Identifying Barriers and Facilitators to Accessing Care for Historically Marginalized Communities Affected by Parkinson Disease: A Qualitative Study.

INTRODUCTION: Parkinson disease (PD) is the second most common neurodegenerative disease. Members of the Black Diaspora (MBD) and Hispanic/Latinx people are less likely to receive a timely diagnosis following the onset of symptoms and more likely to experience greater disease severity due to late diagnosis. Historically marginalized populations (i.e., MBD, Hispanic, and Latinx communities) are not accurately represented in research; this, along with many other barriers, compounds underreporting and lack of recognition of PD. It is important to understand barriers to early diagnosis and healthcare access for these historically marginalized populations from the community's perspective. METHODS: Our team conducted two focus groups to identify barriers and facilitators to PD healthcare-seeking behavior. We sought to identify which barriers are modifiable to ultimately improve engagement in neurological care for MBD and Hispanic individuals affected by PD. RESULTS: We enrolled 15 participants (13 female; African/African American/Black n = 10, Hispanic/Puerto Rican n = 3, other n = 2) for two focus groups. Discussions revealed sources of barriers to healthcare-seeking behavior in three main domains: legacy of racism in the United States, ancestral cultural environment, and healthcare system access. These sources influenced individuals' PD knowledge and familiarity. Additionally, participants expressed a desire to know more about PD and called for increased community-based programming for education and awareness. DISCUSSION: This paper uses a community-based participatory research approach to describe the experiences of MBD, Hispanic, and Latinx people in Manhattan and the surrounding areas in relation to possible sources of healthcare disparities and delayed PD diagnosis. These sources have broad implications and should be addressed through collaborative community programming.

Life-cycle-coupled evolution of mitosis in close relatives of animals.

Eukaryotes have evolved towards one of two extremes along a spectrum of strategies for remodelling the nuclear envelope during cell division: disassembling the nuclear envelope in an open mitosis or constructing an intranuclear spindle in a closed mitosis1,2. Both classes of mitotic remodelling involve key differences in the core division machinery but the evolutionary reasons for adopting a specific mechanism are unclear. Here we use an integrated comparative genomics and ultrastructural imaging approach to investigate mitotic strategies in Ichthyosporea, close relatives of animals and fungi. We show that species in this clade have diverged towards either a fungal-like closed mitosis or an animal-like open mitosis, probably to support distinct multinucleated or uninucleated states. Our results indicate that multinucleated life cycles favour the evolution of closed mitosis.

An Individualized Yoga Intervention for People with Functional Neurological Disorder: Case Series.

Functional neurological disorder (FND) is a heterogeneous condition of neurological symptoms that cannot be linked to a specific neurological cause. Yoga combines movement, breathing, and meditation and has established mind-body effects for people who are managing both psychological and neurological conditions. This case series describes key components of a yoga program for people with FND, evaluating feasibility, acceptability, and efficacy via self-report surveys, clinical assessments, and postintervention interview. Four individuals with FND participated in 45-minute, one-to-one virtual yoga sessions, two times a week for 8 weeks. We measured outcomes in four domains (healthcare utilization, FND symptoms, quality of life and self-efficacy, and function and mobility) at baseline, week 4, and week 8. Assessments included the Psychogenic Movement Disorders Rating Scale, timed up-and-go test, Patient Health Questionnaire-15, Brief Illness Perceptions Questionnaire, 36-Item Short Form Health Survey, and University of Washington Self-Efficacy Scale. Four participants completed at least 8 sessions, and two completed the full intervention (16 sessions). There were no adverse events. Two participants reported positive changes after yoga and improved on all clinical assessments (timed up-and-go test and Psychogenic Movement Disorders Rating Scale). Postintervention interview analysis revealed three themes: negative diagnosis experience, perceived health effects of yoga, and session format preferences. This was an exploratory case series describing a yoga intervention that was associated with some benefits for people with FND (decreased FND symptom severity and increased function, perceived health, quality of life, and self-efficacy). A larger case series is warranted to understand how to best select individuals who would benefit from the program.

