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Mohammed Hussien, Muluken Azage, Negalign Berhanu Bayou

Background The term "community-based health insurance" refers to a broad range of nonprofit, prepaid health financing models designed to meet the health financing needs of disadvantaged populations, particularly those in the rural and informal sectors. Due to their voluntary nature, such initiatives suffer from persistently low coverage in low- and middle-income countries. In Ethiopia, the schemes’ membership growth has not been well investigated so far. This study sought to examine the scheme’s enrollment trend over a five-year period, and to explore the various challenges that underpin membership growth from the perspectives of various key stakeholders. Methods The study employed a mixed methods case study in two purposively selected districts of northeast Ethiopia: Tehulederie and Kallu. By reviewing the databases of health insurance schemes, quantitative data were collected retrospectively from 2017 to 2021 to examine enrollment trends. Trends for each performance indicator were analyzed descriptively for the period under study. Face-to-face interviews were conducted with nine community members and 19 key informants. Study participants were purposely selected using the maximum variation technique. Interviews were audio recorded, transcribed verbatim, and translated into English. Thematic analysis was employed with both deductive and inductive coding approaches. Results Over the course of the study period, enrollment in the scheme at both districts exhibited non-linear trends with both positive and negative growth rates being identified. Overall, the scheme in Tehulederie has a relatively higher population coverage and better membership retention, which could be due to the strong foundation laid by a rigorous public awareness campaign and technical support during the pilot phase. The challenges contributing to the observed level of performance have been summarized under four main themes that include quality of health care, claims reimbursement for insurance holders, governance practices, and community awareness and acceptability. Conclusions The scheme experienced negative growth ratios in both districts, indicating that it is not functionally viable. It will fail to meet its mission unless relevant stakeholders at all levels of government demonstrate political will and commitment to its implementation, as well as advocate for the community. Interventions should target on the highlighted challenges in order to boost membership growth and ensure the scheme’s viability.

Rahma Mkaouar, Zied Riahi, Cherine Charfeddine, Imen Chelly, Hela Boudabbous, Hamza Dallali, Crystel Bonnet, Meriem Hechmi, Soumeya Bekri, Nadia Zitouna, Lotfi Zekri, Amel Tounsi, Rym Kefi, Jihene Marrakchi, Olfa Messaoud, Ichraf Kraoua, Sonia Maalej, Ilhem Turki Ben Youssef, Ahlem Ben Hmid, Fabrice Giraudet, Sami Bouchoucha, Neji Tebib, Ghazi Besbes, Christine Petit, Ridha Mrad, Sonia Abdelhak, Mediha Trabelsi

Alpha-Mannosidosis (AM) is an ultra-rare storage disorder caused by a deficiency of lysosomal alpha-mannosidase encoded by the MAN2B1 gene. Clinical presentation of AM includes mental retardation, recurrent infections, hearing loss, dysmorphic features, and motor dysfunctions. AM has never been reported in Tunisia. We report here the clinical and genetic study of six patients from two Tunisian families with AM. The AM diagnosis was confirmed by an enzymatic activity assay. Genetic investigation was conducted by Sanger sequencing of the mutational hotspots for the first family and by ES analysis for the second one. In the first family, a frameshift duplication p.(Ser802GlnfsTer129) was identified in the MAN2B1 gene. For the second family, ES analysis led to the identification of a missense mutation p.(Arg229Trp) in the MAN2B1 gene in four affected family members. The p.(Ser802GlnfsTer129) mutation induces a premature termination codon which may trigger RNA degradation by the NMD system. The decrease in the levels of MAN2B1 synthesis could explain the severe phenotype observed in the index case. According to the literature, the p.(Arg229Trp) missense variant does not have an impact on MAN2B1 maturation and transportation, which correlates with a moderate clinical sub-type. To explain the intra-familial variability of cognitive impairment, exome analysis allowed the identification of two likely pathogenic variants in GHR and SLC19A3 genes potentially associated to cognitive decline. The present study raises awareness about underdiagnosis of AM in the region that deprives patients from accessing adequate care. Indeed, early diagnosis is critical in order to prevent disease progression and to propose enzyme replacement therapy.

