bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost analysis of acute care resource utilization among individuals with sickle cell disease in a middle-income country
Authors: Lobo Clarisse , Moura Patricia , Fidlarczyk Delaine , Duran Jane , Barbosa Roberto , Oliveira Thais , do Nascimento Emilia Matos , Bhakta Nickhill , Hankins Jane S. 
Published: January 2022

Abstract
Background
The costs associated with the treatment of sickle cell disease (SCD) are understudied in low and middle-income countries (LMIC). We evaluated the cost of treating SCD-related acute complications and the potential cost-savings of hydroxyurea in a specialized hematology center in Brazil.

Methods
The costs (US dollars) of emergency department (ED) and hospitalizations from SCD-related complications between 01.01.2018 and 06.30.2018 were ascertained using absorption and micro-costing approaches. The reasons for acute hospital visits were grouped as: 1) vaso-occlusive (VOC) pain, 2) infection, 3) anemia exacerbation, and 4) chronic organ damage complications. Hydroxyurea adherence was estimated by medication possession ratio (MPR) during the study period.

Results
In total, 1144 patients, median age 17 years (range 0–70), 903 (78.9%) with HbSS/HbSβ0-thalassemia, 441 (38.5%) prescribed hydroxyurea, visited the ED, of whom 381 (33%) were admitted. VOC accounted for 64% of all ED visits and 60% of all admissions. Anemia exacerbation was the most expensive reason for ED visit ($321.87/visit), while chronic organ damage carried the highest admission cost ($2176.40/visit). Compared with other genotypes, individuals with HbSS/HbSβ0-thalassemia were admitted more often (79% versus 21%, p < 0.0001), and their admission costs were higher ($1677.18 versus $1224.47/visit, p = 0.0001). Antibiotics and analgesics accounted for 43% and 42% of the total ED costs, respectively, while housing accounted for 46% of the total admission costs. Costs of ED visits not resulting in admissions were lower among HbSS/HbSβ0-thalassemia individuals with hydroxyurea MPR ≥65% compared with visits by patients with MPR <65% ($98.16/visit versus $182.46/visit, p = 0.0007). No difference in admission costs were observed relative to hydroxyurea use.

Discussion
In a LMIC hematology-specialized center, VOCs accounted for most acute visits from patients with SCD, but costs were highest due to anemia exacerbation. Analgesics, antibiotics, and housing drove most expenses. Hydroxyurea may reduce ED costs among individuals with HbSS/HbSβ0-thalassemia but is dependent on adherence level.
Diabetes and other vascular risk factors in association with the risk of lower extremity amputation in chronic limb-threatening ischemia: a prospective cohort study
Authors: Ying Ariel Fangting , Tang Tjun Yip , Jin Aizhen , Chong Tze Tec , Hausenloy Derek John , Koh Woon-Puay 
Published: January 2022

Abstract
Background
Patients with diabetes are at increased risk of developing chronic limb-threatening ischemia (CLTI) due to peripheral arterial disease, and this often results in lower extremity amputation (LEA). Little is known of the interaction between diabetes and other vascular risk factors in affecting the risk of CLTI.

Methods
We investigated the association of diabetes, and its interaction with hypertension, body mass index (BMI) and smoking, with the risk of LEA due to CLTI in the population-based Singapore Chinese Health Study. Participants were interviewed at recruitment (1993–1998) and 656 incident LEA cases were identified via linkage with nationwide hospital database through 2017. Multivariate-adjusted Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% CIs for the associations.

Results
The HR (95% CI) for LEA risk was 13.41 (11.38–15.79) in participants with diabetes compared to their counterparts without diabetes, and the risk increased in a stepwise manner with duration of diabetes (P for trend < 0.0001). Hypertension and increased BMI independently increased LEA risk in those without diabetes but did not increase the risk in those with diabetes (P for interaction with diabetes ≤ 0.0006). Conversely, current smoking conferred a risk increment of about 40% regardless of diabetes status.