Global Prevalence of Varicella-Associated Complications: A Systematic Review and Meta-Analysis.

INTRODUCTION: Varicella (chickenpox) is an infectious disease caused by the varicella zoster virus affecting children, adolescents, and adults. Varicella symptoms are usually self-limiting; however, different complications with widespread and systemic manifestations can occur. This systematic literature review aims to explore and quantify varicella-associated complication rates. METHODS: Two databases (Embase and MEDLINE), congress abstracts, and reference lists of systematic reviews were screened to identify evidence on varicella complications. Complications were identified and grouped into 14 clinically relevant categories. Proportional meta-analyses were conducted using a random-effects model and tests for heterogeneity and publication bias were performed. Subgroup, sensitivity, and meta-regression analyses were also conducted. A total of 78 studies, spanning 30 countries, were included in the meta-analysis. RESULTS: Pooled prevalence was highest in severe varicella (22.42%; 95% confidence interval [CI] 10.13-37.77), skin-related complications (20.12%; 95% CI 15.48-25.20), and infection-related complications (10.03%; 95% CI 7.47-12.90). Cardiovascular (0.55%; 95% CI 0.08-1.33), genitourinary (1.17%; 95% CI 0.55-1.99), and musculoskeletal (1.54%; 95% CI 1.06-2.11) complications had the lowest pooled prevalence. The remaining complication categories ranged between 1% and 10%. Subgroup analysis showed that complications were more prevalent in children versus adults and in hospitalized patients versus outpatients. Meta-regression analysis found that no ecological level covariates were accurate predictors for the overall prevalence of varicella-associated complications. There was substantial heterogeneity and publication bias across all meta-analyses. CONCLUSION: Results suggest that different types of varicella-associated complications could be frequent, impacting quality of life, and healthcare resource utilisation and budgets. These findings are crucial to raise awareness of the health and economic burden of varicella disease.

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Design, Development, Evaluation, and In Vivo Performance of Buccal Films Embedded with Paliperidone-Loaded Nanostructured Lipid Carriers.

The therapeutic effectiveness of paliperidone in the treatment of schizophrenia has been limited by its poor oral bioavailability; hence, an alternative route could be appropriate. This study investigates the feasibility of developing a buccal film impregnated with paliperidone-loaded nanostructured lipid carriers (NLCs) and assesses the potential to enhance its bioavailability. Box-Behnken-based design optimization of NLCs was performed by examining the particles' physical characteristics. The polymeric film was used to load optimized NLCs, which were then assessed for their pharmaceutical properties, permeability, and pharmacokinetics. The optimization outcomes indicated that selected formulation variables had a considerable (p < 0.05) impact on responses such as particle size, entrapment efficiency, and % drug release. Desired characteristics such as a negative charge, higher entrapment efficiency, and nanoparticles with ideal size distribution were shown by optimized NLC dispersions. The developed film demonstrated excellent physico-mechanical properties, appropriate texture, good drug excipient compatibility (chemically stable formulation), and amorphous drug nature. A sustained Weibull model drug release (p < 0.0005) and superior flux (~5-fold higher, p < 0.005) were seen in NLC-loaded film compared to plain-drug-loaded film. The pharmacokinetics profile in rabbits supports the goal of buccal therapy as evidenced by significantly higher AUC0-12 (p < 0.0001) and greater relative bioavailability (236%) than the control. These results support the conclusion that paliperidone-loaded NLC buccal film has the potential to be an alternate therapy for its effective administration in the treatment of schizophrenia.

Healthcare resource use and costs of varicella and its complications: A systematic literature review.

