Development and validation of the coffee task: a novel functional assessment for prosthetic grip selection.

BACKGROUND: Lack of standardized assessments that explicitly quantify performance during prosthetic grip selection poses difficulty determining whether efforts to improve the design of multi-grip hands and their control approaches are successful. In this study, we developed and validated a novel assessment of multi-grip prosthetic performance: The Coffee Task. METHODS: Individuals without limb loss completed the Box and Block Test and two versions of the Coffee Task - Continuous and Segmented - with a myoelectric prosthetic emulator. On different days, participants selected prosthetic grips using pattern recognition and trigger control. Outcomes of the Continuous and Segmented Coffee Task were completion time and number of errors, respectively. Two independent raters assessed outcomes of the Coffee Task using video recordings to determine inter-rater reliability. Known-group validity was assessed by comparing outcomes with the emulator to those with an intact limb. Convergent validity was assessed through the correlation of the Coffee Task outcomes and those of the Box and Blocks Test. Responsiveness to changes with practice and control approach were assessed using the standardized response mean (SRM). RESULTS: Inter-rater reliability was high for both versions of the Coffee Task (Intra-class coefficient > 0.981). Coffee Task outcomes were moderately correlated with the Box and Blocks outcomes (|r| ≥ 0.412, p ≤ 0.007). Participants completed the Coffee Task faster with their intact limb than with the emulator (p < 0.001). Both versions of the Coffee Task were responsive to changes with training (SRM ≥ 0.81) but not control approach (SRM ≤ 0.12). CONCLUSIONS: The Coffee Task is reliable, has good known-group and convergent validity, and is responsive to changes due to practice. Future work should assess whether the Coffee Task is feasible and reliable for people with upper limb loss who use multi-grip prostheses.

Cortisol and changes in depressive symptoms: The moderating role of DHEA.

Stress is associated with activation of the hypothalamus-adrenal-axis (HPA). Cortisol, a product of the HPA, is thought to predict depression. However, to date, the majority of studies investigating the cortisol-depression relationship have been cross-sectional and results have been mixed. One possible reason for these mixed findings, may be that many studies fail to consider the moderating role of dehydroepiandosterone (DHEA), which is released alongside cortisol and is thought to serve opposing functions. Therefore, the present study investigated the main and interactive effects of cortisol and DHEA on depressive symptoms. Salivary cortisol and DHEA were measured from saliva throughout the Trier Social Stress task for N = 417 participants at baseline. Participants reported on their depressive symptoms using the Beck Depression Inventory - II at both baseline and follow up (ranging from 1-20 months post baseline; M = 11.60, SD = 5.80) as well as general demographics. The lavaan package in R (version 0.6.11; Rosseel, 2012) was used to conduct multiple regression analyses with FIML to explore the relationships between these variables. Results demonstrated no main effect of cortisol or DHEA, but did show a significant interaction with DHEA. The relations between cortisol and depressive symptoms depended on levels of DHEA such that the relationship was positive at low and negative at high levels of DHEA, with the overall interaction significant (ß = -.22, p < .001, 95% CI = [-.333, -.115]). DHEA can act as a protective factor against depression when cortisol levels are high. This presents opportunities for future research on how to improve DHEA levels to potentially reduce depression.

Belonging Exacerbates the Relations Between Racial Climate Stress and Physiological Dysregulation.

OBJECTIVE: Belonging is often considered a buffer against the physical and emotional consequences of discrimination and racial climate stress Youth Soc. 48(5):649-72, 2016. However, recent research suggests that feelings of belonging toward an institution can be detrimental when an individual feels discriminated against by the same institution to which one feels a sense of connection J Behav Med. 44(4):571-8, 2021. Therefore, the present study aimed to investigate the moderating role of institutional belonging in the relationship between racial climate stress and health, as indexed by allostatic load (AL), a multi-system indicator of physiological dysregulation. METHODS: In a sample of Black and White college students (N = 150; White = 82; Black = 68), self-reported racial climate stress, institutional belonging, and various demographic variables were collected. An AL composite was also collected, comprised of six biological measures of the SAM system, HPA axis, cardiovascular system, and metabolic system. Multiple regression analyses were conducted to explore the relationships between these variables. RESULTS: Results demonstrated no main effect of racial climate stress on AL but did show a significant interaction between racial climate stress and belonging, such that the positive relationship between racial climate stress and AL was significant only for those who also felt high levels of institutional belonging (ß int = .05, p = .006, 95% CI = 0.01 - 0.08). CONCLUSIONS: Feeling a sense of belonging may have negative physiological consequences for those who experience racial climate stress in a college setting.