Conclusions
Although diabetes conferred more than tenfold increase in risk of LEA, hypertension and increased BMI did not further increase LEA risk among those with diabetes, suggesting a common mechanistic pathway for these risk factors. In contrast, smoking may act via an alternative pathway and thus confer additional risk regardless of diabetes status.
Pharmacokinetics of chloroquine and primaquine in healthy volunteers
Authors: Daher André , Pinto Douglas Pereira , da Fonseca Laís Bastos , Pereira Heliana Martins , da Silva Diego Medeiros Dias , da Silva Letícia de Sá Fernandes Vallim , Esteves Alessandra Lanzillotta , Soares Medeiros Juliana J. , Mendonça Jorge Souza 
Published: January 2022

Abstract
Background
Vivax malaria is a neglected disease. There is an irrefutable need for better treatments with higher acceptability and efficacy. The treatment efficacy is influenced by many factors, including bioavailability. Hence, a straightforward strategy to improve vivax malaria treatment efficacy is the deployment of good quality formulations of primaquine and chloroquine. As these treatments were developed more than 70 years ago, many of the available data on blood levels of both drugs are based on obsolete analytical methodologies or pharmaceutical formulations, which are not available anymore. Herein, the results of three bioequivalence studies are presented, providing individual pharmacokinetic data on chloroquine and primaquine of more than a hundred healthy volunteers and using up-to-date analytical methods.

Methods
Three trials were designed as a single centre, randomized, single dose, open label, fasting, crossover bioequivalence studies comparing a new coated chloroquine tablet to the uncoated tablet, and 5 and 15 mg primaquine formulations to either an international reference product or the currently distributed tablets. Plasma concentrations of chloroquine and primaquine were measured using a validated HPLC–MS/MS method in accordance with current international regulatory requirements for bio-analytical methods.

Results
In total, a hundred eleven healthy volunteers of both genders were included in the three studies (n = 32; 30 and 56 respectively). No serious adverse events occurred. Drugs levels were measured in 5,520 blood samples. The estimated ratio of the geometric means of Cmax, AUC0-t and AUC0-inf of test and reference drugs and their 90% CI for chloroquine 150 mg, primaquine 15 mg and primaquine 5 mg were: 95.33% (89.18; 101.90), 86. 85% (82.61; 91.31), and 84.45% (76.95; 92.67); 93.28% (81.76; 106.41), 94.52% (86.13; 103.73) and 93.93% (85.83; 102.79); 97.44% (90.60; 104.78), 93.70% (87.04; 100.87) and 91.36% (85.27; 97.89), respectively. As Cmax and AUC0-t 90% CI were within the acceptance interval of 80–125% in all cases, the formulations tested were bioequivalent.

Conclusions
In conclusion, the three studies provided detailed chloroquine and primaquine pharmacokinetic data in accordance with current regulatory standards. Together with other open data initiatives, this individual data may increase the accuracy of pharmacokinetic models guiding best dose, new combinations, regimens and formulations to optimize the current chloroquine and primaquine treatments for vivax malaria. The data presented here may support the deployment of high-quality drugs and evidence-based public health policies.
Presence and potential distribution of malaria-infected New World primates of Costa Rica
Authors: Chaves Andrea , Dolz Gaby , Ibarra-Cerdeña Carlos N. , Núñez Genuar , Ortiz-Malavasi E Edgar , Bernal-Valle Sofia , Gutiérrez-Espeleta Gustavo A. 
Published: January 2022

Abstract
Background
In South and Central America, Plasmodium malariae/Plasmodium brasilianum, Plasmodium vivax, Plasmodium simium, and Plasmodium falciparum has been reported in New World primates (NWP). Specifically in Costa Rica, the presence of monkeys positive to P. malariae/P brasilianum has been identified in both captivity and in the wild. The aim of the present study was to determine the presence of P. brasilianum, P. falciparum, and P. vivax, and the potential distribution of these parasites-infecting NWP from Costa Rica.

Methods
The locations with PCR (Polymerase Chain Reaction) positive results and bioclimatic predictors were used to construct ecological niche models based on a modelling environment that uses the Maxent algorithm, named kuenm, capable to manage diverse settings to better estimate the potential distributions and uncertainty indices of the potential distribution.