Varicella is a highly contagious disease caused by the varicella zoster virus (VZV). While the disease is usually mild, severe complications can occur requiring costly hospitalization. A thorough understanding of the healthcare resource use (HCRU) and costs of varicella is needed to inform health-economic models of preventive strategies. A systematic literature review was carried out to retrieve relevant publications between 1999 and 2021, reporting HCRU and cost outcomes for varicella and its complications. Data were extracted and stratified according to pre-specified age groups and complication categories. Costs were re-based to a $US2020 footing using both purchasing power parity and the medical component of consumer price indexes. Data were summarized descriptively due to high heterogeneity in study design and outcome reporting. Forty-four publications fulfilled the inclusion and exclusion criteria of which 28 were conducted in Europe, 6 in Middle East and Asia, 5 in South America, 3 in North America, and 2 in multiple regions. Primary healthcare visits accounted for 30% to 85% of total direct costs. Hospitalization costs varied between $1,308 and $38,268 per episode depending on country, complication type, and length of stay, contributing between 2% and 60% to total direct costs. Indirect costs, mostly driven by workdays lost, accounted for approximately two-thirds of total costs due to varicella. The management of varicella and related complications can lead to substantial HCRU and costs for patients and the healthcare system. Additional research is needed to further characterize the varicella-associated economic burden and its broader impact from a societal standpoint.

Varicella, also known as chickenpox, is a highly contagious infectious disease which affects mostly children. Indeed, >90% of children will have had chickenpox by the age of 12 years. The symptoms are usually mild, but in some cases, serious complications can occur such as pneumonia, bacterial superinfection of the skin and encephalitis. A clear understanding of the complications of chickenpox for patients and the healthcare system would be helpful so that countries can assess the true health and economic burden of the disease.In this study, we have summarized existing published data from around the world. We have included studies that reported on the number of varicella cases, doctor visits, hospitalizations, and costs due to varicella and associated complications.These data showed that varicella causes high costs to the healthcare system. Even though less than 1% of varicella patients need to be hospitalized, costs remain high because varicella is so common. Furthermore, if the number of workdays lost are counted as well, then varicella-related costs are even higher.

Adaptive Health Technology Assessment: A Scoping Review of Methods.

OBJECTIVES: Health technology assessment (HTA) is an established mechanism for explicit priority setting to support universal health coverage. However, full HTA requires significant time, data, and capacity for each intervention, which limits the number of decisions it can inform. Another approach systematically adapts full HTA methods by leveraging HTA evidence from other settings. We call this "adaptive" HTA (aHTA), although in settings where time is the main constraint, it is also called "rapid HTA." METHODS: The objectives of this scoping review were to identify and map existing aHTA methods, and to assess their triggers, strengths, and weaknesses. This was done by searching HTA agencies' and networks' websites, and the published literature. Findings have been narratively synthesized. RESULTS: This review identified 20 countries and 1 HTA network with aHTA methods in the Americas, Europe, Africa, and South-East Asia. These methods have been characterized into 5 types: rapid reviews, rapid cost-effectiveness analyses, rapid manufacturer submissions, transfers, and de facto HTA. Three characteristics "trigger" the use of aHTA instead of full HTA: urgency, certainty, and low budget impact. Sometimes, an iterative approach to selecting methods guides whether to do aHTA or full HTA. aHTA was found to be faster and more efficient, useful for decision makers, and to reduce duplication. Nevertheless, there is limited standardization, transparency, and measurement of uncertainty. CONCLUSIONS: aHTA is used in many settings. It has potential to improve the efficiency of any priority-setting system, but needs to be better formalized to improve uptake, particularly for nascent HTA systems.

Cost Effectiveness of Strategies for Caring for Critically Ill Patients with COVID-19 in Tanzania.