Alexa Canchola, Ruth Meletz, Riste Ara Khandakar, Megan Woods, Ying-Hsuan Lin

Nearly two years after vitamin E acetate (VEA) was identified as the potential cause of the 2019–2020 outbreak of e-cigarette, or vaping product-associated lung injuries (EVALI), the toxicity mechanisms of VEA vaping are still yet to be fully understood. Studies since the outbreak have found that e-liquids such as VEA undergo thermal degradation during the vaping process to produce various degradation products, which may pose a greater risk of toxicity than exposure to unvaped VEA. Additionally, a wide range of customizable parameters–including the model of e-cigarette used, puffing topography, or the applied power/temperature used to generate aerosols–have been found to influence the physical properties and chemical compositions of vaping emissions. However, the impact of heating coil temperature on the chemical composition of VEA vaping emissions has not been fully assessed. In this study, we investigated the emission product distribution of VEA vaping emissions produced at temperatures ranging from 176 to 356°C, corresponding to a variable voltage vape pen set at 3.3 to 4.8V. VEA degradation was found to be greatly enhanced with increasing temperature, resulting in a shift towards the production of lower molecular weight compounds, such as the redox active duroquinone (DQ) and short-chain alkenes. Low temperature vaping of VEA resulted in the production of long-chain molecules, such as phytol, exposure to which has been suggested to induce lung damage in previous studies. Furthermore, differential product distribution was observed in VEA degradation products generated from vaping and from pyrolysis using a tube furnace in the absence of the heating coil at equivalent temperatures, suggesting the presence of external factors such as metals or oxidation that may enhance VEA degradation during vaping. Overall, our findings indicate that vaping behavior may significantly impact the risk of exposure to toxic vaping products and potential for vaping-related health concerns.

Abhimanyu Sud, Alana Armas, Heather Cunningham, Shawn Tracy, Kirk Foat, Navindra Persaud, Fardous Hosseiny, Sylvia Hyland, Leyna Lowe, Erin Zlahtic, Rhea Murti, Hannah Derue, Ilana Birnbaum, Katija Bonin, Ross Upshur, Michelle L. A. Nelson

Context Opioid related deaths are at epidemic levels in many developed nations globally. Concerns about the contribution of prescribed opioids, and particularly high-dose opioids, continue to mount as do initiatives to reduce prescribing. Evidence around opioid tapering, which can be challenging and potentially hazardous, is not well developed. A recent national guideline has recognized this and recommended referral to multidisciplinary care for challenging cases of opioid tapering. However, multidisciplinary care for opioid tapering is not well understood or defined. Objective Identify the existing literature on any multidisciplinary care programs that evaluate impact on opioid use, synthesize how these programs work and clarify whom they benefit. Study design Systematic rapid realist review. Dataset Bibliographic databases (MEDLINE, EMBASE, CINAHL, PsycINFO, Cochrane Library), grey literature, reference hand search and formal expert consultation. Results 95 studies were identified. 75% of the programs were from the United States and the majority (n = 62) were published after 2000. A minority (n = 23) of programs reported on >12 month opioid use outcomes. There were three necessary but insufficient mechanisms common to all programs: pain relief, behavior change and active medication management. Programs that did not include a combination of all three mechanisms did not result in opioid dose reductions. A concerning 20–40% of subjects resumed opioid use within one year of program completion. Conclusions Providing alternative analgesia is insufficient for reducing opioid doses. Even high quality primary care multidisciplinary care programs do not reduce prescribed opioid use unless there is active medication management accomplished by changing the primary opioid prescriber. Rates of return to use of opioids from these programs are very concerning in the current context of a highly potent and lethal street drug supply. This contextual factor may be powerful enough to undermine the modest benefits of opioid dose reduction via multidisciplinary care.

Mark W. Moore, Kira Westaway, June Ross, Kim Newman, Yinika Perston, Jillian Huntley, Samantha Keats, Michael J. Morwood

The Kimberley region of Western Australia is one of the largest and most diverse rock art provenances in the world, with a complex stylistic sequence spanning at least 16 ka, culminating in the modern art-making of the Wunumbal people. The Gunu Site Complex, in the remote Mitchell River region of the northwest Kimberley, is one of many local expressions of the Kimberley rock art sequence. Here we report excavations at two sites in this complex: Gunu Rock, a sand sheet adjacent to rock art panels; and Gunu Cave, a floor deposit within an extensive rockshelter. Excavations at Gunu Rock provide evidence for two phases of occupation, the first from 7–8 to 2.7 ka, and the second from 1064 cal BP. Excavations at Gunu Rock provide evidence for occupation from the end of the second phase to the recent past. Stone for tools in the early phase were procured from a variety of sources, but quartz crystal reduction dominated the second occupation phase. Small quartz crystals were reduced by freehand percussion to provide small flake tools and blanks for manufacturing small points called nguni by the Wunambal people today. Quartz crystals were prominent in historic ritual practices associated with the Wanjina belief system. Complex methods of making bifacially-thinned and pressure flaked quartzite projectile points emerged after 2.7 ka. Ochre pigments were common in both occupation phases, but evidence for occupation contemporaneous with the putative age of the oldest rock art styles was not discovered in the excavations. Our results show that developing a complete understanding of rock art production and local occupation patterns requires paired excavations inside and outside of the rockshelters that dominate the Kimberley.

