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BackgroundBoth alcohol consumption and HIV infection are associated with worse brain, cognitive, and clinical outcomes in older adults. However, the extent to which brain and cognitive dysfunction is reversible with reduction or cessation of drinking is unknown. ObjectiveThe 30-Day Challenge study was designed to determine whether reduction or cessation of drinking would be associated with improvements in cognition, reduction of systemic and brain inflammation, and improvement in HIV-related outcomes in adults with heavy drinking. MethodsThe study design was a mechanistic experimental trial, in which all participants received an alcohol reduction intervention followed by repeated assessments of behavioral and clinical outcomes. Persons were eligible if they were 45 years of age or older, had weekly alcohol consumption of 21 or more drinks (men) or 14 or more drinks (women), and were not at high risk of alcohol withdrawal. After a baseline assessment, participants received an intervention consisting of contingency management (money for nondrinking days) for at least 30 days followed by a brief motivational interview. After this, participants could either resume drinking or not. Study questionnaires, neurocognitive assessments, neuroimaging, and blood, urine, and stool samples were collected at baseline, 30 days, 90 days, and 1 year after enrollment. ResultsWe enrolled 57 persons with heavy drinking who initiated the contingency management protocol (mean age 56 years, SD 4.6 years; 63%, n=36 male, 77%, n=44 Black, and 58%, n=33 people with HIV) of whom 50 completed 30-day follow-up and 43 the 90-day follow-up. The planned study procedures were interrupted and modified due to the COVID-19 pandemic of 2020-2021. ConclusionsThis was the first study seeking to assess changes in brain (neuroimaging) and cognition after alcohol intervention in nontreatment-seeking people with HIV together with people without HIV as controls. Study design strengths, limitations, and lessons for future study design considerations are discussed. Planned analyses are in progress, after which deidentified study data will be available for sharing. Trial RegistrationClinicalTrials.gov NCT03353701; https://clinicaltrials.gov/study/NCT03353701 International Registered Report Identifier (IRRID)DERR1-10.2196/53684

Abstract Background Multidrug regimens can increase the risk of drug–drug interactions at the level of albumin binding especially for drugs with narrow therapeutic windows such as carbamazepine (CBZ). This risk is particularly heightened for CBZ which is mainly metabolized to the active carbamazepine-10,11-epoxide (CBZE) that has been identified as contributory to both the therapeutic efficacy and severity of toxicity in CBZ-treated individuals. The objective of this study was to investigate the binding affinities of albumin with CBZ and CBZE, and to explore the influence of two competing over-the-counter medicines on the binding characteristics. CBZE was synthesized by epoxidation of CBZ and characterized using IR, NMR and mass spectrometry. The influence of paracetamol and ascorbic acid on the albumin complexes of CBZ and CBZE was investigated using absorption and IR spectrophotometry. Results Protein–ligand complexation produced progressive hyperchromic changes in 278 nm band of bovine serum albumin (BSA) with formation constants of 10.28–10.44 and 12.66–13.02 M−1 for CBZ and CBZE, respectively. Thermodynamic considerations confirmed both binding processes as endothermic, spontaneous and driven by hydrophobic interactions. The presence of ascorbic acid increased the binding constants of both CBZ-BSA and CBZE-BSA complexes by non-competitive interference mechanism. Similarly, paracetamol increased the affinity of CBZ for albumin but then competitively interfered with the CBZE-BSA complex. The ratio of albumin binding affinities of CBZ–CBZE varied from 0.81 in the absence of competing drug to 1.29 and 1.0 with paracetamol and ascorbic acid, respectively. IR study confirmed that both CBZ and CBZE induced a reduction from the 67.34% α-helical content of free BSA to 42.56 and 56.43%, respectively. Competitive binding in the presence of either paracetamol or ascorbic acid induced further reduction in the α-helical content of BSA in the complexes. The most extensive perturbation in the secondary structure of BSA (22.78% α-helical content) which was observed with CBZE-BSA complex in the presence of paracetamol is probably due to the increased interaction of the protein for the analgesic. Conclusion The study has revealed potential interference of paracetamol or ascorbic acid with the albumin binding of carbamazepine and its major metabolite.

OBJECTIVES/GOALS: Early HIV detection and treatment are key to reducing patient morbidity and mortality, yet 40% of people living with HIV do not know their status. “OPT-OUT” approaches to hiv testing, in which patients #_MSOCOM_1 are informed that an HIV test will be conducted unless they decline, are being increasingly recognized as a means to increase HIV testing. METHODS/STUDY POPULATION: the ed at Uhealth tower (UHT) implemented #_MSOCOM_1 the focus program that integrates routine “opt-out” HIV screening into the existing electronic medical record workflow to increase the number of individuals who know their HIV status, optimize linkage to care, and reduce stigma associated with HIV. the emr facilitates the opt-out screening model and maximizes the use of information systems to seamlessly integrate screening as a routine practice in a high-volume ed. our partnership with the florida department of health in miami dade (FDOH) allows uht to verify whether cases are new or known /out-of-care, link individuals immediately to care, and increase efficiencies with real-time data reconciliation. RESULTS/ANTICIPATED RESULTS: since implementation#_MSOCOM_1, from October 2019 - Dec 2022, the UHT ED screened 34, 314 eligible patients for HIV, of which, 17, 850 were tested. 228 people with hiv were identified; 37 were newly diagnosed. of HIV+ Diagnoses, 54.67% of HIV+ individuals were black and 36.89% HISPANIC. HIV+ individuals were referred to the doh with linkage to care at 81%. comparatively, before the onset of focus, the ED ordered 38 HIV tests, with one positive from Oct 2018 TO Sept. 2019. DISCUSSION/SIGNIFICANCE: UHT ED’s focus “OPT-OUT” HIV testing is a valuable conduit for HIV detection, prevention, and care. OPT-OUT screening removes the stigma associated with hiv testing, fosters earlier diagnoses and treatment, reduces health disparities, and decreases the risk of transmission.

