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Background People who inject drugs (PWID) are a medically and socially vulnerable population with a high incidence of overdose, mental illness, and infections like HIV and hepatitis C. Existing literature describes social and economic correlations to increased health risk, including stigma. Injection drug use stigma has been identified as a major contributor to healthcare disparities for PWID. However, data on this topic, particularly in terms of the interface between enacted, anticipated, and internalized stigma, is still limited. To fill this gap, we examined perspectives from PWID whose stigmatizing experiences impacted their views of the healthcare system and syringe service programs (SSPs) and influenced their decisions regarding future medical care. Methods Semi-structured interviews conducted with 32 self-identified PWID in New York City. Interviews were audio recorded and transcribed. Interview transcripts were coded using a grounded theory approach by three trained coders and key themes were identified as they emerged. Results A total of 25 participants (78.1%) reported at least one instance of stigma related to healthcare system engagement. Twenty-three participants (71.9%) reported some form of enacted stigma with healthcare, 19 participants (59.4%) described anticipated stigma with healthcare, and 20 participants (62.5%) reported positive experiences at SSPs. Participants attributed healthcare stigma to their drug injection use status and overwhelmingly felt distrustful of, and frustrated with, medical providers and other healthcare staff at hospitals and local clinics. PWID did not report internalized stigma, in part due to the availability of non-stigmatizing medical care at SSPs. Conclusions Stigmatizing experiences of PWID in formal healthcare settings contributed to negative attitudes toward seeking healthcare in the future. Many participants describe SSPs as accessible sites to receive high-quality medical care, which may curb the manifestation of internalized stigma derived from negative experiences in the broader healthcare system. Our findings align with those reported in the literature and reveal the potentially important role of SSPs. With the goal of limiting stigmatizing interactions and their consequences on PWID health, we recommend that future research include explorations of mechanisms by which PWID make decisions in stigmatizing healthcare settings, as well as improving medical care availability at SSPs.

Background Methadone Maintenance Treatment (MMT) is widely recognized as one of the most effective ways of reducing risk of overdose, arrest, and transmission of blood-borne viruses like HIV and HCV among people that use opioids. Yet, MMT’s use of restrictive take-home dose policies that force most patients to attend their clinic on a daily, or near-daily, basis may be unpopular with many patients and lead to low rates of treatment uptake and retention. In response, this article examines how clinics’ take-home dosing policies have affected patients’ experiences of treatment and lives in general. Methods This article is based on semi-structured, qualitative interviews with a variety of stakeholders in MMT. Interviews explored: reasons for engaging with, or not engaging with MMT; how MMT is conceptualized by patients and treatment providers (e.g., as harm reduction or route to abstinence and/or recovery); experiences with MMT; perception of barriers to MMT (e.g., organizational/regulatory, social) and how MMT might be improved to support peoples’ substance use treatment needs and goals. Results Nearly all of the patients with past or present MMT use were highly critical of the limited access to take-home doses and consequent need for daily or near daily clinic attendance. Participants described how the use of restrictive take-home dose policies negatively impacted their ability to meet day-to-day responsibilities and also cited the need for daily attendance as a reason for quitting or avoiding OAT. Responses also demonstrate how such policies contribute to an environment of cruelty and stigma within many clinics that exposes this already-stigmatized population to additional trauma. Conclusions Take-home dose policies in MMT are not working for a substantial number of patients and are reasonably seen by participants as degrading and dehumanizing. Revision of MMT regulations and policies regarding take home doses are essential to improve patient satisfaction and the quality and effectiveness of MMT as a key evidence-based treatment and harm reduction strategy.