Marine Potez, Verdiana Trappetti, Audrey Bouchet, Cristian Fernandez-Palomo, Esra Güç, Witold W. Kilarski, Ruslan Hlushchuk, Jean Laissue, Valentin Djonov

The common experimental use of B16-F10 melanoma cells focuses on exploring their metastatic potential following intravenous injection into mice. In this study, B16-F10 cells are used to develop a primary tumor model by implanting them directly into the ears of C57BL/6J mice. The model represents a reproducible and easily traceable tool for local tumor growth and for making additional in vivo observations, due to the localization of the tumors. This model is relatively simple and involves (i) surgical opening of the ear skin, (ii) removal of a square-piece of cartilage followed by (iii) the implantation of tumor cells with fibrin gel. The remodeling of the fibrin gel within the cartilage chamber, accompanying tumor proliferation, results in the formation of blood vessels, lymphatics and tissue matrix that can be readily distinguished from the pre-existing skin structures. Moreover, this method avoids the injection-enforced artificial spread of cells into the pre-existing lymphatic vessels. The tumors have a highly reproducible exponential growth pattern with a tumor doubling time of around 1.8 days, reaching an average volume of 85mm3 16 days after implantation. The melanomas are densely cellular with proliferative indices of between 60 and 80%. The induced angiogenesis and lymphangiogenesis resulted in the development of well-vascularized tumors. Different populations of immunologically active cells were also present in the tumor; the population of macrophages decreases with time while the population of T cells remained quasi constant. The B16-F10 tumors in the ear frequently metastasized to the cervical lymph nodes, reaching an incidence of 75% by day 16. This newly introduced B16-F10 melanoma model in the ear is a powerful tool that provides a new opportunity to study the local tumor growth and metastasis, the associated angiogenesis, lymphangiogenesis and tumor immune responses. It could potentially be used to test different treatment strategies.

Yuan-Yuei Chen, Wen-Hui Fang, Chung-Ching Wang, Tung-Wei Kao, Yaw-Wen Chang, Chen-Jung Wu, Yi-Chao Zhou, Yu-Shan Sun, Wei-Liang Chen

Objective The effect of obesity-induced metabolic abnormalities on bone mineral density (BMD) and osteoporosis are well established. However, the association between metabolically healthy obesity (MHO) and BMD remains unclear. Our aim was to investigate whether different obesity phenotypes in MHO were associated with BMD in a cross-sectional study. Methods All eligible adults receiving a health examination at the Tri-Service General Hospital from 2010 to 2016 were included. They were categorized based on body mass index (BMI) or percentage body fat (PBF). The associations between BMI or PBF and BMD were analyzed by adjusting for pertinent covariables. Results Males with normal weight and overweight and females with underweight and normal weight were associated with reduced BMD (β = 0.221, 95%CI = -0.354, -0.088; β = -0.155, 95%CI = -0.286, -0.023) (β = -0.736, 95%CI = -1.043, 0.429; β = -0.340, 95%CI = -0.567, -0.112), respectively. Females in Q1 had close to significant associations with reduced BMD (β = -0.253, 95%CI = -0.465, -0.041). Normal weight, overweight, Q2, and Q3 had stronger prediction of low BMD with ORs of 0.402 (95%CI = 0.204–0.791), 0.539 (95%CI = 0.321–0.905), 0.694 (95%CI = 0.490–0.982), and 0.466 (95%CI = 0.342–0.636), respectively. The relationship remained significant in male population that PBF was associated with reduced BMD with ORs of 0.435 (95%CI = 0.203, 0.935), 0.494 (95%CI = 0.247, 0.991), 0.268 (95%CI = 0.120, 0.597) in Q1, Q2, Q3 respectively. Conclusion Increased PBF had a significant association with low BMD in the MHO population. Obesity defined by PBF might be a useful indicator for low BMD. The association between body fat and bone health deserves further investigation regarding the potential pathophysiological mechanisms.

