reported from Africa. Tanzania, a Sub-Saharan African country, has an exceptionally high malaria prevalence (3.6 million in 2023). The aim of the present study was to assess malaria prevalence rates in the Arusha Region, northern Tanzania. This region is famous for its national parks and wildlife reserves, and it is visited by thousands of tourists from all over the world each year. The assessment of malaria prevalence in the region is important in the context of the necessity to administer antimalarial chemoprophylaxis to international travellers.
MATERIAL AND METHODS
The study group consisted of 101 people, residents of the Karatu District in the Arusha Region, aged between 1 and 73 years, who volunteered to participate in the screening. Phase I of the study was conducted in July 2022 in the Karatu Lutheran Hospital in Karatu Town (located close to the Ngorongoro Conservation Area and the Serengeti National Park). During this phase a venous blood sample was collected from each patient. The samples were tested for malaria using a rapid diagnostic test (mRDT); the same samples were also used to measure haemoglobin concentration and next they were applied onto the Whatman FTA micro cards for further molecular diagnostics in Poland (phase II).
RESULTS
mRDT detected two (2.0%) infections caused by Plasmodium (the etiological factor of malaria), the molecular tests (RT-PCR) confirmed the two positive results by mRDT but also detected infections in six other samples (7.9% in total). The study found that six patients were infected with the Plasmodium falciparum species, while two other subjects had co-infections (P. falciparum + P. ovale, P. falciparum + P. vivax + P. malariae).
CONCLUSIONS
The study findings confirm the prevalence of malaria in areas located close to national parks in northern Tanzania and support the use of antimalarial chemoprophylaxis in international travellers visiting the area. The present study found co-infections caused by four different species of Plasmodium species which supports the prevalence of different parasitic species in Sub-Saharan Africa and is in line with CDC reports but contrary to WHO reports which estimate that 100% of malaria cases in Sub-Saharan Africa are caused by P. falciparum.
Topics: Humans; Tanzania; Prevalence; Adult; Middle Aged; Adolescent; Male; Female; Child; Aged; Young Adult; Child, Preschool; Malaria; Infant; Antimalarials
PubMed: 38949218
DOI: 10.5603/imh.100440 -
JPMA. the Journal of the Pakistan... Jun 2024
Topics: Humans; Hydroxychloroquine; Retinal Diseases
PubMed: 38949015
DOI: 10.47391/JPMA.11206 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024Infertility affects an estimated 10 to 15 percent of couples worldwide, with approximately half of the cases attributed to male-related issues. Most men diagnosed with... (Review)
Review
Infertility affects an estimated 10 to 15 percent of couples worldwide, with approximately half of the cases attributed to male-related issues. Most men diagnosed with infertility exhibit symptoms such as oligospermia, asthenospermia, azoospermia, and compromised sperm quality. Spermatogenesis is a complex and tightly coordinated process of germ cell differentiation, precisely regulated at transcriptional, posttranscriptional, and translational levels to ensure stage-specific gene expression during the development of spermatogenic cells and normal spermiogenesis. N-methyladenosine (mA) stands out as the most prevalent modification on eukaryotic mRNA, playing pivotal roles in various biological processes, including mRNA splicing, transportation, and translation. RNA methylation modification is a dynamic and reversible process primarily mediated by "writers", removed by "erasers", and recognized by "readers". In mammals, the aberrant methylation modification of mA on mRNA is associated with a variety of diseases, including male infertility. However, the precise involvement of disrupted mA modification in the pathogenesis of human male infertility remains unresolved. Intriguingly, a significant correlation has been found between the expression levels of mA regulators in the testis and the severity of sperm concentration, motility, and morphology. Aberrant expression patterns of mA regulatory proteins have been detected in anomalous human semen samples, including those of oligospermia, asthenozoospermia, and azoospermia. Furthermore, the examination of both sperm samples and testicular tissues revealed abnormal mRNA mA modification, leading to reduced sperm motility and concentration in infertile men. Consequently, it is hypothesized that dysregulation of mA modification might serve as an integral link in the mechanism of male infertility. This paper presents a comprehensive review of the recent discoveries regarding the spatial and temporal expression dynamics of mA regulators in testicular tissues and the correlation between deregulated mA regulators and human male