Results
PCR analysis for the Plasmodium presence was conducted in 384 samples of four primates (Howler monkey [n = 130], White-face monkey [n = 132], Squirrel monkey [n = 50], and red spider monkey [n = 72]), from across Costa Rica. Three Plasmodium species were detected in all primate species (P. falciparum, P. malariae/P. brasilianum, and P. vivax). Overall, the infection prevalence was 8.9%, but each Plasmodium species ranged 2.1–3.4%. The niche model approach showed that the Pacific and the Atlantic coastal regions of Costa Rica presented suitable climatic conditions for parasite infections. However, the central pacific coast has a more trustable prediction for malaria in primates.

Conclusions
The results indicate that the regions with higher suitability for Plasmodium transmission in NWP coincide with regions where most human cases have been reported. These regions were also previously identified as areas with high suitability for vector species, suggesting that enzootic and epizootic cycles occur.
Monitoring of the Village Malaria Workers to conduct activities of Malaria Elimination Demonstration Project in Mandla, Madhya Pradesh
Authors: Rajvanshi Harsh , Bharti Praveen K. , Sharma Ravendra K. , Nisar Sekh , Saha Kalyan B. , Jayswar Himanshu , Mishra Ashok K. , Das Aparup , Kaur Harpreet , Lal Altaf A. 
Published: January 2022

Abstract
Background
The capacity of the field staff to conduct activities related to disease surveillance, case management, and vector control has been one of the key components for successfully achieving malaria elimination. India has committed to eliminate malaria by 2030, and it has placed significance on monitoring and evaluation at the district level as one of the key strategies in its national framework. To support and guide the country’s malaria elimination objectives, the Malaria Elimination Demonstration Project was conducted in the tribal district of Mandla, Madhya Pradesh. Robust monitoring of human resources received special attention to help the national programme formulate a strategy to plug the gaps in its supply chain and monitoring and evaluation systems.

Methods
A monitoring tool was developed to test the capabilities of field workers to conduct activities related to malaria elimination work. Between November 2018 to February 2021, twenty-five Malaria Field Coordinators (MFCs) of the project utilized this tool everyday during the supervisory visits for their respective Village Malaria Workers (VMWs). The data was analysed and the scores were tested for variations against different blocks, educational status, duration of monitoring, and post-training scores.

Results
During the study period, the VMWs were monitored a total of 8974 times using the monitoring tool. Each VMW was supervised an average of 1.8 times each month. The critical monitoring indicators scored well in all seven quarters of the study as monitored by the MFCs. Monitoring by MFCs remained stable at 97.3% in all quarters. Contrary to expectations, the study observed longer diagnosis to treatment initiation time in urban areas of the district.

Conclusion
This study demonstrated the significance of a robust monitoring tool as an instrument to determine the capacity of the field workers in conducting surveillance, case management, and vector control related work for the malaria elimination programme. Similar tools can be replicated not only for malaria elimination, but other public health interventions as well.
Nanofiber/hydrogel core–shell scaffolds with three-dimensional multilayer patterned structure for accelerating diabetic wound healing
Authors: Li Jiankai , Zhang Tianshuai , Pan Mingmang , Xue Feng , Lv Fang , Ke Qinfei , Xu He 
Published: January 2022

AbstractImpaired angiogenesis is one of the predominant reasons for non-healing diabetic wounds. Herein, a nanofiber/hydrogel core–shell scaffold with three-dimensional (3D) multilayer patterned structure (3D-PT-P/GM) was introduced for promoting diabetic wound healing with improved angiogenesis. The results showed that the 3D-PT-P/GM scaffolds possessed multilayered structure with interlayer spacing of about 15–80 μm, and the hexagonal micropatterned structures were uniformly distributed on the surface of each layer. The nanofibers in the scaffold exhibited distinct core–shell structures with Gelatin methacryloyl (GelMA) hydrogel as the shell and Poly (d, l-lactic acid) (PDLLA) as the core. The results showed that the porosity, water retention time and water vapor permeability of the 3D-PT-P/GM scaffolds increased to 1.6 times, 21 times, and 1.9 times than that of the two-dimensional (2D) PDLLA nanofibrous scaffolds, respectively. The in vitro studies showed that the 3D-PT-P/GM scaffolds could significantly promote cell adhesion, proliferation, infiltration and migration throughout the scaffolds, and the expression of cellular communication protein-related genes, as well as angiogenesis-related genes in the same group, was remarkably upregulated. The in vivo results further demonstrated that the 3D-PT-P/GM scaffolds could not only effectively absorb exudate and provide a moist environment for the wound sites, but also significantly promote the formation of a 3D network of capillaries. As a result, the healing of diabetic wounds was accelerated with enhanced angiogenesis, granulation tissue formation, and collagen deposition. These results indicate that nanofiber/hydrogel core–shell scaffolds with 3D multilayer patterned structures could provide a new strategy for facilitating chronic wound healing.
Graphical Abstract
Functional signaling test identifies HER2 negative breast cancer patients who may benefit from c-Met and pan-HER combination therapy
Authors: MacNeil Ian A. , Khan Salmaan A. , Sen Adrish , Soltani Sajjad M. , Burns David J. , Sullivan Brian F. , Laing Lance G. 
Published: January 2022