BACKGROUND: The resources for critical care are limited in many settings, exacerbating the significant morbidity and mortality associated with critical illness. Budget constraints can lead to choices between investing in advanced critical care (e.g. mechanical ventilators in intensive care units) or more basic critical care such as Essential Emergency and Critical Care (EECC; e.g. vital signs monitoring, oxygen therapy, and intravenous fluids). METHODS: We investigated the cost effectiveness of providing EECC and advanced critical care in Tanzania in comparison with providing 'no critical care' or 'district hospital-level critical care' using coronavirus disease 2019 (COVID-19) as a tracer condition. We developed an open-source Markov model ( https://github.com/EECCnetwork/POETIC_CEA ) to estimate costs and disability-adjusted life-years (DALYs) averted, using a provider perspective, a 28-day time horizon, patient outcomes obtained from an elicitation method involving a seven-member expert group, a normative costing study, and published literature. We performed a univariate and probabilistic sensitivity analysis to assess the robustness of our results. , RESULTS: EECC is cost effective 94% and 99% of the time when compared with no critical care (incremental cost-effectiveness ratio [ICER] $37 [-$9 to $790] per DALY averted) and district hospital-level critical care (ICER $14 [-$200 to $263] per DALY averted), respectively, relative to the lowest identified estimate of the willingness-to-pay threshold for Tanzania ($101 per DALY averted). Advanced critical care is cost effective 27% and 40% of the time, when compared with the no critical care or district hospital-level critical care scenarios, respectively. CONCLUSION: For settings where there is limited or no critical care delivery, implementation of EECC could be a highly cost-effective investment. It could reduce mortality and morbidity for critically ill COVID-19 patients, and its cost effectiveness falls within the range considered 'highly cost effective'. Further research is needed to explore the potential of EECC to generate even greater benefits and value for money when patients with diagnoses other than COVID-19 are accounted for.

Design, Development, and Evaluation of Treprostinil Embedded Adhesive Transdermal Patch.

Clinical application of treprostinil in pulmonary arterial hypertension is hampered by adverse effects caused by its high dosing frequency. The objective of this investigation was to Formulate an adhesive-type transdermal patch of treprostinil and evaluate it both in vitro and in vivo. A 32-factorial design was utilized to optimize the selected independent variables (X1: drug amount, X2: enhancer concentration) on the response variables (Y1: drug release, Y2: transdermal flux). The optimized patch was evaluated for various pharmaceutical properties, skin irritation, and pharmacokinetics in rats. Optimization results signify considerable influence (p < 0.0001) of X1 on both Y1 and Y2, as compared to X2. The optimized patch possesses higher drug content (>95%), suitable surface morphology, and an absence of drug crystallization. FTIR analysis revealed compatibility of the drug with excipients, whereas DSC thermograms indicate that the drug exists as amorphous in the patch. The adhesive properties of the prepared patch confirm adequate adhesion and painless removal, while the skin irritation study confirms its safety. A steady drug release via Fickian diffusion and greater transdermal delivery (~23.26 µg/cm2/h) substantiate the potential of the optimized patch. Transdermal therapy resulted in higher treprostinil absorption (p < 0.0001) and relative bioavailability (237%) when compared to oral administration. Overall, the results indicate that the developed drug in the adhesive patch can effectively deliver treprostinil through the skin and could be a promising treatment option for pulmonary arterial hypertension.

Qbd-Based Approach to Optimize Niosomal Gel of Levosulpiride for Transdermal Drug Delivery.