In this study, the in vitro DNA-binding interactions of the food/drug additive, 5-hydroxymethylfurfural (HMF) and its major degradant, 5, 5'[oxy-bis(methylene)]bis-2-furfural (OBMF) were investigated. OBMF was synthesized and characterized using IR, NMR and mass spectrometry. Photometric titrations revealed OBMF induced more extensive perturbations in the 258 nm band of DNA and exhibited binding constants that were 5–12-folds higher than those of HMF. The greatest net changes in viscosity of DNA induced by HMF and OBMF were 10.5 and 8.9%, respectively which confirmed both compounds as minor groove binders. Docking revealed that OBMF and HMF bound to the guanine–cytosine regions of minor groove of DNA with global binding energies of −36.36 and −26.12 kcal/mol, respectively. DFT calculations revealed the higher electrophilicity of OBMF contributed to its increased interaction with the negatively charged DNA backbone. There is a need for stricter control of permissible levels of OBMF in food and drug products.

Background. Identification of potential hazards, their adverse health effects, and predisposing factors in the workplace are critical to improving safety. The objective of the study was to assess the knowledge of occupational hazards, the prevalence of perceived health problems and their predictors among textile dye workers in Abeokuta Nigeria who work in unsupervised settings. Materials and Methods. In this cross-sectional study, data were collected from 199 participants using a validated semi-structured interviewer-administered questionnaire. Multiple linear regression analysis was used to determine the predictors of knowledge while Pearson Chi-square was employed to test the association between perceived health problems, sociodemographics and work environment characteristics. Results. The mean age of the respondents was 40 (SD=12) years with an average work experience of 19 years. The majority of respondents 139 (69.8%) had lower than average scores on knowledge of 25 questions on chemical hazards. There was no correlation between knowledge score and work experience (P=0.492) or age (P=0.462) but the knowledge was significantly associated with exposure score (P=0.004), gender (P=0.002) and adherence to instructions on chemicals usage (P=0.041) after adjusting for safe practice. The most frequent health problems among the dye workers were respiratory disorders (53.8%), allergies (51.8%), and skin disorders (24.1%). Airborne gaseous pollutants from the mixing of chemicals were associated with allergies (P=0.045), circulatory (P=0.02) and skin disorders (P=0.049) while air-borne textile fiber/dye particles could predict allergies (P=0.028). Conclusions. Findings revealed that exposure, gender and adherence to instruction labels on dye/chemical containers could determine knowledge of chemical hazards while physical work environment characteristics could determine health problems.

Background & Aims: Increased expression of IFN-stimulated gene 15 (ISG15) and subsequently increased ISGylation are key factors in the host response to viral infection. In this study, we sought to characterize the expression of ISG15, ISGylation, and associated enzymes at each stage of differentiation from induced pluripotent stem cells (iPSCs) to hepatocytes. Methods: To study the regulation of ISGylation, we utilized patient samples and in vitro cell culture models including iPSCs, hepatocytes-like cells, immortalized cell lines, and primary human hepatocytes. Protein/mRNA expression were measured following treatment with poly(I:C), IFNα and HCV infection. Results: When compared to HLCs, we observed several novel aspects of the ISGylation pathway in iPSCs. These include a lower baseline expression of the ISGylation-activating enzyme, UBE1L, a lack of IFN-induced expression of the ISGylation-conjugation enzyme UBE2L6, an attenuated activation of the transcription factor STAT1 and constitutive expression of SOCS1. ISGylation was observed in iPSCs following downregulation of SOCS1, which facilitated STAT1 activation and subsequently increased expression of UBE2L6. Intriguingly, HCV permissive transformed hepatoma cell lines demonstrated higher intrinsic expression of SOCS1 and weaker ISGylation following IFN treatment. SOCS1 downregulation in HCV-infected Huh 7.5.1 cells led to increased ISGylation. Conclusions: Herein, we show that high basal levels of SOCS1 inhibit STAT1 activation and subsequently IFN-induced UBE2L6 and ISGylation in iPSCs. Furthermore, as iPSCs differentiate into hepatocytes, epigenetic mechanisms regulate ISGylation by modifying UBE1L and SOCS1 expression levels. Overall, this study demonstrates that the development of cell-intrinsic innate immunity during the differentiation of iPSCs to hepatocytes provides insight into cell type-specific regulation of host defense responses and related oncogenic processes. Impact and implications: To elucidate the mechanism underlying regulation of ISGylation, a key process in the innate immune response, we studied changes in ISGylation-associated genes at the different stages of differentiation from iPSCs to hepatocytes. We found that high basal levels of SOCS1 inhibit STAT1 activation and subsequently IFN-induced UBE2L6 and ISGylation in iPSCs. Importantly, epigenetic regulation of SOCS1 and subsequently ISGylation may be important factors in the development of cell type-specific host defense responses in hepatocytes that should be considered when studying chronic infections and oncogenic processes in the liver.