Evaluation of the Elements of Short Hairpin RNAs in Developing shRNA-Containing CAR T Cells.

Short hairpin RNAs (shRNAs) have emerged as a powerful tool for gene knockdown in various cellular systems, including chimeric antigen receptor (CAR) T cells. However, the elements of shRNAs that are crucial for their efficacy in developing shRNA-containing CAR T cells remain unclear. In this study, we evaluated the impact of different shRNA elements, including promoter strength, orientation, multiple shRNAs, self-targeting, and sense and antisense sequence composition on the knockdown efficiency of the target gene in CAR T cells. Our findings highlight the importance of considering multiple shRNAs and their orientation to achieve effective knockdown. Moreover, we demonstrate that using a strong promoter and avoiding self-targeting can enhance CAR T cell functionality. These results provide a framework for the rational design of CAR T cells with shRNA-mediated knockdown capabilities, which could improve the therapeutic efficacy of CAR T cell-based immunotherapy.

Long-term upper-extremity prosthetic control using regenerative peripheral nerve interfaces and implanted EMG electrodes.

Objective.Extracting signals directly from the motor system poses challenges in obtaining both high amplitude and sustainable signals for upper-limb neuroprosthetic control. To translate neural interfaces into the clinical space, these interfaces must provide consistent signals and prosthetic performance.Approach.Previously, we have demonstrated that the Regenerative Peripheral Nerve Interface (RPNI) is a biologically stable, bioamplifier of efferent motor action potentials. Here, we assessed the signal reliability from electrodes surgically implanted in RPNIs and residual innervated muscles in humans for long-term prosthetic control.Main results.RPNI signal quality, measured as signal-to-noise ratio, remained greater than 15 for up to 276 and 1054 d in participant 1 (P1), and participant 2 (P2), respectively. Electromyography from both RPNIs and residual muscles was used to decode finger and grasp movements. Though signal amplitude varied between sessions, P2 maintained real-time prosthetic performance above 94% accuracy for 604 d without recalibration. Additionally, P2 completed a real-world multi-sequence coffee task with 99% accuracy for 611 d without recalibration.Significance.This study demonstrates the potential of RPNIs and implanted EMG electrodes as a long-term interface for enhanced prosthetic control.

"If You Do Not Take the Medicine and Complete the Dose It Could Cause You More Trouble": Bringing Awareness, Local Knowledge and Experience into Antimicrobial Stewardship in Tanzania.

Antimicrobial resistance (AMR) is a global health issue disproportionately affecting low- and middle-income countries. In Tanzania, multi-drug-resistant bacteria (MDR) are highly prevalent in clinical and community settings, inhibiting effective treatment and recovery from infection. The burden of AMR can be alleviated if antimicrobial stewardship (AMS) programs are coordinated and incorporate local knowledge and systemic factors. AMS includes the education of health providers to optimise antimicrobial use to improve patient outcomes while minimising AMR risks. For programmes to succeed, it is essential to understand not just the awareness of and receptiveness to AMR education, but also the opportunities and challenges facing health professionals. We conducted in-depth interviews (n = 44) with animal and human health providers in rural northern Tanzania in order to understand their experiences around AMR. In doing so, we aimed to assess the contextual factors surrounding their practices that might enable or impede the translation of knowledge into action. Specifically, we explored their motivations, training, understanding of infections and AMR, and constraints in daily practice. While providers were motivated in supporting their communities, clear issues emerged regarding training and understanding of AMR. Community health workers and retail drug dispensers exhibited the most variation in training. Inconsistencies in understandings of AMR and its drivers were apparent. Providers cited the actions of patients and other providers as contributing to AMR, perpetuating narratives of blame. Challenges related to AMR included infrastructural constraints, such as a lack of diagnostic testing. While health and AMR-specific training would be beneficial to address awareness, equally important, if not more critical, is tackling the challenges providers face in turning knowledge into action.