Poor aqueous solubility besides extensive hepatic first effect significantly decreases the oral absorption of levosulpiride, which in turn minimizes its therapeutic effectiveness. Niosomes have been extensively investigated as a transdermal vesicular nanocarrier to increase the delivery of low permeable compounds into and across the skin. This research work was to design, develop and optimize levosulpiride-loaded niosomal gel and to evaluate its prospects for transdermal delivery. The Box-Behnken design was used to optimize niosomes by analyzing the impact of three factors (cholesterol; X1, Span 40; X2, and sonication time; X3) on the responses (particle size, Y1, and entrapment efficiency, Y2). Optimized formulation (NC) was incorporated into gel and evaluated for pharmaceutical properties, drug release study, ex vivo permeation, and in vivo absorption. The design experiment data suggest that all three independent variables influence both response variables significantly (p < 0.01). Pharmaceutical characteristics of NC vesicles showed the absence of drug excipient interaction, nanosize (~102.2 nm), narrow distribution (~0.218), adequate zeta potential (-49.9 mV), and spherical shape, which are suitable for transdermal therapy. The levosulpiride release rates varied significantly (p < 0.01) between niosomal gel formulation and control. Greater flux (p < 0.01) was observed with levosulpiride-loaded niosomal gel than with control gel formulation. Indeed, the drug plasma profile of niosomal gel was significantly higher (p < 0.005), with ~3 folds higher Cmax and greater bioavailability (~500% higher; p < 0.0001) than its counterpart. Overall, these findings imply that the use of an optimized niosomal gel formulation can increase the therapeutic efficacy of levosulpiride and may represent a promising alternative to conventional therapy.

Intranasal Administration of Dolutegravir-Loaded Nanoemulsion-Based In Situ Gel for Enhanced Bioavailability and Direct Brain Targeting.

Dolutegravir's therapeutic effectiveness in the management of neuroAIDS is mainly limited by its failure to cross the blood-brain barrier. However, lipid-based nanovesicles such as nanoemulsions have demonstrated their potential for the brain targeting of various drugs by intranasal delivery. Thus, the purpose of this study was to develop a Dolutegravir-loaded nanoemulsion-based in situ gel and evaluate its prospective for brain targeting by intranasal delivery. Dolutegravir-loaded nanoemulsions were prepared using dill oil, Tween® 80, and Transcutol® P. Optimization of the nanoemulsion particle size and drug release was carried out using a simplex lattice design. Formulations (F1-F7 and B1-B6) were assessed for various pharmaceutical characteristics. Ex vivo permeation and ciliotoxicity studies of selected in situ gels (B1) were conducted using sheep nasal mucosa. Drug targeting to the brain was assessed in vivo in rats following the nasal delivery of B1. The composition of oil, surfactant, and cosurfactant significantly (p < 0.05) influenced the dependent variables (particle size and % of drug release in 8 h). Formulation B1 exhibits pharmaceutical characteristics that are ideal for intranasal delivery. The mucosal steady-state flux noticed with BI was significantly greater (p < 0.005) than for the control gel. A histopathology of nasal mucosa treated with BI showed no signs of toxicity or cellular damage. Intranasal administration of B1 resulted in greater Cmax (~six-fold, p < 0.0001) and AUC0-α (~five-fold, p < 0.0001), and decreased Tmax (1 h) values in the brain, compared to intravenous administration. Meantime, the drug level in the plasma was relatively low, suggesting less systemic exposure to Dolutegravir through intranasal delivery. In summary, the promising data observed here signifies the prospective of B1 to enhance the brain targeting of Dolutegravir by intranasal delivery and it could be used as a feasible and practicable strategy for the management of neuroAIDS.

Essential emergency and critical care as a health system response to critical illness and the COVID19 pandemic: what does it cost?

Essential Emergency and Critical Care (EECC) is a novel approach to the care of critically ill patients, focusing on first-tier, effective, low-cost, life-saving care and designed to be feasible even in low-resourced and low-staffed settings. This is distinct from advanced critical care, usually conducted in ICUs with specialised staff, facilities and technologies. This paper estimates the incremental cost of EECC and advanced critical care for the planning of care for critically ill patients in Tanzania and Kenya.The incremental costing took a health systems perspective. A normative approach based on the ingredients defined through the recently published global consensus on EECC was used. The setting was a district hospital in which the patient is provided with the definitive care typically provided at that level for their condition. Quantification of resource use was based on COVID-19 as a tracer condition using clinical expertise. Local prices were used where available, and all costs were converted to USD2020.The costs per patient day of EECC is estimated to be 1 USD, 11 USD and 33 USD in Tanzania and 2 USD, 14 USD and 37 USD in Kenya, for moderate, severe and critical COVID-19 patients respectively. The cost per patient day of advanced critical care is estimated to be 13 USD and 294 USD in Tanzania and USD 17 USD and 345 USD in Kenya for severe and critical COVID-19 patients, respectively.EECC is a novel approach for providing the essential care to all critically ill patients. The low costs and lower tech approach inherent in delivering EECC mean that EECC could be provided to many and suggests that prioritizing EECC over ACC may be a rational approach when resources are limited.