This study aimed to investigate the impact of varying concentrations of nano zinc oxide compared to the conventional form affected the productivity, tibia bone characteristics, and cecal and intestinal microbiota in broilers from 1 to 35 days of age. The Arbor Acres 360-day-old male chicks were divided into six treatment groups (6 groups × 6 replicates × 10 chicks each). Except for zinc, which was given at three levels of 100% of the strain guide necessary level (110 mg), 50% (55 mg), and 25% (27.5 mg) of traditional or nano zinc oxide, six diets were formulated to meet the nutritional requirements of Arbor Acres chicks. The findings indicated that birds fed diets containing nano zinc oxide exhibited superior productive performance. There were no statistically significant differences ( P  > 0.05) observed between the various levels of nano zinc oxide. Furthermore, the study documented the ideal characteristics of the tibia bone in birds that were provided with diets supplemented with nano zinc oxide. These characteristics encompassed tibia weight, length, width, and breaking strength. Moreover, the birds that were fed nano zinc oxide had the best levels of tibia bone ash, calcium, phosphorus, and zinc content. The bone mineral density and concentration of birds fed nano zinc oxide were assessed using X-ray and dual-energy X-ray absorptiometry (DXA) techniques, revealing the most optimal results. The addition of zinc oxide in nano form led to enhanced intestinal microbiota by enhanced beneficial bacteria and decreased harmful bacteria. From the current results, the addition of nano zinc oxide at 25% recorded the best productive inclusion of nano zinc oxide provided the best productive performance, bone quality and gut microbiota (Lactobacilli, Enterobacteriaceae, and Salmonella ).

Complement proteins can form membrane attack complex (MAC) pores that directly kill Gram-negative bacteria. MAC pores assemble by stepwise binding of C5b, C6, C7, C8 and finally C9, which can polymerize into a transmembrane ring of up to 18 C9 monomers. It is still unclear if the assembly of a polymeric-C9 ring is necessary to sufficiently damage the bacterial cell envelope to kill bacteria. In this paper, polymerization of C9 was prevented without affecting binding of C9 to C5b-8, by locking the first transmembrane helix domain of C9. Using this system, we show that polymerization of C9 strongly enhanced damage to both the bacterial outer and inner membrane, resulting in more rapid killing of several Escherichia coli and Klebsiella strains in serum. By comparing binding of wildtype and ‘locked’ C9 by flow cytometry, we also show that polymerization of C9 is impaired when the amount of available C9 per C5b-8 is limited. This suggests that an excess of C9 is required to efficiently form polymeric-C9. Finally, we show that polymerization of C9 was impaired on complement-resistant E . coli strains that survive killing by MAC pores. This suggests that these bacteria can specifically block polymerization of C9. All tested complement-resistant E . coli expressed LPS O-antigen (O-Ag), compared to only one out of four complement-sensitive E . coli . By restoring O-Ag expression in an O-Ag negative strain, we show that the O-Ag impairs polymerization of C9 and results in complement-resistance. Altogether, these insights are important to understand how MAC pores kill bacteria and how bacterial pathogens can resist MAC-dependent killing.

Mitochondrial dysfunction is a recent emerging research scope that proved to be involved in many cardiovascular diseases culminating in chronic heart failure (CHF), which remains one of the primary causes of morbidity and mortality. This study investigated the added cardio-protective effects of exogenous melatonin administration to conventional captopril therapy in isoproterenol (ISO) exposed rats with CHF. Five groups of Wistar rats were recruited; (I): Control group, (II): (ISO group), (III): (ISO + captopril group), (IV): (ISO + melatonin group) and (V): (ISO + melatonin/captopril group). Cardiac function parameters and some oxidant, inflammatory and fibrotic markers were investigated. Moreover; mRNA expression of mitochondrial mitophagy [parkin & PTEN induced kinase 1 (PINK1)], biogenesis [Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)], fusion [mitofusin 2 (Mfn2)] and fission [dynamin-related protein 1 (DRP-1)] parameters in rat’s myocardium were evaluated. Rats’ myocardium was histo-pathologically and immunohistochemically evaluated for Beclin1 and Sirt3 expression. The present study revealed that captopril and melatonin ameliorated cardiac injury, oxidative stress biomarkers, and pro-inflammatory cytokines in ISO-exposed rats. These protective effects could be attributed to mitochondrial dynamic proteins control (i.e. enhanced the mRNA expression of parkin, PINK1, PGC-1α and Mfn2, while reduced DRP-1 mRNA expression). Also, Beclin1 and Sirt3 cardiac immunoreactivity were improved. Combined captopril and melatonin therapy showed a better response than either agent alone. Melatonin enhanced myocardial mitochondrial dynamics and Sirt3 expression in CHF rats and may represent a promising upcoming therapy added to conventional heart failure treatment.

