Functions and Effectiveness of Unloader, Patellofemoral, and Knee Sleeve Orthoses: A Review.

Background: Knee orthoses have been extensively used as a nonsurgical approach to improving knee deficiencies. Currently, arthritic knee conditions remain the leading cause of disability, and this number is expected to increase. As the use of knee orthoses varies widely, so has their effectiveness which is still largely debatable. Here, we present the functions and effectiveness of the three most prominent knee orthotic models dedicated to supporting knee osteoarthritis-unloader, patellofemoral, and knee sleeves. Purpose/Research Question: Considering the depth and diversity of the many clinical studies and documented laboratory reports published to date, this literature review was created to educate the clinician, patient, and researcher on common knee orthoses used for the management of arthritic knee conditions. In doing so, we discuss their design, biomechanical effects, and clinical efficacy, as well as broader outcomes, limitations, and recommendations for use. Results/Synthesis: The knee orthoses discussed within the scope of this paper are dedicated to protecting the knee against strenuous compressive loads that may affect the patellofemoral and tibiofemoral joints of the knee. Since the knee has multiple axes of motion and articulating surfaces that experience different loads during functional activities, it can be implied that, to a large extent, knee brace designs can differ drastically. Unloader knee orthoses are designed to decrease tibiofemoral and patellofemoral joint pressures. Patellofemoral knee orthoses are designed to decrease strain on the patellofemoral and quadriceps tendons while stabilizing the patella. Knee sleeves are designed to stabilize movements, reduce pain in joints, and improve proprioception across the knee joint. Conclusion: Although patients often report benefits from wearing braces, these benefits have not been confirmed by clinicians and scientific investigators. Results from these three orthosis types show that clinical efficacy is still elusive due to the different methodologies used by researchers. Layman Summary: Knee orthoses also referred to as knee brace are commonly used for support and stability of the knee. Unloader knee braces are designed to relieve and support those suffering from knee osteoarthritis by improving physical impairment and reducing pain. Patellofemoral knee braces aim to help patients manage patellofemoral pain syndrome. Rehabilitative compression sleeves, also known as knee sleeves, are often used to assist patients suffering from knee pain and laxity. Important findings on the three knee braces discussed show discrepancies in results. Their effectiveness and validity are yet to be understood.

Maleimide functionalized polycaprolactone micelles for glutathione quenching and doxorubicin delivery.

High glutathione production is known to be one of the defense mechanisms by which many cancer cells survive elevated oxidative stress. By explicitly targeting glutathione in these cancer cells and diminishing its levels, oxidative stress can be intensified, ultimately triggering apoptosis or programmed cell death. Herein, we developed a novel approach by creating maleimide-functionalized polycaprolactone polymers, specifically using 2,3-diiodomaleimide functionality to reduce the level of glutathione in cancer cells. Polycaprolactone was chosen to conjugate the 2,3-diiodomaleimide functionality due to its biodegradable and biocompatible properties. The amphiphilic block copolymer was synthesized using PEG as a macroinitiator to make corresponding polymeric micelles. The resulting 2,3-diiodomaleimide-conjugated polycaprolactone micelles effectively quenched glutathione, even at low concentrations (0.01 mg mL-1). Furthermore, we loaded these micelles with the anticancer drug doxorubicin (DOX), which exhibited pH-dependent drug release. We obtained a loading capacity (LC) of 3.5% for the micelles, one of the highest LC reported among functional PCL-based micelles. Moreover, the enhanced LC doesn't affect their release profile. Cytotoxicity experiments demonstrated that empty and DOX-loaded micelles inhibited cancer cell growth, with the DOX-loaded micelles displaying the highest cytotoxicity. The ability of the polymer to quench intracellular GSH was also confirmed. This approach of attaching maleimide to polycaprolactone polymers shows promise in depleting elevated glutathione levels in cancer cells, potentially improving cancer treatment efficacy.

Dentate gyrus is needed for memory retrieval.