Abstract
Background
Research is revealing the complex coordination between cell signaling systems as they adapt to genetic and epigenetic changes. Tools to uncover these highly complex functional linkages will play an important role in advancing more efficacious disease treatments. Current tumor cell signal transduction research is identifying coordination between receptor types, receptor families, and transduction pathways to maintain tumor cell viability despite challenging tumor microenvironment conditions.

Methods
In this report, coactivated abnormal levels of signaling activity for c-Met and HER family receptors in live tumor cells were measured by a new clinical test to identify a subpopulation of breast cancer patients that could be responsive to combined targeted therapies. The CELsignia Multi-Pathway Signaling Function (CELsignia) Test uses an impedance biosensor to quantify an individual patient’s ex vivo live tumor cell signaling response in real-time to specific HER family and c-Met co-stimulation and targeted therapies.

Results
The test identified breast tumors with hyperactive HER1, HER2, HER3/4, and c-Met coordinated signaling that express otherwise normal amounts of these receptors. The supporting data of the pre-clinical verification of this test included analyses of 79 breast cancer patients’ cell response to HER and c-Met agonists. The signaling results were confirmed using clinically approved matching targeted drugs, and combinations of targeted drugs in addition to correlative mouse xenograft tumor response to HER and c-Met targeted therapies.

Conclusions
The results of this study demonstrated the potential benefit of a functional test for identifying a subpopulation of breast cancer patients with coordinated abnormal HER and c-Met signaling for a clinical trial testing combination targeted therapy.
Different decay of antibody response and VOC sensitivity in naïve and previously infected subjects at 15 weeks following vaccination with BNT162b2
Authors: Siracusano Gabriel , Ruggiero Alessandra , Bisoffi Zeno , Piubelli Chiara , Carbonare Luca Dalle , Valenti Maria Teresa , Mayora-Neto Martin , Temperton Nigel , Lopalco Lucia , Zipeto Donato 
Published: January 2022

Abstract
Background
COVID-19 vaccines have demonstrated effectiveness in reducing SARS-CoV-2 mild and severe outcomes. In vaccinated subjects with SARS-CoV-2 history, RBD-specific IgG and pseudovirus neutralization titers were rapidly recalled by a single BTN162b2 vaccine dose to higher levels than those in naïve recipients after the second dose, irrespective of waning immunity. In this study, we inspected the long-term kinetic and neutralizing responses of S-specific IgG induced by two administrations of BTN162b2 vaccine in infection-naïve subjects and in subjects previously infected with SARS-CoV-2.

Methods
Twenty-six naïve and 9 previously SARS-CoV-2 infected subjects during the second wave of the pandemic in Italy were enrolled for this study. The two groups had comparable demographic and clinical characteristics. By means of ELISA and pseudotyped-neutralization assays, we investigated the kinetics of developed IgG-RBD and their neutralizing activity against both the ancestral D614G and the SARS-CoV-2 variants of concern emerged later, respectively. The Wilcoxon matched pair signed rank test and the Kruskal–Wallis test with Dunn’s correction for multiple comparison were applied when needed.

Results
Although after 15 weeks from vaccination IgG-RBD dropped in all participants, naïve subjects experienced a more dramatic decline than those with previous SARS-CoV-2 infection. Neutralizing antibodies remained higher in subjects with SARS-CoV-2 history and conferred broad-spectrum protection.