Mark A. Hayes, Rick A. Adams

Recent research has demonstrated that temperature and precipitation conditions correlate with successful reproduction in some insectivorous bat species that live in arid and semiarid regions, and that hot and dry conditions correlate with reduced lactation and reproductive output by females of some species. However, the potential long-term impacts of climate-induced reproductive declines on bat populations in western North America are not well understood. We combined results from long-term field monitoring and experiments in our study area with information on vital rates to develop stochastic age-structured population dynamics models and analyzed how simulated fringed myotis (Myotis thysanodes) populations changed under projected future climate conditions in our study area near Boulder, Colorado (Boulder Models) and throughout western North America (General Models). Each simulation consisted of an initial population of 2,000 females and an approximately stable age distribution at the beginning of the simulation. We allowed each population to be influenced by the mean annual temperature and annual precipitation for our study area and a generalized range-wide model projected through year 2086, for each of four carbon emission scenarios (representative concentration pathways RCP2.6, RCP4.5, RCP6.0, RCP8.5). Each population simulation was repeated 10,000 times. Of the 8 Boulder Model simulations, 1 increased (+29.10%), 3 stayed approximately stable (+2.45%, +0.05%, -0.03%), and 4 simulations decreased substantially (-44.10%, -44.70%, -44.95%, -78.85%). All General Model simulations for western North America decreased by >90% (-93.75%, -96.70%, -96.70%, -98.75%). These results suggest that a changing climate in western North America has the potential to quickly erode some forest bat populations including species of conservation concern, such as fringed myotis.

Karolina Barszcz, Marta Kupczyńska, Michał Polguj, Joanna Klećkowska-Nawrot, Maciej Janeczek, Karolina Goździewska-Harłajczuk, Małgorzata Dzierzęcka, Paweł Janczyk

The aim of this study was to measure the area of the coronary ostia, assess their localization in the coronary sinuses and to determine the morphology of the stem of the left and right coronary arteries in the domestic shorthair cat. The study was conducted on 100 hearts of domestic shorthair cats of both sexes, aged 2–18 years, with an average body weight of 4.05 kg. A morphometric analysis of the coronary ostia was carried out on 52 hearts. The remaining 48 hearts were injected with a casting material in order to carry out a morphological assessment of the left and right coronary arteries. In all the studied animals, the surface of the left coronary artery ostium was larger than the surface of the right coronary artery ostium. There were four types of the left main coronary artery: type I (23 animals, 49%)–double-branched left main stem (giving off the left circumflex branch and the interventricular paraconal branch, which in turn gave off the septal branch), type II (12 animals, 26%)–double-branched left main stem (giving off the left circumflex branch and the interventricular paraconal branch without the septal branch), type III (11 animals, 23%)–triple-branched left main stem (giving off the left circumflex branch, interventricular branch and the septal branch, type IV (1 animal, 2%)–double-branched left main stem (giving off the interventricular paraconal branch and the left circumflex branch, which in turn gave off the septal branch). The left coronary artery ostium is greater than the right one. There is considerable diversity in the branches of proximal segment of the left coronary artery, while the right coronary artery is more conservative. These results can be useful in defining the optimal strategies in the endovascular procedures involving the coronary arteries or the aortic valve in the domestic shorthair cat.

Wissam Chiha, Chrisna J. LeVaillant, Carole A. Bartlett, Alex W. Hewitt, Phillip E. Melton, Melinda Fitzgerald, Alan R. Harvey

Background Partial transection (PT) of the optic nerve is an established experimental model of secondary degeneration in the central nervous system. After a dorsal transection, retinal ganglion cells (RGCs) with axons in ventral optic nerve are intact but vulnerable to secondary degeneration, whereas RGCs in dorsal retina with dorsal axons are affected by primary and secondary injuries. Using microarray, we quantified gene expression changes in dorsal and ventral retina at 1 and 7 days post PT, to characterize pathogenic pathways linked to primary and secondary degeneration. Results In comparison to uninjured retina Cryba1, Cryba2 and Crygs, were significantly downregulated in injured dorsal retina at days 1 and 7. While Ecel1, Timp1, Mt2A and CD74, which are associated with reducing excitotoxicity, oxidative stress and inflammation, were significantly upregulated. Genes associated with oxygen binding pathways, immune responses, cytokine receptor activity and apoptosis were enriched in dorsal retina at day 1 after PT. Oxygen binding and apoptosis remained enriched at day 7, as were pathways involved in extracellular matrix modification. Fewer changes were observed in ventral retina at day 1 after PT, most associated with the regulation of protein homodimerization activity. By day 7, apoptosis, matrix organization and signal transduction pathways were enriched. Discriminant analysis was also performed for specific functional gene groups to compare expression intensities at each time point. Altered expression of selected genes (ATF3, GFAP, Ecel1, TIMP1, Tp53) and proteins (GFAP, ECEL1 and ATF3) were semi-quantitatively assessed by qRT-PCR and immunohistochemistry respectively. Conclusion There was an acute and complex primary injury response in dorsal retina indicative of a dynamic interaction between neuroprotective and neurodegenerative events; ventral retina vulnerable to secondary degeneration showed a delayed injury response. Both primary and secondary injury resulted in the upregulation of numerous genes linked to RGC death, but differences in the nature of these changes strongly suggest that death occurred via different molecular mechanisms.