Viral hepatitis is a leading cause of liver disease and mortality. Infection can occur acutely or chronically, but the mechanisms that govern the clearance of virus or lack thereof are poorly understood and merit further investigation. Though cures for viral hepatitis have been developed, they are expensive, not readily accessible in vulnerable populations and some patients may remain at an increased risk of developing hepatocellular carcinoma (HCC) even after viral clearance. To sustain infection in vitro, hepatocytes must be fully mature and remain in a differentiated state. However, primary hepatocytes rapidly dedifferentiate in conventional 2D in vitro platforms. Physiologically relevant or physiomimetic microsystems, are increasingly popular alternatives to traditional two-dimensional (2D) monocultures for in vitro studies. Physiomimetic systems reconstruct and incorporate elements of the native cellular microenvironment to improve biologic functionality in vitro. Multiple elements contribute to these models including ancillary tissue architecture, cell co-cultures, matrix proteins, chemical gradients and mechanical forces that contribute to increased viability, longevity and physiologic function for the tissue of interest. These microsystems are used in a wide variety of applications to study biological phenomena. Here, we explore the use of physiomimetic microsystems as tools for studying viral hepatitis infection in the liver and how the design of these platforms is tailored for enhanced investigation of the viral lifecycle when compared to conventional 2D cell culture models. Although liver-based physiomimetic microsystems are typically applied in the context of drug studies, the platforms developed for drug discovery purposes offer a solid foundation to support studies on viral hepatitis. Physiomimetic platforms may help prolong hepatocyte functionality in order to sustain chronic viral hepatitis infection in vitro for studying virus-host interactions for prolonged periods.

Abstract Background Poultry red mite (PRM) (Dermanyssus gallinae) infestations are a cause of anaemia, impaired productivity and stress-related behaviours linked to reduced hen welfare. A study investigated the potential health, welfare and productivity benefits following fluralaner treatment to eliminate PRM from infested hens. Methods A PRM-infested layer house was selected on a free-range farm (5400 hens) and an aviary farm (42,400 hens). Fluralaner (Exzolt®; 0.5 mg/kg body weight) was administered twice, 7 days apart (Weeks 0 and 1), via drinking water. Mite populations were monitored by traps. Cameras recorded nighttime hen behaviours weekly, pre- and post-treatment. On the free-range farm, daytime behaviours were also recorded weekly. For pre- and post-treatment corticosterone assessments, eggs were randomly collected on both farms, and blood samples were collected from 50 randomly selected aviary farm hens. Production parameters were assessed using farm records. Results Throughout the post-treatment period, fluralaner efficacy against PRM was > 99% on both farms. On the aviary and free-range farms, treatment was followed by significant nighttime increases in the proportion of resting hens (P

Over the course of the COVID-19 pandemic, SARS-CoV-2 variants of concern (VOCs) with increased transmissibility and immune escape capabilities, such as Delta and Omicron, have triggered waves of new COVID-19 infections worldwide, and Omicron subvariants continue to represent a global health concern. Tracking the prevalence and dynamics of VOCs has clinical and epidemiological significance and is essential for modeling the progression and evolution of the COVID-19 pandemic. Next generation sequencing (NGS) is recognized as the gold standard for genomic characterization of SARS-CoV-2 variants, but it is labor and cost intensive and not amenable to rapid lineage identification. Here we describe a two-pronged approach for rapid, cost-effective surveillance of SARS-CoV-2 VOCs by combining reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) and periodic NGS with the ARTIC sequencing method. Variant surveillance by RT-qPCR included the commercially available TaqPath COVID-19 Combo Kit to track S-gene target failure (SGTF) associated with the spike protein deletion H69-V70, as well as two internally designed and validated RT-qPCR assays targeting two N-terminal-domain (NTD) spike gene deletions, NTD156-7 and NTD25-7. The NTD156-7 RT-qPCR assay facilitated tracking of the Delta variant, while the NTD25-7 RT-qPCR assay was used for tracking Omicron variants, including the BA.2, BA.4, and BA.5 lineages. In silico validation of the NTD156-7 and NTD25-7 primers and probes compared with publicly available SARS-CoV-2 genome databases showed low variability in regions corresponding to oligonucleotide binding sites. Similarly, in vitro validation with NGS-confirmed samples showed excellent correlation. RT-qPCR assays allow for near-real-time monitoring of circulating and emerging variants allowing for ongoing surveillance of variant dynamics in a local population. By performing periodic sequencing of variant surveillance by RT-qPCR methods, we were able to provide ongoing validation of the results obtained by RT-qPCR screening. Rapid SARS-CoV-2 variant identification and surveillance by this combined approach served to inform clinical decisions in a timely manner and permitted better utilization of sequencing resources.