The hippocampus is crucial for acquiring and retrieving episodic and contextual memories. In previous studies, the inactivation of dentate gyrus (DG) neurons by chemogenetic- and optogenetic-mediated hyperpolarization led to opposing conclusions about DG's role in memory retrieval. One study used Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-mediated clozapine N-oxide (CNO)-induced hyperpolarization and reported that the previously formed memory was erased, thus concluding that denate gyrus is needed for memory maintenance. The other study used optogenetic with halorhodopsin induced hyperpolarization and reported and dentate gyrus is needed for memory retrieval. We hypothesized that this apparent discrepancy could be due to the length of hyperpolarization in previous studies; minutes by optogenetics and several hours by DREADD/CNO. Since hyperpolarization interferes with anterograde and retrograde neuronal signaling, it is possible that the memory engram in the dentate gyrus and the entorhinal to hippocampus trisynaptic circuit was erased by long-term, but not with short-term hyperpolarization. We developed and applied an advanced chemogenetic technology to selectively silence synaptic output by blocking neurotransmitter release without hyperpolarizing DG neurons to explore this apparent discrepancy. We performed in vivo electrophysiology during trace eyeblink in a rabbit model of associative learning. Our work shows that the DG output is required for memory retrieval. Based on previous and recent findings, we propose that the actively functional anterograde and retrograde neuronal signaling is necessary to preserve synaptic memory engrams along the entorhinal cortex to the hippocampal trisynaptic circuit.

Delivery at an inadequate level of maternal care is associated with severe maternal morbidity.

BACKGROUND: Implementing levels of maternal care is one strategy proposed to reduce maternal morbidity and mortality. The levels of maternal care framework outline individual medical and obstetrical comorbidities, along with hospital resources required for individuals with these different comorbidities to deliver safely. The overall goal is to match individuals to hospitals so that all birthing people get appropriate resources and personnel during delivery to reduce maternal morbidity. OBJECTIVE: This study examined the association between delivery in a hospital with an inappropriate level of maternal care and the risk of experiencing severe maternal morbidity. STUDY DESIGN: The 40 birthing hospitals in Massachusetts were surveyed using the Centers for Disease Control and Prevention's Levels of Care Assessment Tool. We linked individual delivery hospitalizations from the Massachusetts Pregnancy to Early Life Longitudinal Data System to hospital-level data from the Levels of Care Assessment Tool surveys. Level of maternal care guidelines were used to outline 16 high-risk conditions warranting delivery at hospitals with resources beyond those considered basic (level I) obstetrical care. We then used the Levels of Care Assessment Tool assigned levels to determine if delivery occurred at a hospital that had the resources to meet an individual's needs (ie, if a patient received risk-appropriate care). We conducted our analyses in 2 stages. First, multivariable logistic regression models predicted if an individual delivered in a hospital that did not have the resources for their risk condition. The main explanatory variable of interest was if the hospital self-assessed their level of maternal care to be higher than the Levels of Care Assessment Tool assigned level. We then used logistic regression to examine the association between delivery at an inappropriate level hospital and the presence of severe maternal morbidity at delivery. RESULTS: Among 64,441 deliveries in Massachusetts from January 1 to December 31, 2019, 33.2% (21,415/64,441) had 1 or more of the 16 high-risk conditions that require delivery at a center designated as a level I or higher. Of the 21,415 individuals with a high-risk condition, 13% (2793/21,415), equating to 4% (2793/64,441) of the entire sample, delivered at an inappropriate level of maternal care. Birthing individuals with high-risk conditions who delivered at a hospital with an inappropriate level had elevated odds (adjusted odds ratio, 3.34; 95% confidence interval, 2.24-4.96) of experiencing severe maternal morbidity after adjusting for patient comorbidities, demographics, average hospital severe maternal morbidity rate, hospital level of maternal care, and geographic region. CONCLUSION: Birthing people who delivered in a hospital with risk-inappropriate resources were substantially more likely to experience severe maternal morbidity. Delivery in a hospital with a discrepancy in their self-assessment and the Levels of Care Assessment Tool assigned level substantially predicted delivery in a hospital with an inappropriate level of maternal care, suggesting inadequate knowledge of hospitals' resources and capabilities. Our data demonstrate the potential for the levels of maternal care paradigm to decrease severe maternal morbidity while highlighting the need for robust implementation and education to ensure everyone receives risk-appropriate care.

Reversible Cross-linked Thermoresponsive Polycaprolactone Micelles for Enhanced Stability and Controlled Release.