Use of regenerative peripheral nerve interfaces and intramuscular electrodes to improve prosthetic grasp selection: a case study.

Objective.Advanced myoelectric hands enable users to select from multiple functional grasps. Current methods for controlling these hands are unintuitive and require frequent recalibration. This case study assessed the performance of tasks involving grasp selection, object interaction, and dynamic postural changes using intramuscular electrodes with regenerative peripheral nerve interfaces (RPNIs) and residual muscles.Approach.One female with unilateral transradial amputation participated in a series of experiments to compare the performance of grasp selection controllers with RPNIs and intramuscular control signals with controllers using surface electrodes. These experiments included a virtual grasp-matching task with and without a concurrent cognitive task and physical tasks with a prosthesis including standardized functional assessments and a functional assessment where the individual made a cup of coffee ('Coffee Task') that required grasp transitions.Main results.In the virtual environment, the participant was able to select between four functional grasps with higher accuracy using the RPNI controller (92.5%) compared to surface controllers (81.9%). With the concurrent cognitive task, performance of the virtual task was more consistent with RPNI controllers (reduced accuracy by 1.1%) compared to with surface controllers (4.8%). When RPNI signals were excluded from the controller with intramuscular electromyography (i.e. residual muscles only), grasp selection accuracy decreased by up to 24%. The participant completed the Coffee Task with 11.7% longer completion time with the surface controller than with the RPNI controller. She also completed the Coffee Task with 11 fewer transition errors out of a maximum of 25 total errors when using the RPNI controller compared to surface controller.Significance.The use of RPNI signals in concert with residual muscles and intramuscular electrodes can improve grasp selection accuracy in both virtual and physical environments. This approach yielded consistent performance without recalibration needs while reducing cognitive load associated with pattern recognition for myoelectric control (clinical trial registration number NCT03260400).

Crossover-Use of Human Antibiotics in Livestock in Agricultural Communities: A Qualitative Cross-Country Comparison between Uganda, Tanzania and India.

Antibiotic use in animal agriculture contributes significantly to antibiotic use globally and is a key driver of the rising threat of antibiotic resistance. It is becoming increasingly important to better understand antibiotic use in livestock in low-and-middle income countries where antibiotic use is predicted to increase considerably as a consequence of the growing demand for animal-derived products. Antibiotic crossover-use refers to the practice of using antibiotic formulations licensed for humans in animals and vice versa. This practice has the potential to cause adverse drug reactions and contribute to the development and spread of antibiotic resistance between humans and animals. We performed secondary data analysis of in-depth interview and focus-group discussion transcripts from independent studies investigating antibiotic use in agricultural communities in Uganda, Tanzania and India to understand the practice of antibiotic crossover-use by medicine-providers and livestock-keepers in these settings. Thematic analysis was conducted to explore driving factors of reported antibiotic crossover-use in the three countries. Similarities were found between countries regarding both the accounts of antibiotic crossover-use and its drivers. In all three countries, chickens and goats were treated with human antibiotics, and among the total range of human antibiotics reported, amoxicillin, tetracycline and penicillin were stated as used in animals in all three countries. The key themes identified to be driving crossover-use were: (1) medicine-providers' and livestock-keepers' perceptions of the effectiveness and safety of antibiotics, (2) livestock-keepers' sources of information, (3) differences in availability of human and veterinary services and antibiotics, (4) economic incentives and pressures. Antibiotic crossover-use occurs in low-intensity production agricultural settings in geographically distinct low-and-middle income countries, influenced by a similar set of interconnected contextual drivers. Improving accessibility and affordability of veterinary medicines to both livestock-keepers and medicine-providers is required alongside interventions to address understanding of the differences between human and animal antibiotics, and potential dangers of antibiotic crossover-use in order to reduce the practice. A One Health approach to studying antibiotic use is necessary to understand the implications of antibiotic accessibility and use in one sector upon antibiotic use in other sectors.

Inter-epidemic Rift Valley fever virus infection incidence and risks for zoonotic spillover in northern Tanzania.