infertility. Previous studies predominantly utilized constitutive or conditional knockout animal models for testicular phenotypic investigations. However, gene suppression in additional tissues could potentially influence the testis in constitutive knockout models. Furthermore, considering the compromised spermatogenesis observed in constitutive animals, distinguishing between the indirect effects of gene depletion on testicular development and its direct impact on the spermatogenic process is challenging, due to their intricate relationship. Such confounding factors might compromise the validity of the findings. To address this challenge, an inducible and conditional gene knockout model may serve as a superior approach. To date, nearly all reported studies have concentrated solely on the level changes of mA and its regulators in germs cells, while the understanding of the function of mA modification in testicular somatic cells remains limited. Testicular somatic cells, including peritubular myoid cells, Sertoli cells, and Leydig cells, play indispensable roles during spermatogenesis. Hence, comprehensive exploration of mA modification within these cells as an additional crucial regulatory mechanism is warranted. In addition, exploration into the presence of unique methylation mechanisms or mA regulatory factors within the testes is warranted. To elucidate the role of mA modification in germ cells and testicular somatic cells, detailed experimental strategies need to be implemented. Among them, manipulation of the levels of key enzymes involved in mA methylation and demethylation might be the most effective approach. Moreover, comprehensive analysis of the gene expression profiles involved in various signaling pathways, such as Wnt/β-catenin, Ras/MAPK, and Hippo, in mA-modified germ cells and testicular somatic cells can provide more insight into its regulatory role in the spermatogenesis process. Further research in this area could provide valuable insights for developing innovative strategies to treat male infertility. Finally, considering the mitigation impact of mA imbalance regulation on disease, investigation concerning whether restoring the equilibrium of mA modification regulation can restore normal spermatogenesis function is essential, potentially elucidating the pivotal clinical significance of mA modulation in male infertility.
Topics: Male; Humans; Adenosine; Spermatogenesis; Infertility, Male; RNA, Messenger; Methylation; Animals; Methyltransferases; Spermatozoa; Testis
PubMed: 38948273
DOI: 10.12182/20240560103 -
Theranostics 2024Device implantation frequently triggers cardiac remodeling and fibrosis, with monocyte-driven inflammatory responses precipitating arrhythmias. This study investigates...
Device implantation frequently triggers cardiac remodeling and fibrosis, with monocyte-driven inflammatory responses precipitating arrhythmias. This study investigates the role of mA modification enzymes METTL3 and METTL14 in these responses and explores a novel therapeutic strategy targeting these modifications to mitigate cardiac remodeling and fibrosis. Peripheral blood mononuclear cells (PBMCs) were collected from patients with ventricular septal defects (VSD) who developed conduction blocks post-occluder implantation. The expression of METTL3 and METTL14 in PBMCs was measured. METTL3 and METTL14 deficiencies were induced to evaluate their effect on angiotensin II (Ang II)-induced myocardial inflammation and fibrosis. mA modifications were analyzed using methylated RNA immunoprecipitation followed by quantitative PCR. NF-κB pathway activity and levels of monocyte migration and fibrogenesis markers (CXCR2 and TGF-β1) were assessed. An erythrocyte microvesicle-based nanomedicine delivery system was developed to target activated monocytes, utilizing the METTL3 inhibitor STM2457. Cardiac function was evaluated via echocardiography. Significant upregulation of METTL3 and METTL14 was observed in PBMCs from patients with VSD occluder implantation-associated persistent conduction block. Deficiencies in METTL3 and METTL14 significantly reduced Ang II-induced myocardial inflammation and fibrosis by decreasing mA modification on and mRNAs. This disruption reduced NF-κB pathway activation, lowered CXCR2 and TGF-β1 levels, attenuated monocyte migration and fibrogenesis, and alleviated cardiac remodeling. The erythrocyte microvesicle-based nanomedicine delivery system effectively targeted inflamed cardiac tissue, reducing inflammation and fibrosis and improving cardiac function. Inhibiting METTL3 and METTL14 in monocytes disrupts the NF-κB feedback loop, decreases monocyte migration and fibrogenesis, and improves cardiac function. Targeting mA modifications of monocytes with STM2457, delivered via erythrocyte microvesicles, reduces inflammation and fibrosis, offering a promising therapeutic strategy for cardiac remodeling associated with device implantation.