Thermoresponsive amphiphilic poly(ε-caprolactone)s (PCL)s are excellent candidates for drug delivery due to their biodegradability, biocompatibility, and controlled release. However, the thermoresponsivity of modified PCL can often lead to premature drug release because their lower critical solution temperature (LCST) is close to physiological temperature conditions. To address this issue, we developed a novel approach that involves functionalizing redox-responsive lipoic acid to the hydrophobic block of PCL. Lipoic acid has disulfide bonds that undergo reversible cross-linking after encapsulating the drug. Herein, we synthesized an ether-linked propargyl-substituted PCL as the hydrophobic block of an amphiphilic copolymer along with unsubstituted PCL. The propargyl group was used to attach lipoic acid through a postpolymerization modification reaction. The hydrophilic block is composed of an ether-linked, thermoresponsive tri(ethylene glycol)-substituted PCL. Anticancer drug doxorubicin (DOX) was encapsulated within the core of the micelles and induced cross-linking in the presence of a reducing agent, dithiothreitol. The developed micelles are thermodynamically stable and demonstrated thermoresponsivity with an LCST value of 37.5 °C but shifted to 40.5 °C after cross-linking. The stability and release of both uncross-linked (LA-PCL) and cross-linked (CLA-PCL) micelles were studied at physiological temperatures. The results indicated that CLA-PCL was stable, and only 35% release was observed after 46 h at 37 °C while LA-PCL released more than 70% drug at the same condition. Furthermore, CLA-PCL was able to release a higher amount of DOX in the presence of glutathione and above the LCST condition (42 °C). Cytotoxicity experiments revealed that CLA-PCL micelles are more toxic toward MDA-MB-231 breast cancer cells at 42 °C than at 37 °C, which supported the thermoresponsive release of the drug. These results indicate that the use of reversible cross-linking is a great approach toward synthesizing stable thermoresponsive micelles with reduced premature drug leakage.

Pre- and postsynaptic N-methyl-D-aspartate receptors are required for sequential printing of fear memory engrams.

The organization of fear memory involves the participation of multiple brain regions. However, it is largely unknown how fear memory is formed, which circuit pathways are used for "printing" memory engrams across brain regions, and the role of identified brain circuits in memory retrieval. With advanced genetic methods, we combinatorially blocked presynaptic output and manipulated N-methyl-D-aspartate receptor (NMDAR) in the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) before and after cued fear conditioning. Further, we tagged fear-activated neurons during associative learning for optogenetic memory recall. We found that presynaptic mPFC and postsynaptic BLA NMDARs are required for fear memory formation, but not expression. Our results provide strong evidence that NMDAR-dependent synaptic plasticity drives multi-trace systems consolidation for the sequential printing of fear memory engrams from BLA to mPFC and, subsequently, to the other regions, for flexible memory retrieval.

Injectable and biodegradable piezoelectric hydrogel for osteoarthritis treatment.

Osteoarthritis affects millions of people worldwide but current treatments using analgesics or anti-inflammatory drugs only alleviate symptoms of this disease. Here, we present an injectable, biodegradable piezoelectric hydrogel, made of short electrospun poly-L-lactic acid nanofibers embedded inside a collagen matrix, which can be injected into the joints and self-produce localized electrical cues under ultrasound activation to drive cartilage healing. In vitro, data shows that the piezoelectric hydrogel with ultrasound can enhance cell migration and induce stem cells to secrete TGF-ß1, which promotes chondrogenesis. In vivo, the rabbits with osteochondral critical-size defects receiving the ultrasound-activated piezoelectric hydrogel show increased subchondral bone formation, improved hyaline-cartilage structure, and good mechanical properties, close to healthy native cartilage. This piezoelectric hydrogel is not only useful for cartilage healing but also potentially applicable to other tissue regeneration, offering a significant impact on the field of regenerative tissue engineering.

Recent Advances in Polycaprolactones for Anticancer Drug Delivery.