A menace to fraternity: Early congenital syphilis - A rare case report.

Congenital syphilis (CS), once a forgotten disease, has now remerged. A 2-month-old male child presented with multiple discrete skin-colored papules over the trunk, back, bilateral lower limbs, and groin. He also had a deformity of bilateral lower limbs and a widening at the wrist. Radiological findings suggested syphilitic changes in long bones. Nontreponemal as well as treponemal tests were positive in the baby and both parents confirming the diagnosis of CS. The father had a history of multiple sex partners and untreated genital lesions in the past. The case emphasizes the importance of awareness regarding sexually transmitted infections and its timely treatment and judicious antenatal screening for the same.

Resource use, availability and cost in the provision of critical care in Tanzania: a systematic review.

OBJECTIVES: Critical care is essential in saving lives of critically ill patients, however, provision of critical care across lower resource settings can be costly, fragmented and heterogenous. Despite the urgent need to scale up the provision of critical care, little is known about its availability and cost. Here, we aim to systematically review and identify reported resource use, availability and costs for the provision of critical care and the nature of critical care provision in Tanzania. DESIGN: This is a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. DATA SOURCES: Medline, Embase and Global Health databases were searched covering the period 2010 to 17 November 2020. ELIGIBILITY CRITERIA: We included studies that reported on forms of critical care offered, critical care services offered and/or costs and resources used in the provision of care in Tanzania published from 2010. DATA EXTRACTION AND SYNTHESIS: Quality assessment of the articles and data extraction was done by two independent researchers. The Reference Case for Estimating the Costs of Global Health Services and Interventions was used to assess quality of included studies. A narrative synthesis of extracted data was conducted. Costs were adjusted and reported in 2019 US$ and TZS using the World Bank GDP deflators. RESULTS: A total 31 studies were found to fulfil the inclusion and exclusion criteria. Critical care identified in Tanzania was categorised into: intensive care unit (ICU) delivered critical care and non-ICU critical care. The availability of ICU delivered critical care was limited to urban settings whereas non-ICU critical care was found in rural and urban settings. Paediatric critical care equipment was more scarce than equipment for adults. 15 studies reported on the costs of services related to critical care yet no study reported an average or unit cost of critical care. Costs of medication, equipment (eg, oxygen, personal protective equipment), services and human resources were identified as inputs to specific critical care services in Tanzania. CONCLUSION: There is limited evidence on the resource use, availability and costs of critical care in Tanzania. There is a strong need for further empirical research on critical care resources availability, utilisation and costs across specialties and hospitals of different level in low/middle-income countries like Tanzania to inform planning, priority setting and budgeting for critical care services. PROSPERO REGISTRATION NUMBER: CRD42020221923.

CRISPR engineered mouse embryonic stem cells with Sox2-tdTomato and Gata6-GFP knock-in for endoderm differentiation.

An Embryonic stem line was engineered with CRISPR mediated knock-in to tag the endogenous locus of Sox2 with tdTomato and Gata6 with GFP. The site-specific knock-ins were genotyped by PCR and DNA sequencing. The timely expression of Gata6 and loss of Sox2 upon differentiation in cells and Embryoid bodies (EBs) were studied by microscopy. The GFP and tdtomato expressing population from day 4 EBs showed exclusive expression of GATA6 and SOX2 protein, confirming the appropriate expression of the fluorescent reporters in the cell line.