For the last two decades, schistosomiasis control efforts have focussed on preventive treatment. The disease, however, still affects over 200 million people worldwide. Behaviour change (BC) interventions can strengthen control by interrupting transmission through modifying exposure behaviour (water contact) or transmission practices (open urination/defaecation); or through fostering treatment seeking or acceptance. This review examines these interventions to assess their effectiveness in modifying risk practices and affecting epidemiological trends. A systematic multi-database literature search (PROSPERO CRD42021252368) was conducted for peer-reviewed publications released at any time before June 2021 assessing BC interventions for schistosomiasis control in low- and middle-income countries. 2,593 unique abstracts were identified, 66 were assigned to full text review, and 32 met all inclusion criteria. A typology of intervention models was outlined according to their use of behaviour change techniques and overarching rationale: health education (HEIs), social-environmental (SEIs), physical-environmental (PEIs), and incentives-centred interventions (ICIs). Available evidence does not allow to identify which BC approach is most effective in controlling risk behaviour to prevent schistosomiasis transmission. HEIs' impacts were observed to be limited by structural considerations, like infrastructure underdevelopment, economic obligations, socio-cultural traditions, and the natural environment. SEIs may address those challenges through participatory planning and implementation activities, which enable social structures, like governance and norms, to support BC. Their effects, however, appear context-sensitive. The importance of infrastructure investments was highlighted by intervention models. To adequately support BC, however, they require users' inputs and complementary services. Whilst ICIs reported positive impacts on treatment uptake, there are cost-effectiveness and sustainability concerns. Evaluation studies yielded limited evidence of independent epidemiological impacts from BC, due to limited use of suitable indicators and comparators. There was indicative evidence, however, that BC projects could sustain gains through treatment campaigns. There is a need for integrated interventions combining information provision, community-based planning, and infrastructure investments to support BC for schistosomiasis control. Programmes should carefully assess local conditions before implementation and consider that long-term support is likely needed. Available evidence indicates that BC interventions may contribute towards schistosomiasis control when accompanied by treatment activities. Further methodologically robust evidence is needed to ascertain the direct epidemiological benefits of BC.

Monoclonal IgG antibodies constitute the fastest growing class of therapeutics. Thus, there is an intense interest to design more potent antibody formats, where long plasma half-life is a commercially competitive differentiator affecting dosing, frequency of administration and thereby potentially patient compliance. Here, we report on an Fc-engineered variant with three amino acid substitutions Q311R/M428E/N434W (REW), that enhances plasma half-life and mucosal distribution, as well as allows for needle-free delivery across respiratory epithelial barriers in human FcRn transgenic mice. In addition, the Fc-engineered variant improves on-target complement-mediated killing of cancer cells as well as both gram-positive and gram-negative bacteria. Hence, this versatile Fc technology should be broadly applicable in antibody design aiming for long-acting prophylactic or therapeutic interventions. Antibody based biologics are a rapidly growing class of therapeutics with interest to enhance their performance, distribution, longevity and effectivity. Here, authors report the engineering of human IgG Fc to enhance plasma half-life, mucosal distribution and killing of cancer cells and bacteria.

Infections with Gram-negative bacteria form an increasing risk for human health due to antibiotic resistance. Our immune system contains various antimicrobial proteins that can degrade the bacterial cell envelope. However, many of these proteins do not function on Gram-negative bacteria, because the impermeable outer membrane of these bacteria prevents such components from reaching their targets. Here we show that complement-dependent formation of Membrane Attack Complex (MAC) pores permeabilizes this barrier, allowing antimicrobial proteins to cross the outer membrane and exert their antimicrobial function. Specifically, we demonstrate that MAC-dependent outer membrane damage enables human lysozyme to degrade the cell wall of E . coli . Using flow cytometry and confocal microscopy, we show that the combination of MAC pores and lysozyme triggers effective E . coli cell wall degradation in human serum, thereby altering the bacterial cell morphology from rod-shaped to spherical. Completely assembled MAC pores are required to sensitize E . coli to the antimicrobial actions of lysozyme and other immune factors, such as Human Group IIA-secreted Phospholipase A2. Next to these effects in a serum environment, we observed that the MAC also sensitizes E . coli to more efficient degradation and killing inside human neutrophils. Altogether, this study serves as a proof of principle on how different players of the human immune system can work together to degrade the complex cell envelope of Gram-negative bacteria. This knowledge may facilitate the development of new antimicrobials that could stimulate or work synergistically with the immune system.