Poly(ε-Caprolactone)s are biodegradable and biocompatible polyesters that have gained considerable attention for drug delivery applications due to their slow degradation and ease of functionalization. One of the significant advantages of polycaprolactone is its ability to attach various functionalities to its backbone, which is commonly accomplished through ring-opening polymerization (ROP) of functionalized caprolactone monomer. In this review, we aim to summarize some of the most recent advances in polycaprolactones and their potential application in drug delivery. We will discuss different types of polycaprolactone-based drug delivery systems and their behavior in response to different stimuli, their ability to target specific locations, morphology, as well as their drug loading and release capabilities.

Risk of Severe Maternal Morbidity in Birthing People With Opioid Use Disorder.

INTRODUCTION: We examined severe maternal morbidity (SMM) among birthing people with opioid use disorder (OUD) and evaluated the extent to which differences in SMM exist by race and ethnicity. METHODS: We performed a retrospective cohort study using hospital discharge data for all Massachusetts births between 2016 and 2020. SMM rates for all SMM indicators, except transfusions, were computed for those diagnosed with and without OUD. Multivariable logistic regression was used to examine the association between OUD and SMM after adjusting for patient and hospital characteristics, including race and ethnicity. RESULTS: Among 324,012 childbirths, the SMM rate was 148 (95% confidence interval [CI]. 115-189) per 10,000 childbirths among birthing people with OUD compared with 88 (95% CI, 85-91) for those without. In adjusted models, both OUD and race/ethnicity were significantly associated with SMM. Birthing people with OUD had 2.12 (95% CI, 1.64-2.75) times the odds of experiencing an SMM event compared with those without. Non-Hispanic Black and Hispanic birthing people were at 1.85 (95% CI, 1.65-2.07) and 1.26 (95% CI, 1.13-1.41) higher odds of experiencing SMM compared with non-Hispanic White birthing people. Among birthing people with OUD, the odds of SMM were not significantly different between birthing people of color and non-Hispanic White individuals. CONCLUSIONS: Birthing people with OUD are at an elevated risk of SMM, underscoring the need for improved access to OUD treatment and increased support. Perinatal quality improvement collaboratives should measure SMM in bundles aimed at improving outcomes for birthing people with OUD.

Corrosion of Metals During Use in Arthroplasty.

Arthroplasty implants can undergo corrosion at the modular components, trunnion, and hinges, owing to implant material makeup, micromotion, and interaction with body fluid. In this review, various mechanisms of corrosion in arthroplasty were explored with suggestions on means of improvement. We identified 10 methods including pitting, crevice, mechanically assisted crevice corrosion, fretting, fretting initiated crevice corrosion, mechanically assisted taper corrosion, galvanic corrosion, stress/tension, fatigue corrosion, and inflammatory cell induced corrosion. The position of implants on the galvanic series, and their ability to maintain passivation contribute to their longevity in service. Due to the relative motion of arthroplastic components, bio-tribocorrosion may disrupt passive oxide films, and pitting is initiated at interfaces. Thus, corrosion in arthroplasty as an electrochemical phenomenon mainly starts on one spot and progresses in 3 steps: (1) the oxidative dissolution of metal from implant surfaces into the aqueous active environment, releasing cations, (2) the attraction of electrons to the opposite charge created at another point of the implant surface, producing current flow, and (3) the formation of oxides of metal and metal hydroxides deposited as rust at the surface of the implant. Recent innovations in material manufacturing continue to improve the efficiency of arthroplasty; however, the component parts remain susceptible to bio-tribocorrosion. Thus, a complete eradication of corrosion in arthroplasty would require futuristic materials with improvement in recent materials and designs, derived from knowledge of existing retrieved implants, and strategies to provide overall surface finishes that protect against bio-tribocorrosion.

Qualitative assessment of infant sleep practices and other risk factors of sudden infant death syndrome (SIDS) among mothers in Lusaka, Zambia.