Secukinumab and Dead Sea treatment result in clear skin for many psoriasis patients, through distinct mechanisms. However, recurrence in the same areas after treatments suggests the existence of a molecular scar. We aimed to compare the molecular and genetic differences in psoriasis patients who achieved complete response from secukinumab and Dead Sea climatotherapy treatments. We performed quantitative immunohistochemical and transcriptomic analysis, in addition to digital spatial profiling of skin punch biopsies. Histologically, both treatments resulted in a normalization of the lesional skin to a level resembling nonlesional skin. Interestingly, the transcriptome was not normalized by either treatments. We revealed 479 differentially expressed genes between secukinumab and Dead Sea climatotherapy at the end of treatment, with a psoriasis panel identifying SERPINB4, SERPINB13, IL36G, IL36RN, and AKR1B10 as upregulated in Dead Sea climatotherapy compared with secukinumab. Using digital spatial profiling, pan-RAS was observed to be differentially expressed in the microenvironment surrounding CD103+ cells, and IDO1 was differentially expressed in the dermis when comparing the two treatments. The differences observed between secukinumab and Dead Sea climatotherapy suggest the presence of a molecular scar, which may stem from mechanistically different pathways and potentially contribute to disease recurrence. This may be important for determining treatment response duration and disease memory. [ABSTRACT FROM AUTHOR]

Abstract Background The poultry red mite Dermanyssus gallinae (De Geer, 1778) is a major ectoparasite of poultry. Infestations are found in most laying hen farms in Europe, and breeder flocks have also been reported to be affected. Mite infestation has detrimental effects on animal welfare, it causes significant economic losses, and, additionally, D. gallinae is often considered as a vector for pathogens. Despite suspicion of a close relationship between the poultry red mite and Salmonella enterica enterica serovar Gallinarum biovar Gallinarum (serovar Gallinarum), the causative agent of fowl typhoid disease (FT), there has been no definitive proof of mite-mediated transmission. Therefore, an investigation was conducted to determine if D. gallinae-mediated transmission of serovar Gallinarum could be demonstrated among four different hen groups. Methods Two groups of 8 hens (A and B) were experimentally infected with serovar Gallinarum in two isolators. After 7 days, when birds showed signs of FT, about 25,000 mites were introduced. After 3 days, mites were harvested and used to infest two other hen groups of 8 (C and D), in two separate isolators. The health status of hens was constantly monitored; detection and quantification of serovar Gallinarum were performed by PCR and qPCR from mites and organs of dead hens. The maximum likelihood estimation of the infection rate and mite vectorial capacity were calculated. Results Clinical disease was observed in groups infected with serovar Gallinarum (A and B) and in hens of groups C and D infested with mites harvested from the isolators containing groups A and B. In all four groups, serovar Gallinarum was detected from liver, spleen, ovary, and cecum of hens, thus confirming the diagnosis of FT. Mite analysis demonstrated the presence of the pathogen, with an estimated infection rate ranging between 13.72 and 55.21 infected per thousand mites. Vectorial capacity was estimated to be 73.79. Conclusions Mites harvested from birds infected with serovar Gallinarum were shown to carry the mite, and then to transfer serovar Gallinarum to isolated groups of pathogen-free birds that subsequently showed signs of FT. Mite vectorial capacity was high, demonstrating that D. gallinae should be considered an effective vector of FT.

Abstract Background Successful canine sarcoptic mange treatment requires immediate efficacy to eliminate active mites, and sustained activity to prevent re-infestation from in-contact animals and fomites. With extended acaricidal activity, fluralaner has been shown to be effective for treating this disease. To confirm this potential under field conditions, two fluralaner formulations were administered to mite-infested, client-owned dogs. Methods Households qualified for inclusion if they had at least one dog positive for Sarcoptes scabiei mites, confirmed by skin scraping, and at least one dog with clinical signs evocative of sarcoptic mange. Households were allocated to groups of dogs to receive a single treatment with either oral (Bravecto® chewable tablets, MSD Animal Health) or topical (Bravecto® Spot-on, MSD Animal Health), fluralaner at a dose of ≥ 25 mg/kg (range 25–56 mg/kg) on Day 0, or two treatments with oral sarolaner (Simparica® tablets, Zoetis) (Days 0 and 28) at ≥ 2 mg/kg (2–4 mg/kg). All dogs in each household were treated with the same product. On the enrolment day and subsequently on Days 28, 56 and 84, deep skin scrapings were taken from at least five different body areas judged to be most likely to have active mite infestation. At each visit, the dog’s mange-associated skin lesions were recorded, and pruritus level was assessed. Results There were 98 participating households and 135 dogs enrolled across Albania, France, Italy and Portugal. On Day 28, more than 90% of dogs in each group were negative for mites. On Days 56 and 84, all study dogs were free of mites and most dermatological signs of sarcoptic mange had resolved. There were no treatment-related adverse events in any group. Conclusions A single treatment of client-owned, sarcoptic mange-affected dogs with either fluralaner chewable tablets or fluralaner spot-on formulation proved a safe and effective treatment of infestations with S. scabiei var. canis, maintained through 84 days (12 weeks) after treatment.