Rift Valley fever virus (RVFV) is a mosquito-borne pathogen that has caused epidemics involving people and animals across Africa and the Arabian Peninsula. A number of studies have found evidence for the circulation of RVFV among livestock between these epidemics but the population-level incidence of infection during this inter-epidemic period (IEP) is rarely reported. General force of infection (FOI) models were applied to age-adjusted cross-sectional serological data to reconstruct the annual FOI and population-level incidence of RVFV infection among cattle, goats, and sheep in northern Tanzania from 2009 through 2015, a period without reported Rift Valley fever (RVF) cases in people or animals. To evaluate the potential for zoonotic RVFV spillover during this period, the relationship between village-level livestock RVFV FOI and human RVFV seropositivity was quantified using multi-level logistic regression. The predicted average annual incidence was 72 (95% Credible Interval [CrI] 63, 81) RVFV infections per 10,000 animals and 96 (95% CrI 81, 113), 79 (95% CrI 62, 98), and 39 (95% CrI 28, 52) per 10,000 cattle, sheep, and goats, respectively. There was variation in transmission intensity between study villages, with the highest estimated village-level FOI 2.49% (95% CrI 1.89, 3.23) and the lowest 0.12% (95% CrI 0.02, 0.43). The human RVFV seroprevalence was 8.2% (95% Confidence Interval 6.2, 10.9). Human seropositivity was strongly associated with the village-level FOI in livestock, with the odds of seropositivity in an individual person increasing by around 1.2 times (95% CrI 1.1, 1.3) for each additional annual RVFV seroconversion per 1,000 animals. A history of raw milk consumption was also positively associated with human seropositivity. RVFV has circulated at apparently low levels among livestock in northern Tanzania in the period since the last reported epidemic. Although our data do not allow us to confirm human RVFV infections during the IEP, a strong association between human seropositivity and the FOI in cattle, goats, and sheep supports the hypothesis that RVFV circulation among livestock during the IEP poses a risk for undetected zoonotic spillover in northern Tanzania. We provide further evidence for the likely role of raw milk consumption in RVFV transmission from animals to people.

Small molecule-mediated allosteric activation of the base excision repair enzyme 8-oxoguanine DNA glycosylase and its impact on mitochondrial function.

8-Oxoguanine DNA glycosylase (OGG1) initiates base excision repair of the oxidative DNA damage product 8-oxoguanine. OGG1 is bifunctional; catalyzing glycosyl bond cleavage, followed by phosphodiester backbone incision via a ß-elimination apurinic lyase reaction. The product from the glycosylase reaction, 8-oxoguanine, and its analogues, 8-bromoguanine and 8-aminoguanine, trigger the rate-limiting AP lyase reaction. The precise activation mechanism remains unclear. The product-assisted catalysis hypothesis suggests that 8-oxoguanine and analogues bind at the product recognition (PR) pocket to enhance strand cleavage as catalytic bases. Alternatively, they may allosterically activate OGG1 by binding outside of the PR pocket to induce an active-site conformational change to accelerate apurinic lyase. Herein, steady-state kinetic analyses demonstrated random binding of substrate and activator. 9-Deazaguanine, which can't function as a substrate-competent base, activated OGG1, albeit with a lower Emax value than 8-bromoguanine and 8-aminoguanine. Random compound screening identified small molecules with Emax values similar to 8-bromoguanine. Paraquat-induced mitochondrial dysfunction was attenuated by several small molecule OGG1 activators; benefits included enhanced mitochondrial membrane and DNA integrity, less cytochrome c translocation, ATP preservation, and mitochondrial membrane dynamics. Our results support an allosteric mechanism of OGG1 and not product-assisted catalysis. OGG1 small molecule activators may improve mitochondrial function in oxidative stress-related diseases.

Harnessing Rift Valley fever virus NSs gene for cancer gene therapy.