Conclusions
These data suggest that hybrid immunity to SARS-CoV-2 has a relevant impact on the development of IgG-RBD upon vaccination. However, the rapid decay of vaccination-elicited antibodies highlights that the administration of a third dose is expected to boost the response and acquire high levels of cross-neutralizing antibodies.
Edible red seaweed Campylaephora hypnaeoides J. Agardh alleviates obesity and related metabolic disorders in mice by suppressing oxidative stress and inflammatory response
Authors: Murakami Shigeru , Hirazawa Chihiro , Yoshikawa Rina , Mizutani Toshiki , Ohya Takuma , Ma Ning , Ikemori Takahiko , Ito Takashi , Matsuzaki Chiaki 
Published: January 2022

Abstract
Background
The obesity epidemic has become a serious public health problem in many countries worldwide. Seaweed has few calories and is rich in active nutritional components necessary for health promotion and disease prevention. The aim of this study was to investigate the effects of the Campylaephora hypnaeoides J. Agardh (C. hypnaeoides), an edible seaweed traditionally eaten in Japan, on high-fat (HF) diet-induced obesity and related metabolic diseases in mice.

Methods
Male C57BL/6J mice were randomly divided into the following groups: normal diet group, HF diet group, HF diet supplemented with 2% C. hypnaeoides, and HF diet supplemented with 6% C. hypnaeoides. After 13 weeks of treatment, the weight of the white adipose tissue and liver, and the serum levels of glucose, insulin, adipokines, and lipids were measured. Hepatic levels of adipokines, oxidant markers, and antioxidant markers were also determined. Insulin resistance was assessed by a glucose tolerance test. Polysaccharides of C. hypnaeoides were purified and their molecular weight was determined by high-performance seize exclusion chromatography. The anti-inflammatory effects of purified polysaccharides were evaluated in RAW264.7 cells.

Results
Treatment of HF diet-induced obese mice with C. hypnaeoides for 13 weeks suppressed the increase in body weight and white adipose tissue weight. It also ameliorated insulin resistance, hyperglycemia, hepatic steatosis, and hypercholesterolemia. The ingestion of an HF diet increased serum levels of malondialdehyde (MDA), tumor necrosis factor α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1), while it decreased serum adiponectin levels. In the liver, an HF diet markedly increased the MDA, TNF-α, and interleukin-6 (IL-6) levels, while it decreased glutathione and superoxide dismutase. These metabolic changes induced by HF diet feeding were ameliorated by dietary C. hypnaeoides. Purified polysaccharides and ethanol extract from C. hypnaeoides inhibited the lipopolysaccharide-induced overproduction of nitric oxide and TNF-α in macrophage RAW264.7 cells.

Conclusions
The present results indicated that C. hypnaeoides was able to alleviate HF diet-induced metabolic disorders, including obesity, hyperglycemia, hepatic steatosis, and hypercholesterolemia by attenuating inflammation and improving the antioxidant capacity in mice. Polysaccharides and polyphenols may be involved in these beneficial effects of C. hypnaeoides.
Evolution of policy for the treatment of substance use disorders in Qatar
Authors: Alabdulla Majid , Samarasinghe Nimesh , Tulley Iain , Reagu Shuja 
Published: January 2022

AbstractThere is a marked paucity of published evidence on the extent and nature of substance use disorders in the State of Qatar. This is mirrored by a dearth of information on the policy for the treatment of substance use disorders in the public domain. Between 2007 and 2017, substance use disorders have risen from the third to leading cause of disability in Qatar. More recently, Qatar has shifted from applying a punitive only paradigm in managing substance use problems to recognizing the role of treatment and care for people with substance use disorders. Recently published official documents in Qatar define addiction as a disease and as a chronic condition where people with substance use disorders should be treated as patients who need care and assistance. This shifts the onus of providing, and developing services, for individuals with substance use disorders with healthcare providers rather than purely with the criminal justice system. Following cabinet approval, the recently established Permanent Committee for Addiction Treatment headed by the Minister of Public Health, signals the need to institutionalize systems and structures to upscale demand reduction programmes in the country. This article is a descriptive examination of the shifts in substance abuse treatment policy in Qatar, the major factors influencing this evolution, and will utilise some of the policy science theories to describe and analyse policy outcomes. The article will also frame the substance use problem in Qatar for the first time, based on documents published by various government organisations.