Abstract Background Recent reports indicate that the isoxazoline compounds have the potential to provide safe and effective treatment of canine generalized demodicosis, a condition that has been traditionally difficult to cure. Controlled field studies are needed to confirm this potential. A study was therefore initiated to investigate the efficacy of a single oral or spot-on treatment with fluralaner, an isoxazoline, compared with multiple topical treatments with imidacloprid-moxidectin, in dogs naturally affected by generalized demodicosis. Methods Veterinary clinics in 5 European countries enrolled 134 dogs diagnosed with generalized demodicosis. Dogs were randomized to treatment with either fluralaner chewables, fluralaner spot-on, or topical imidacloprid-moxidectin in a 2:2:1 ratio. Both fluralaner formulations were administered once, at the approved dose rate, on Day 0. Imidacloprid-moxidectin was administered per label on Day 0, and every 4 weeks, more frequently if necessary. At each visit (Days 0, 28, 56, 84), dogs were monitored for demodectic mites using deep skin scrapings and observed for health and for severity of skin lesions. Treatment was considered efficacious if more than 90% of the dogs were free of live mites at both Days 56 and 84. Results Of 124 dogs completing the study, 57 were diagnosed with juvenile-onset demodicosis and 67 with the adult-onset form. A single treatment with oral or spot-on fluralaner was efficacious, each eliminating mites from at least 98.0% of treated dogs on Days 56 and 84. Against juvenile-onset demodicosis, efficacy of the oral and spot-on formulations was 96.0% and 100%, respectively, and against adult-onset demodicosis 100% and 96.7%. Multiple administrations of imidacloprid-moxidectin were not efficacious, eliminating mites from 87.5% of dogs (92.0% with juvenile-onset demodicosis cured; 81.8% with adult-onset demodicosis). All groups showed a marked reduction in skin lesions by Day 28, with continuing clinical improvement at each subsequent visit through Day 84. There were no treatment-related adverse events. Conclusions A single administration of fluralaner chewables or fluralaner spot-on is highly effective against with juvenile-onset and adult-onset forms of generalized canine demodicosis. Topically applied imidacloprid-moxidectin at weekly to monthly intervals over the 84-day study did not achieve the proportion of mite-free dogs required to demonstrate efficacy.

Abstract Background Underserved ethnic minority populations experience significant disparities in HIV, hepatitis C virus (HCV), colorectal cancer (CRC), and cervical cancer incidence and mortality. Much of the excess burden of these diseases among underserved communities is due to lack of preventive care, including screening. Barriers to disease screening include low awareness, lack of access to care and health insurance, and cultural beliefs regarding disease prevention. Our current trial aims to examine community health worker (CHW)-delivered, home-based multi-modality screening for HIV, HCV, CRC, and cervical cancer simultaneously. Design We are conducting a randomized pragmatic trial among 900 Haitian, Hispanic, and African-American participants from diverse underserved communities in South Florida. People between the ages of 50 and 65 who have not had appropriate HIV, HCV, CRC, and cervical cancer screening per United States Preventive Services Task Force (USPSTF) recommendations are eligible for the study. Participants are recruited by CHWs and complete a structured interview to assess multilevel determinants of disease risk. Participants are then randomized to receive HIV, HCV, CRC, and cervical cancer screening via navigation to care by a CHW (Group 1) or via CHW-delivered home-based screening (Group 2). The primary outcome is completion of screening for each of these diseases within 6 months post-enrollment. Discussion Our trial is among the first to examine the effectiveness of a CHW-delivered, multimodality, home-based disease-screening approach. If found to be effective, this approach may represent a cost-effective strategy for disease screening within underserved and underscreened minority groups. Trial registration Clinical Trials.gov # NCT02970136 , registered November 21, 2016.

Objective: We aimed to identify disparities in self-reported HCV testing among persons living with HIV (PLWH) in Florida. Methods: We utilized a cross-sectional study of 646 PLWH from the Florida Cohort study's baseline survey. Our analysis included chi-squared tests and logistic regression. Results: Participants that were 55 years old or above had more than twice the odds of reporting a past HCV test than those 18–34 years old (OR 2.47, 95% CI 1.22–5.0), which contrasted with Non-Hispanic Blacks who had lower odds of reporting a past HCV test than non-Hispanic Whites (OR 0.63, 95% CI 0.35–1.1). Drug use was also associated with higher odds of reporting a past HCV test for injection drugs (OR 2.9, 95% CI 1.0–8.43) and non-injection drugs (OR 1.52 CI 0.99–2.21). Individuals with education beyond high school had higher odds of reporting a past HCV test than those that did not attend/complete high school (OR 1.9 CI 1.11–3.16). Conclusion: Our findings highlight the success of the Center for Disease Control and the U.S. Preventive Services Task Force's campaign in groups at high risk of HCV, such as baby boomers and Injection Drug Users (IDUs). However, they also reflect the current low HCV testing in PLWH that are 18–34 years old, have a low level of education, and are non-Hispanic Black. Our findings are of crucial public health significance because untreated HCV in PLWH is a major cause of severe liver disease and death. They reveal the current deficiencies in HCV testing, which is the initial step to identify underlying reasons for inadequate testing in specific groups and develop practical solutions.