One of the greatest challenges in the treatment of cancer is tumor heterogeneity which results in differential responses to chemotherapy and drugs that work through a single pathway. A therapeutic agent that targets cancer cells for death through multiple mechanisms could be advantageous as a broad inhibitor for many types of cancers and the heterogeneous alterations they possess. Several viral proteins have been exploited for antiproliferative and apoptotic effect in cancer cells by disrupting critical survival pathways. Here, we report the use of the non-structural protein on the S segment (NSs) gene from the Rift Valley fever virus (RVFV) to induce cancer cell death. NSs has immune evasion functions in the context of RVFV with many of these functions affecting proliferation pathways and DNA damage signaling, which could be leveraged against cancer cells. We find that expression of NSs in multiple cancer cell lines leads to a rapid decline in cell viability and induction of apoptosis. Interestingly, we observed reduced toxicity in normal cells suggesting cancer cells may be more susceptible to NSs-mediated cell death. To enhance specificity of NSs for use in hepatocellular carcinoma, we incorporated four miR-122 binding sites in the 3' untranslated region (UTR) of the NSs mRNA to achieve cell type specific expression. Observations presented here collectively suggest that delivery of the NSs gene may provide a unique therapeutic approach in a broad range of cancers.

"Using the same hand": The complex local perceptions of integrated one health based interventions in East Africa.

BACKGROUND: Neglected Tropical Diseases (NTDs) such as soil transmitted helminths (STH) and human rabies represent a significant burden to health in East Africa. Control and elimination remains extremely challenging, particularly in remote communities. Novel approaches, such as One Health based integrated interventions, are gaining prominence, yet there is more to be learned about the ways in which social determinants affect such programmes. METHODOLOGY: In 2015 a mixed method qualitative study was conducted in northern Tanzania to determine community perceptions towards integrated delivery of two distinct healthcare interventions: treatment of children for STH and dog vaccination for rabies. In order to assess the effectiveness of the integrated approach, villages were randomly allocated to one of three intervention arms: i) Arm A received integrated mass drug administration (MDA) for STH and mass dog rabies vaccination (MDRV); ii) Arm B received MDA only; iii) Arm C received MDRV only. PRINCIPLE FINDINGS: Integrated interventions were looked upon favourably by communities with respondents in all arms stating that they were more likely to either get their dogs vaccinated if child deworming was delivered at the same time and vice versa. Participants appreciated integrated interventions, due to time and cost savings and increased access to essential health care. Analysis of qualitative data allowed deeper exploration of responses, revealing why people appreciated these benefits as well as constraints and barriers to participation in integrated programmes. CONCLUSIONS/SIGNIFICANCE: An interdisciplinary One Health approach that incorporates qualitative social science can provide key insights into complex local perceptions for integrated health service delivery for STH and human rabies. This includes providing insights into how interventions can be improved while acknowledging and addressing critical issues around awareness, participation and underlying health disparities in remote pastoralist communities.

Hypoxia-directed tumor targeting of CRISPR-Cas9 and HSV-TK suicide gene therapy using lipid nanoparticles.

Hypoxia is a characteristic feature of solid tumors that contributes to tumor aggressiveness and is associated with resistance to cancer therapy. The hypoxia inducible factor-1 (HIF-1) transcription factor complex mediates hypoxia-specific gene expression by binding to hypoxia-responsive element (HRE) sequences within the promoter of target genes. HRE-driven expression of therapeutic cargo has been widely explored as a strategy to achieve cancer-specific gene expression. By utilizing this system, we achieve hypoxia-specific expression of two therapeutically relevant cargo elements: the herpes simplex virus thymidine kinase (HSV-tk) suicide gene and the CRISPR-Cas9 nuclease. Using an expression vector containing five copies of the HRE derived from the vascular endothelial growth factor gene, we are able to show high transgene expression in cells in a hypoxic environment, similar to levels achieved using the cytomegalovirus (CMV) and CBh promoters. Furthermore, we are able to deliver our therapeutic cargo to tumor cells with high efficiency using plasmid-packaged lipid nanoparticles (LNPs) to achieve specific killing of tumor cells in hypoxic conditions while maintaining tight regulation with no significant changes to cell viability in normoxia.

How public health crises expose systemic, day-to-day health inequalities in low- and-middle income countries: an example from East Africa.