Topics: Humans; Methyltransferases; Monocytes; Fibrosis; Male; Animals; NF-kappa B; Erythrocytes; Adenosine; Female; Methylation; Mice; Transforming Growth Factor beta1; Cell-Derived Microparticles; Leukocytes, Mononuclear; Angiotensin II; Receptors, Interleukin-8B; Ventricular Remodeling; Myocardium; Nanomedicine
PubMed: 38948064
DOI: 10.7150/thno.95664 -
ACS Omega Jun 2024Chikungunya virus (CHIKV) has been reported in over 120 countries and is the causative agent of Chikungunya fever. The debilitating nature of this disease, which can...
Chikungunya virus (CHIKV) has been reported in over 120 countries and is the causative agent of Chikungunya fever. The debilitating nature of this disease, which can persist months to years after acute infection, drastically impacts the quality of life of patients. Yet, specific antivirals are lacking for the treatment of this disease, which makes the search for new drugs necessary. In this context, the nsP2 protease emerges as an attractive therapeutic target, and drug repurposing strategies have proven to be valuable. Therefore, we combined in silico and in vitro methods to identify known drugs as potential CHIKV nsP2 protease inhibitors with antiviral properties within DrugBank. Herein, we developed a hybrid virtual screening pipeline comprising pharmacophore- and target-based screening, drug-like, and pharmaceutical filtering steps. Six virtual hits were obtained, and two of them, capecitabine (CPB) and oxibendazole (OBZ), were evaluated against CHIKV replication in Vero cells. CPB did not present antiviral activity, whereas OBZ inhibited the replication of two different strains of CHIKV, namely, 181-25 (Asian genotype) and BRA/RJ/18 (clinical isolate from ECSA genotype). OBZ showed potent antiviral activity against the CHIKV BRA/RJ/18 (EC = 11.4 μM) with a high selectivity index (>44). Analogs of OBZ (albendazole, fenbendazole, and mebendazole) were also evaluated, but none exhibited anti-CHIKV activity, and further, their stereoelectronic features were analyzed. Additionally, we observed that OBZ acts mainly at post-entry steps. Hence, our results support further in vivo studies to investigate the antiviral potential of OBZ, which offers a new alternative to fight CHIKV infections.
PubMed: 38947813
DOI: 10.1021/acsomega.4c03417 -
Analytical Cellular Pathology... 2024Biliary atresia (BA) is a devastating congenital disease characterized by inflammation and progressive liver fibrosis. Activation of hepatic stellate cells (HSCs) plays...
BACKGROUND
Biliary atresia (BA) is a devastating congenital disease characterized by inflammation and progressive liver fibrosis. Activation of hepatic stellate cells (HSCs) plays a central role in the pathogenesis of hepatic fibrosis. Our study aimed to investigate the pharmacological effect and potential mechanism of pirfenidone (PFD) and andrographolide (AGP) separately and together on liver fibrosis of BA.
MATERIALS AND METHODS
The bile ducts of male C57BL/6J mice were ligated or had the sham operation. The effects of PFD and/or AGP on liver fibrosis of BA were evaluated. Human hepatic stellate cells (LX-2) were also treated with PFD and/or AGP .