Background Type-II diabetes mellitus (T2DM) is a major risk factor for cognitive impairment. Protecting the brain environment against inflammation, and neurodegeneration, as well as preservation of the BBB veracity through modulating the crosstalk between insulin/AKT/GSK-3β and Wnt/β-catenin signaling, might introduce novel therapeutic targets. Purpose This study aimed at exploring the possible neuroprotective potential of vitamin D3 (VitD) and/or rosuvastatin (RSV) in T2DM-induced cognitive deficits. Methods T2DM was induced by a high-fat sucrose diet and a single streptozotocin (STZ) dose. Diabetic rats were allocated into a diabetic control and three groups treated with RSV (15 mg/kg/day, PO), VitD (500 IU/kg/day, PO), or their combination. Results Administration of VitD and/or RSV mitigated T2DM-induced metabolic abnormalities and restored the balance between the anti-inflammatory, IL 27 and the proinflammatory, IL 23 levels in the hippocampus. In addition, they markedly activated both the canonical and noncanonical Wnt/β-catenin cassettes with stimulation of their downstream molecular targets. VitD and/or RSV upregulated insulin and α7 nicotinic acetylcholine (α7nACh) receptors gene expression, as well as blood-brain barrier integrity markers including Annexin A1, claudin 3, and VE-cadherin. Also, they obliterated hippocampal ApoE-4 content, Tau hyperphosphorylation, and Aβ deposition. These biochemical changes were reflected as improved behavioral performance in Morris water maze and novel object recognition tests and restored hippocampal histological profile. Conclusion The current findings have accentuated the neuroprotective potential of VitD and RSV and provide new incentives to expand their use in T2DM-induced cognitive and memory decline. This study also suggests a superior benefit of combining both treatments over either drug alone.

Genus Iris comprises numerous and diverse phytoconstituents displaying marked biological activities. The rhizomes, and aerial parts of Iris pseudacorus L. cultivars from Egypt and Japan were subjected to comparative metabolic profiling using UPLC-ESI-MS/MS. The antioxidant capacity was determined using DPPH assay. In vitro enzyme inhibition potential against α -glucosidase, tyrosinase and lipase was evaluated. In silico molecular docking was conducted on the active sites of human α -glucosidase and human pancreatic lipase. Forty-three compounds were tentatively identified including flavonoids, isoflavonoids, phenolics and xanthones. I. pseudacorus rhizomes extracts (IPR-J and IPR-E) exhibited the highest radical scavenging activity with IC 50 values of 40.89 µg/mL and 97.97 µg/mL, respectively (Trolox IC 50 value was 14.59 µg/mL). Moreover, IPR-J and IPR-E exhibited promising α -glucosidase inhibitory activity displaying IC 50 values of 18.52 µg/mL, 57.89 µg/mL, respectively being more potent as compared to acarbose with IC 50 value of 362.088 µg/mL. All extracts exerted significant lipase inhibitory activity exhibiting IC 50 values of 2.35, 4.81, 2.22 and 0.42 µg/mL, respectively compared to cetilistat with IC 50 value of 7.47 µg/mL. However, no tyrosinase inhibitory activity was observed for all I. pseudacorus extracts up to 500 µg/mL. In silico molecular modelling revealed that quercetin, galloyl glucose, and irilin D exhibited the highest fitting scores within the active sites of human α -glucosidase and pancreatic lipase. ADMET prediction (absorption, distribution, metabolism, excretion, and toxicity) showed that most of the phytoconstituents exhibited promising pharmacokinetic, pharmacodynamics and tolerable toxicity properties. According to our findings, I. pseudacorus might be considered as a valuable source for designing novel phytopharmaceuticals.