BACKGROUND: The current Coronavirus disease pandemic reveals political and structural inequities of the world's poorest people who have little or no access to health care and yet the largest burdens of poor health. This is in parallel to a more persistent but silent global health crisis, antimicrobial resistance (AMR). We explore the fundamental challenges of health care in humans and animals in relation to AMR in Tanzania. METHODS: We conducted 57 individual interviews and focus groups with providers and patients in high, middle and lower tier health care facilities and communities across three regions of Tanzania between April 2019 and February 2020. We covered topics from health infrastructure and prescribing practices to health communication and patient experiences. RESULTS: Three interconnected themes emerged about systemic issues impacting health. First, there are challenges around infrastructure and availability of vital resources such as healthcare staff and supplies. Second, health outcomes are predicated on patient and provider access to services as well as social determinants of health. Third, health communication is critical in defining trusted sources of information, and narratives of blame emerge around health outcomes with the onus of responsibility for action falling on individuals. CONCLUSION: Entanglements between infrastructure, access and communication exist while constraints in the health system lead to poor health outcomes even in 'normal' circumstances. These are likely to be relevant across the globe and highly topical for addressing pressing global health challenges. Redressing structural health inequities can better equip countries and their citizens to not only face pandemics but also day-to-day health challenges.

microRNA-142 guards against autoimmunity by controlling Treg cell homeostasis and function.

Regulatory T (Treg) cells are critical in preventing aberrant immune responses. Posttranscriptional control of gene expression by microRNA (miRNA) has recently emerged as an essential genetic element for Treg cell function. Here, we report that mice with Treg cell-specific ablation of miR-142 (hereafter Foxp3CremiR-142fl/fl mice) developed a fatal systemic autoimmune disorder due to a breakdown in peripheral T-cell tolerance. Foxp3CremiR-142fl/fl mice displayed a significant decrease in the abundance and suppressive capacity of Treg cells. Expression profiling of miR-142-deficient Treg cells revealed an up-regulation of multiple genes in the interferon gamma (IFNγ) signaling network. We identified several of these IFNγ-associated genes as direct miR-142-3p targets and observed excessive IFNγ production and signaling in miR-142-deficient Treg cells. Ifng ablation rescued the Treg cell homeostatic defect and alleviated development of autoimmunity in Foxp3CremiR-142fl/fl mice. Thus, our findings implicate miR-142 as an indispensable regulator of Treg cell homeostasis that exerts its function by attenuating IFNγ responses.

Surgically Implanted Electrodes Enable Real-Time Finger and Grasp Pattern Recognition for Prosthetic Hands.

Currently available prosthetic hands are capable of actuating anywhere from five to 30 degrees of freedom (DOF). However, grasp control of these devices remains unintuitive and cumbersome. To address this issue, we propose directly extracting finger commands from the neuromuscular system. Two persons with transradial amputations had bipolar electrodes implanted into regenerative peripheral nerve interfaces (RPNIs) and residual innervated muscles. The implanted electrodes recorded local electromyography with large signal amplitudes. In a series of single-day experiments, participants used a high speed movement classifier to control a virtual prosthetic hand in real-time. Both participants transitioned between 10 pseudo-randomly cued individual finger and wrist postures with an average success rate of 94.7% and trial latency of 255 ms. When the set was reduced to five grasp postures, metrics improved to 100% success and 135 ms trial latency. Performance remained stable across untrained static arm positions while supporting the weight of the prosthesis. Participants also used the high speed classifier to switch between robotic prosthetic grips and complete a functional performance assessment. These results demonstrate that pattern recognition systems can use intramuscular electrodes and RPNIs for fast and accurate prosthetic grasp control.

"He Who Relies on His Brother's Property Dies Poor": The Complex Narratives of Livestock Care in Northern Tanzania.