RESULTS
PFD and/or AGP ameliorates liver fibrosis and inflammation in the mice model of BA, as evidenced by significant downregulated in the accumulation of collagen fibers, hepatic fibrosis markers (-SMA, collagen I, and collagen IV), and inflammatory markers (IL-1, IL-6, and TNF-). Moreover, compared with monotherapy, these changes are more obvious in the combined treatment of PFD and AGP. Consistent with animal experiments, hepatic fibrosis markers (-SMA, collagen I, and CTGF) and inflammatory markers (IL-1, IL-6, and TNF-) were significantly decreased in activated LX-2 cells after PFD and/or AGP treatment. In addition, PFD and/or AGP inhibited the activation of HSCs by blocking the TGF-/Smad signaling pathway, and the combined treatment of PFD and AGP synergistically inhibited the phosphorylation of Smad2 and Smad3.
CONCLUSION
The combined application of PFD and AGP exerted superior inhibitive effects on HSC activation and liver fibrosis by mediating the TGF-/Smad signaling pathway as compared to monotherapy. Therefore, the combination of PFD and AGP may be a promising treatment strategy for liver fibrosis in BA.
Topics: Hepatic Stellate Cells; Animals; Liver Cirrhosis; Signal Transduction; Diterpenes; Male; Transforming Growth Factor beta; Mice, Inbred C57BL; Smad Proteins; Humans; Pyridones; Cell Line; Mice; Biliary Atresia; Disease Models, Animal; Drug Therapy, Combination
PubMed: 38946862
DOI: 10.1155/2024/2751280 -
Journal of Indian Prosthodontic Society Jul 2024The aim of this study was to evaluate the effect of proanthocyanidin and C. sinensis-polyphenols on microtensile bonding properties of prepared teeth with resin-modified... (Comparative Study)
Comparative Study
Comparison of microtensile bond strength of prepared teeth treated with proanthocyanidin, Camellia sinensis - Polyphenols, and metal crowns luted with resin-modified glass ionomer cement: An in vitro study.
AIM
The aim of this study was to evaluate the effect of proanthocyanidin and C. sinensis-polyphenols on microtensile bonding properties of prepared teeth with resin-modified glass ionomer cement (GIC).
SETTING AND DESIGN
This was an in vitro study.
MATERIALS AND METHODS
Seventy-eight maxillary premolars were selected and mounted into auto-polymerizing acrylic resin blocks. The samples were prepared and metal crowns were fabricated. The samples were randomly divided into three groups. Samples under Group 1 were not treated with any of the extracts and followed conventional bonding protocol. Samples under Group 2 and Group 3 were treated with proanthocyanidin and C. sinensis-polyphenols, respectively. After dentin treatment, these samples were luted to metal crowns using resin-modified GIC. Universal testing machine was used to measure the load at which the crowns were debonded and microtensile bond strength in MPa was calculated.
STATISTICAL ANALYSIS
The results were statistically analyzed using one-way ANOVA and post hoc Tukey HSD.
RESULTS
Samples treated with C. sinensis polyphenols (Group 3) had maximum bond strength followed by Group 2, where the samples were treated with proanthocyanidin.
CONCLUSION
C. sinensis polyphenols due to their anti-proteolytic and antioxidant properties showed improved bond strength compared to proanthocyanidin, a cross-linking agent, followed by conventional bonding protocol.
Topics: Proanthocyanidins; Tensile Strength; Glass Ionomer Cements; Polyphenols; Humans; Crowns; Dental Bonding; Camellia sinensis; In Vitro Techniques; Resin Cements; Plant Extracts; Dental Stress Analysis
PubMed: 38946512
DOI: 10.4103/jips.jips_127_24 -
Acta Dermatovenerologica Croatica : ADC Mar 2024Cutaneous leishmaniasis (CL) is common in the pediatric population, but there are only a limited number of studies focused on the clinical and epidemiological...