Specific T cell populations in the skin have been demonstrated as important disease drivers in several dermatoses. Due to the unique skin architecture, these cells are not grouped together in structures but dispersedly spread out throughout the epidermis. Following tissue disruption and isolation, only about 10% of skin T cells are recovered and any in vitro expansion may alter their bona fide phenotype. The Nanostring GeoMx system was developed to address cellular phenotype and protein expression in a tissue spatial context. To do so, regions of interest (ROI) must exceed a certain area threshold (usually 100 μm in diameter) to generate a sufficient signal‐to‐noise ratio. Here, we present an approach that allows for the pooling of numerous smaller ROIs within the skin, enabling T cell and melanocyte phenotyping. Skin samples from healthy individuals and vitiligo patients were analysed using the GeoMx system and several immune profiling panels. A sufficient signal‐to‐noise ratio was achieved by pooling smaller ROIs and analysing them as a single group. While this prevents spatial analysis, this method allows for detailed analysis of cells as a population in the context of their physiological environment, making it possible to investigate in situ phenotype of rare cells in different tissue compartments. [ABSTRACT FROM AUTHOR]

Abstract Background Canine demodicosis is classified as localised or generalised according to the extent of the disease. Chronic generalised demodicosis is a difficult skin disease to treat and unlikely to resolve without therapy. This laboratory study compared the efficacy of two topical spot-on medications, fluralaner or a combination of imidacloprid and moxidectin, against naturally acquired generalised demodicosis in dogs. Methods Sixteen client-owned dogs with naturally acquired generalised demodicosis were randomly allocated to 1 of 2 study groups consisting of 8 dogs each. On Day 0, dogs in 1 group were treated once with fluralaner spot-on solution. Dogs in the other group were treated with the imidacloprid/moxidectin spot-on solution on 3 occasions (Days 0, 28 and 56) or weekly in severe cases. Mites were counted in skin scrapings and demodectic lesions were evaluated on each dog before treatment, and at 28-day intervals over the 12-week period. Deep skin scrapings were made from the same 5 sites on each dog at each examination. Results After administration of fluralaner, miticidal efficacy was 99.7% at Day 28, > 99.9% at Day 56 and 100% at Day 84. Efficacy in dogs treated topically with the imidacloprid and moxidectin combination, was 9.8% at Day 28, 45.4% at Day 56 and 0% at Day 84, and was significantly (P < 0.01) lower than the fluralaner treated group at each post-treatment time point. Conclusions A single topical administration of fluralaner eliminated Demodex sp. mites on dogs with generalised demodicosis. Topical imidacloprid/moxidectin combination treatment administered 3 times at 28-day intervals, or more frequently, did not eliminate mites from most treated dogs.

Hepatitis C virus (HCV) infections occur in approximately 3% of the world population. The development of an enhanced and extensive-scale screening is required to accomplish the World Health Organization’s (WHO) goal of eliminating HCV as a public health problem by 2030. However, standard testing methods are time-consuming, expensive, and challenging to deploy in remote and underdeveloped areas. Therefore, a cost-effective, rapid, and accurate point-of-care (POC) diagnostic test is needed to properly manage the disease and reduce the economic burden caused by high case numbers. Herein, we present a fully automated reverse-transcription loop-mediated isothermal amplification (RT-LAMP)-based molecular diagnostic set-up for rapid HCV detection. The set-up consists of an automated disposable microfluidic chip, a small surface heater, and a reusable magnetic actuation platform. The microfluidic chip contains multiple chambers in which the plasma sample is processed. The system utilizes SYBR green dye to detect the amplification product with the naked eye. The efficiency of the microfluidic chip was tested with human plasma samples spiked with HCV virions, and the limit of detection observed was 500 virions/mL within 45 min. The entire virus detection process was executed inside a uniquely designed, inexpensive, disposable, and self-driven microfluidic chip with high sensitivity and specificity.

The poultry red mite (PRM), Dermanyssus gallinae, a potential vector of pathogens to animals and humans, causes impaired bird welfare. A study investigated changes in behavioural variables, physiological biomarkers, and health parameters following acaricidal treatment of PRM infestation of laying hens on a commercial farm. Mite traps determined the challenge to 12,700 hens before and after drinking water administration of the acaricide, fluralaner (Exzolt®, 0.5 mg/kg; Weeks 0 and 1). Weekly daytime direct observations and night-time video recordings monitored bird behaviours from Weeks -6 through +6. Blood samples were collected from randomly-selected birds (Weeks -6, -1, and +6). Following treatment, mite count reductions (>99%) were statistically significant (P < 0.0001), as were night-time reductions in the percent of hens showing activity, preening, head scratching (all P < 0.0001), and head shaking (P = 0.0007). Significant daytime reductions were observed in preening and head scratching (both P < 0.0001), head shaking (P = 0.0389), severe feather pecking (P = 0.0002), and aggressive behaviour (P = 0.0165). Post-treatment, comb wounds were significantly reduced (P = 0.0127), and comb colour was significantly improved (P < 0.0001). Heterophil/lymphocyte ratio was significantly reduced at Weeks 1 and 6 (P = 0.0009 and P < 0.0001, respectively). At Week 6, blood corticosterone (P = 0.0041) and total oxidant status (P < 0.0001) were significantly reduced, and haemoglobin and mean corpuscular haemoglobin significantly increased (P < 0.0001). Farm production records indicated that those post-treatment improvements were accompanied by significant reductions in weekly mortality rate (P = 0.0169), and significant recovery in mean weekly egg weights (P < 0.0001) and laying rate (P < 0.0001). The improvements in behavioural variables, physiological biomarkers, and health parameters that were observed following the elimination of PRM on a commercial farm indicate that infestations can be a cause of reduced hen welfare.