Background: Endemic zoonoses have important impacts for livestock-dependent households in East Africa. In these communities, people's health and livelihoods are severely affected by livestock disease losses. Understanding how livestock keepers undertake remedial actions for livestock illness has the potential for widespread benefits such as improving health interventions. Yet, studies about livestock and human health behaviours in the global south tend to focus on individual health choices. In reality, health behaviours are complex, and not solely about individualised health experiences. Rather, they are mediated by a range of "upstream" factors (such as unequal provision of services), which are beyond the control of the individual. Methods: This paper presents qualitative research conducted from 2014 to 2019 for a study focused on the Social, Economic, and Environmental Drivers of Zoonoses in Tanzania (SEEDZ). Qualitative data were collected via focus group discussions, community meetings, informal interviews, formal in-depth interviews, observations and surveys that addressed issues of health, disease, zoonotic disease risks, and routes for treatment across 21 villages. Thematic analysis was carried out on in-depth interviews and focus group discussions. Conceptual analyses and observations were made through application of social science theories of health. Findings: Livestock keepers undertake a range of health seeking strategies loosely categorised around self and formal treatment. Two key themes emerged that are central to why people make the decisions they do: access to resources and trust in health care providers. These two issues affect individual sense of agency which impacts their ability to act to improve livestock health outcomes. We suggest that individual choice and agency in veterinary health seeking decisions are only beneficial if health systems can offer adequate care and health equity is addressed. Significance: This study demonstrates the value of in-depth qualitative research which reveals the nuance and complexity of people's decisions around livestock health. Most importantly, it explains why "better" knowledge does not always translate into "better" practise. The paper suggests that acknowledging and addressing these aspects of veterinary health seeking will lead to more effective provision.

Recommendations for the Successful Implementation of Upper Limb Prosthetic Technology.

Despite the numerous prosthetic hand designs that are commercially available, people with upper limb loss still frequently report dissatisfaction and abandonment. Over the past decade there have been numerous advances in prosthetic design, control, sensation, and device attachment. Each offers the potential to enhance function and satisfaction, but most come at high costs and involve surgical risks. Here, we discuss potential barriers and solutions to promote the widespread use of novel prosthetic technology. With appropriate reimbursement, multidisciplinary care teams, device-specific rehabilitation, and patient and clinician education, such technology has the potential to revolutionize the field and improve patient outcomes.

Addressing antimicrobial resistance by improving access and quality of care-A review of the literature from East Africa.

Universal access to healthcare, including quality medicines, is a fundamental human right but is still out of reach for many in low- and middle-income countries (LMICs). An existing framework capturing variability of access to healthcare in low-resource settings includes the 5 dimensions: availability, accessibility, affordability, adequacy, and acceptability. This framework encompasses key components, including health infrastructure and means to access it as well as service organisation, costs, and factors that influence users' satisfaction. However, in reality, the effectiveness of accessed healthcare is measured by the likelihood of a positive outcome. We therefore propose an expansion of this framework to include an additional dimension, "aspects of quality," incorporating quality, which critically influences the ability of the accessed services to generate optimal health outcomes. Within this framework, we explore literature from East Africa likely relevant to a range of LMIC contexts, mainly focusing on the provision of widely used antimicrobials such as antimalarials and antibiotics. We argue that major inadequacies exist across all 6 dimensions of access and quality of drugs and their provision. While the global focus is on curbing excessive antimicrobial use to tackle the antimicrobial resistance (AMR) crisis, major constraints around access shape patients' health-seeking decisions leading to potentially problematic practices that might exacerbate the AMR problem. We advocate for a holistic approach to tackling these inadequacies, encompassing all dimensions of access and quality of healthcare in order to improve health outcomes while simultaneously counteracting the AMR crisis.

A SARS-CoV-2 targeted siRNA-nanoparticle therapy for COVID-19.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in humans. Despite several emerging vaccines, there remains no verifiable therapeutic targeted specifically to the virus. Here we present a highly effective small interfering RNA (siRNA) therapeutic against SARS-CoV-2 infection using a novel lipid nanoparticle (LNP) delivery system. Multiple siRNAs targeting highly conserved regions of the SARS-CoV-2 virus were screened, and three candidate siRNAs emerged that effectively inhibit the virus by greater than 90% either alone or in combination with one another. We simultaneously developed and screened two novel LNP formulations for the delivery of these candidate siRNA therapeutics to the lungs, an organ that incurs immense damage during SARS-CoV-2 infection. Encapsulation of siRNAs in these LNPs followed by in vivo injection demonstrated robust repression of virus in the lungs and a pronounced survival advantage to the treated mice. Our LNP-siRNA approaches are scalable and can be administered upon the first sign of SARS-CoV-2 infection in humans. We suggest that an siRNA-LNP therapeutic approach could prove highly useful in treating COVID-19 disease as an adjunctive therapy to current vaccine strategies.