Cutaneous leishmaniasis (CL) is common in the pediatric population, but there are only a limited number of studies focused on the clinical and epidemiological characteristics of patients in this age group. In this study, our objective was to investigate the epidemiological and clinical characteristics of pediatric subjects diagnosed with CL. A total of 8047 patients who had been diagnosed with CL between 2010 and 2021 in an endemic region were included in this retrospective study. The clinical and demographic characteristics such as age, gender, number, size, duration, location, and type of lesions and the administered CL treatments were recorded. In order to better understand the epidemiological and clinical characteristics of patients with pediatric CL (PCL), the study patients were divided into three groups according to their age (0-6, 7-12, and 13-18 years) and the clinical and epidemiological characteristics of these groups were compared. When patients with PCL were compared according to age groups, it was found that the highest number of patients were in the 13-18 age group. It was determined that the patients in the 6-12 age group had fewer lesions, that and the size of the lesions was smaller than the other groups. The disease duration was the longest in the 0-5 age group. The highest rate of nodular, ulcerated, and recurrent lesions was in the 13-18 age group, and the highest rate of papular lesions was in the 6-12 age group. Systemic pentavalent antimony therapy (IM or IV) was administered to 438 patients with PCL (5.44%), while intralesional pentavalent antimony therapy (IL) was administered to 7447 patients (92.54%). Patients receiving systemic therapy had larger lesions compared with patients receiving IL therapy and no treatment. The lesion duration was longer in patients who received systemic treatment, and the number of lesions was higher than those who received IL treatment. The highest rate of systemic treatment was in the 13-18 age group (43.8%). In conclusion, our study found that the intragroup comparison of the age group with the highest CL rate displayed similar clinico-epidemiological characteristics reported in previous studies conducted in the same region.
Topics: Humans; Leishmaniasis, Cutaneous; Child; Retrospective Studies; Turkey; Adolescent; Male; Female; Child, Preschool; Infant; Infant, Newborn; Antiprotozoal Agents
PubMed: 38946187
DOI: No ID Found -
Yakugaku Zasshi : Journal of the... 2024Venetoclax (VEN) is used in patients with acute myeloid leukemia (AML) and is primarily metabolized by CYP3A4, a major drug-metabolizing enzyme. Patients with AML...
Venetoclax (VEN) is used in patients with acute myeloid leukemia (AML) and is primarily metabolized by CYP3A4, a major drug-metabolizing enzyme. Patients with AML simultaneously administered VEN and CYP3A4 inhibitors require a more appropriate management of drug-drug interactions (DDIs). Here, we report two cases of patients with AML (54-year-old man and 22-year-old woman) administrated VEN and CYP3A4 inhibitors, such as posaconazole, cyclosporine, or danazol. In the first case, we evaluated the appropriateness of timing for adjusting VEN dosage subsequent to the cessation of posaconazole. Consequently, modifying the VEN dosage in conjunction with the cessation of Posaconazole simultaneously may result in elevated plasma VEN levels. In the second case, plasma VEN concentrations were markedly elevated when co-administered with several CYP3A4 inhibitors. Additionally, in vitro assays were conducted for reverse translational studies to analyze CYP3A4 inhibition. CYP3A4 inhibition by combinatorial administration of cyclosporine A and danazol was demonstrated in vitro, which potentially explains the increasing plasma VEN concentrations observed in clinical settings. Although the acquisition of therapeutic effects is a major priority for patients, frequent therapeutic drug monitoring and dosage adjustments considering DDIs would be important factors in chemotherapy.
Topics: Humans; Sulfonamides; Leukemia, Myeloid, Acute; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Male; Young Adult; Middle Aged; Bridged Bicyclo Compounds, Heterocyclic; Female; Drug Monitoring; Cytochrome P-450 CYP3A; Cyclosporine; Triazoles; Antineoplastic Agents
PubMed: 38945852
DOI: 10.1248/yakushi.24-00018