Abstract Background Leishmaniosis/leishmaniasis consists of a wide group of diseases, caused by different Leishmania species and having different hosts. Leishmaniosis caused by Leishmania infantum, a disease primarily of dogs and humans, occurs after susceptible hosts are exposed to the feeding behavior of infected sand flies. A one-year laboratory study in dogs was designed to determine the 364-day anti-feeding efficacy of a slow release deltamethrin collar against the sand fly P. perniciosus, a common host of L. infantum in the Mediterranean basin. Methods In this assessor-blinded study, 16 Beagle dogs were randomized into two groups using P. perniciosus engorgement rates from a Day -7 challenge. On Day 0, dogs in Group 1 received a placebo collar, while dogs in Group 2 received a deltamethrin collar (Scalibor® Protector Band). All dogs were caged, sedated and then exposed for 1 h to 85 (± 10) female and 15 (± 5) male P. perniciosus on Day 7 and every 28 days through Day 364. All flies, alive and dead, were aspirated from cages and from dogs, immediately counted and then frozen for assessment of blood engorgement. Anti-feeding efficacy was determined by comparing the arithmetic means of engorged female flies (alive, dead and moribund) in the deltamethrin group to the control group means. Insecticidal efficacy at the time flies were retrieved was assessed by comparisons between groups of mean live female fly counts. Results In the deltamethrin group, relative to the control group, there was a significant reduction in arithmetic mean numbers of engorged P. perniciosus of 94–98% from Day 7 through Day 364. On Day 28, in the treated group relative to the control group, there was a 74% reduction in mean live fly counts, with between-group differences significant from Days 7 through 196, although insecticidal activity remained less than 50% from Day 56. Conclusion Deltamethrin collar application to dogs reduced sand fly feeding by ≥ 94%, relative to unprotected control dogs, for 364 days. Thus, one collar applied to a dog can prevent or reduce the risk of sand fly transmission of Leishmania for one full year.

Abstract Background The poultry red mite Dermanyssus gallinae negatively impacts bird welfare and health, and interferes with egg production and quality, while emerging acaricide resistance limits control options. Fluralaner, a novel miticide for administration in drinking water, is approved for control of D. gallinae infestations. Mite sensitivity testing is relevant to gauge field isolate susceptibility to available treatments. Methods Thirteen D. gallinae isolates collected during 2014 through 2016 from farms in Germany, France, Spain and Brazil, and a 2001 laboratory-maintained isolate were used for acaricide contact sensitivity testing. Tested compounds were cypermethrin, deltamethrin, phoxim, propoxur, and the recently available acaricides, spinosad and fluralaner. In each study, at least one isolate was exposed to increasing concentrations of at least one acaricide. In one study, additional testing determined the sensitivity of the 2001 isolate to fluralaner using a mite-feeding test, and of fluralaner, phoxim and spinosad using an immersion test. At least two replicates were used for each dilution. Vehicle and untreated controls were also included. Results Based on 90% mortality (LC90) values, the laboratory isolate was susceptible to fluralaner (15.6–62.5 parts per million, ppm), phoxim (< 500 ppm), propoxur (< 125 ppm), and deltamethrin (500–1000 ppm). All field isolates remained sensitive to fluralaner concentrations ≤ 125 ppm. Spinosad LC90 values for laboratory and field isolates ranged between 2000–4000 ppm. For phoxim, relative to the laboratory isolate, there was reduced sensitivity of two German isolates (LC90 up to 4000 ppm) and two French isolates (> 4000 ppm). An isolate from Spain demonstrated reduced sensitivity to phoxim, propoxur and deltamethrin; an isolate from Brazil showed reduced sensitivity to propoxur and cypermethrin. Mite LC90 when exposed to fluralaner by blood feeding was < 0.1 ppm. Conclusions Contact sensitivity testing indicated apparent resistance to at least one of phoxim, deltamethrin, cypermethrin and propoxur in 13 field isolates from Europe and Brazil. All isolates were highly susceptible to fluralaner. Fluralaner was approximately 1000 times more active by feeding than by contact. Fluralaner’s distinct mode of action and efficacy against isolates largely refractory to those acaricides, makes it a promising option for the control of D. gallinae infestations of poultry.

Abstract Background Hepatitis C virus (HCV) treatment regimens (DAAs) are well tolerated, efficacious but costly. Their high cost and restricted availability, raises concerns about the outcome of treatment in uninsured patients. This study investigated sustained virologic response (SVR) outcomes in a predominately uninsured patient population and completion of four steps along the HCV treatment cascade. Methods A retrospective chart review was conducted to characterize the patient population and analyze covariates to determine association with insurance status, attainment of SVR and progression through the HCV treatment cascade. Results Out of a total of 216 patients, 154 (71%) were uninsured. Approximately 50% of patients (109 of 216 patients) were male and 57% were Hispanic (123 of 216 patients). Sex, race, ethnicity, treatment compliance, and rates of complications were not associated with insurance status. Insured patients were older (median 60 years vs 57 years, p-value

Purpose of Review Given the rapid development of diagnostic approaches to test for and diagnose infection with SARS-CoV-2 and its associated variants including Omicron (B.1.1.529), many options are available to diagnose infection. Multiple established diagnostic companies are now providing testing platforms whereas initially, testing was being performed with simple PCR-based tests using standard laboratory reagents. Recent Findings Additional testing platforms continue to be developed, including those to detect specific variants, but challenges with testing, including obtaining testing reagents and other related supplies, are frequently encountered. With time, the testing supply chain has improved, and more established companies are providing materials to support these testing efforts. In the United States (U.S.), the need for rapid assay development and subsequent approval through the attainment of emergency use authorization (EUA) has superseded the traditional arduous diagnostic testing approval workflow mandated by the FDA. Through these efforts, the U.S. has been able to continue to significantly increase its testing capabilities to address this pandemic; however, challenges still remain due to the diversity of the performance characteristics of tests being utilized and newly discovered viral variants. Summary This review provides an overview of the current diagnostic testing landscape, with pertinent information related to SARS-CoV-2 virology, variants and antibody responses that are available to diagnose infection in the U.S.

Abstract Background Welfare concerns, production losses caused by Dermanyssus gallinae, the poultry red mite (PRM), and widespread mite resistance to environmentally applied acaricides continue to drive an urgent need for new and effective control measures. Fluralaner is a novel systemic acaricide developed to address that need. A series of field studies was initiated to investigate the safety and efficacy of a fluralaner solution (10 mg/ml) administered in drinking water at a dose rate of 0.5 mg/kg on two occasions with a 7-day interval, for treatment of natural PRM infestations in chickens. Methods Blinded, negative-controlled studies were completed in Europe across eight layer, two breeder, and two replacement chicken farms. At each farm, two similar flocks were housed in similar PRM-infested units (either rooms within a building, or separate buildings) varying from 550 to 100,000 birds per unit. One unit at each farm was allocated to fluralaner treatment, administered in drinking water on Days 0 and 7. One unit remained untreated. Mite traps were placed throughout each unit on Days -1, 0 or 1, 3, 6, 9, and 13 or 14, then at weekly or two-weekly intervals, retrieved after 24 h and processed for mite counts. Efficacy at each farm was assessed by mean PRM count reductions from traps in treated units compared with those from control units. Production parameters and safety were also monitored. Results Efficacy was 95.3 to 99.8% on Day 3 and 97.8 to 100% on Day 9, thereafter remaining above 90% for 56 to 238 days after treatment initiation. Post-treatment improvement in egg-laying rate was greater by 0.9 to 12.6% in the treated group at 9 of the 10 layer or breeder farms. There were no treatment-related adverse events. Conclusion Fluralaner administered at 0.5 mg/kg via drinking water twice, 7 days apart, was well tolerated and highly efficacious against the PRM in naturally infested chickens representing a range of production types and management systems. The results indicate that this novel treatment has potential to be the cornerstone of an integrated approach to reducing or eliminating the welfare and productivity costs of this increasingly threatening pest.

Abstract The poultry red mite, Dermanyssus gallinae, has been described for decades as a threat to the egg production industry, posing serious animal health and welfare concerns, adversely affecting productivity, and impacting public health. Research activities dedicated to controlling this parasite have increased significantly. Their veterinary and human medical impact, more particularly their role as a disease vector, is better understood. Nevertheless, red mite infestation remains a serious concern, particularly in Europe, where the prevalence of red mites is expected to increase, as a result of recent hen husbandry legislation changes, increased acaricide resistance, climate warming, and the lack of a sustainable approach to control infestations. The main objective of the current work was to review the factors contributing to this growing threat and to discuss their recent development in Europe. We conclude that effective and sustainable treatment approach to control poultry red mite infestation is urgently required, included integrated pest management.

Chronic infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) affects an estimated 35 million and 75 million individuals worldwide, respectively. These viruses induce persistent inflammation which often drives the development or progression of organ-specific diseases and even cancer including Hepatocellular Carcinoma (HCC). In this study, we sought to examine inflammatory responses following HIV or HCV stimulation of macrophages or Kupffer cells (KCs), that may contribute to virus mediated inflammation and subsequent liver disease. KCs are liver-resident macrophages and reports have provided evidence that HIV can stimulate and infect them. In order to characterize HIV-intrinsic innate immune responses that may occur in the liver, we performed microarray analyses on KCs following HIV stimulation. Our data demonstrate that KCs upregulate several innate immune signaling pathways involved in inflammation, myeloid cell maturation, stellate cell activation, and Triggering Receptor Expressed on Myeloid cells 1 (TREM1) signaling. TREM1 is a member of the immunoglobulin superfamily of receptors and it is reported to be involved in systemic inflammatory responses due to its ability to amplify activation of host defense signaling pathways. Our data demonstrate that stimulation of KCs with HIV or HCV induces the upregulation of TREM1. Additionally, HIV viral proteins can upregulate expression of TREM1 mRNA through NF-кB signaling. Furthermore, activation of the TREM1 signaling pathway, with a targeted agonist, increased HIV or HCV-mediated inflammatory responses in macrophages due to enhanced activation of the ERK1/2 signaling cascade. Silencing TREM1 dampened inflammatory immune responses elicited by HIV or HCV stimulation. Finally, HIV and HCV infected patients exhibit higher expression and frequency of TREM1 and CD68 positive cells. Taken together, TREM1 induction by HIV contributes to chronic inflammation in the liver and targeting TREM1 signaling may be a therapeutic option to minimize HIV induced chronic inflammation.