BACKGROUND: There is very little information on the beliefs and perceptions of mothers about SIDS and its related risk factors in Africa. To better understand parental decisions about infant sleep practices and other risk factors for SIDS, we conducted focus group discussions (FGDs) with mothers of infants in Lusaka, Zambia. METHODS: FGDs involved 35 purposively sampled mothers aged 18-49 years. FGDs were conducted using a semi-structured interview guide in the local language, Nyanja. These were translated, transcribed verbatim into English, and then coded and analyzed using thematic analysis in NVivo 12. RESULTS: Six FGDs were conducted with 35 mothers in April-May 2021 across two study sites. FGD Participants were generally aware of sudden unexplained infant deaths, with several describing stories of apparent SIDS in the community. The side sleeping position was preferred and perceived to be safer for the infant with most believing the supine position posed an aspiration or choking risk to the infant. Bedsharing was also preferred and perceived to be convenient for breastfeeding and monitoring of the infant. Experienced family members such as grandmothers and mothers-in-law, and health care workers were frequently cited as sources of information on infant sleep position. A heightened awareness of the infant's sleeping environment was suggested as a mechanism to prevent SIDS and smothering. CONCLUSIONS: Decisions about bedsharing and infant sleep position were guided by maternal beliefs and perceptions about what is convenient for breastfeeding and safer for the infant. These concerns are vital to designing tailored interventions to address sleep-related sudden infant losses in Zambia. Public health campaigns with tailored messages that address these concerns are likely to be effective at ensuring optimal uptake of safe sleep recommendations.

Entomological surveillance on Aedes aegypti during covid 19 period in Cape Coast, Ghana: Risk of arboviral outbreaks, multiple insecticide resistance and distribution of F1534C, V410L and V1016I kdr mutations.

BACKGROUND: The study assessed the risk of transmission of Aedes-borne arboviruses in a community at Cape Coast during the Covid-19 restriction period in 2020 based on entomological indices. The spatial distribution of insecticide resistance was also assessed in Ae. aegypti population from Cape Coast. METHODS: Three larval indices were calculated from a household larval survey in 100 randomly selected houses. WHO susceptibility bioassay was performed on female adult Ae. aegypti that were reared from the larvae collected from household containers and other receptacles located outside houses against four insecticides. The mosquitoes were also screened for F1534C, V1016I, and V410L kdr mutations. RESULTS: The estimated larval indices in the study community were House index- 34%, Container index- 22.35%, and Breteau index- 2.02. The mosquito population was resistant to Deltamethrin (0.05%), DDT (4%), Fenitrothion (1%), and Bendiocarb (0.1%). A triple kdr mutation, F1534C, V410L and V1016I were detected in the mosquito population. CONCLUSION: The study found the risk of an outbreak of Aedes-borne diseases lower in the covid-19 lockdown period than before the pandemic period. The low risk was related to frequent clean-up exercises in the community during the Covid-19 restriction period. Multiple insecticide resistance couple with three kdr mutations detected in the study population could affect the effectiveness of control measures, especially in emergency situations. The study supports sanitation improvement as a tool to control Ae. aegypti and could complement insecticide-based tools in controlling this vector.

Causes of death and post-mortem testing for SARS-CoV-2 in a tertiary hospital during the COVID-19 pandemic in Ghana.

Background: Causes of death during the coronavirus disease 2019 (COVID-19) pandemic ranhttp://crossmark.crossref.org/dialog/?doi=10.4102/ajlm.v11i1.1766=pdf&date_stamp=2022-11-23ge from direct consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to deaths unrelated to SARS-CoV-2. Another feature of the pandemic is the post-mortem testing for SARS-CoV-2. Understanding these aspects of COVID-19 are essential in planning and limiting the impact of SARS-CoV-2 virus on healthcare systems. Objective: This study investigated the underlying causes of death and the presence of SARS-CoV-2 in bodies received at the 37 Military Hospital, Accra, Ghana, during the COVID-19 pandemic. Methods: The study was conducted from 4-27 May 2020. Deceased patients that met the inclusion criteria were prospectively selected during the expanded surveillance period for SARS-CoV-2 testing, autopsy and determination of underlying and immediate cause of death. Results: A total of 161 deceased patients were analysed with 53 autopsies. The overall positive test rate for SARS-CoV-2 was 14.9% (24/161 patients), with a positive rate of 5.0% (8/161 patients) for nasopharyngeal samples and 30.2% (16/161 patients) for bronchopulmonary samples. The underlying causes of death were not related to SARS-CoV-2 infection in 85.1% (137/161) of patients, SARS-CoV-2-associated 12.4% (20/161) and SARS-CoV-2-induced in 2.5% (4/161). Cardiovascular complications formed the most common cause of death in patients with or without SARS-CoV-2. Conclusion: There was a high positive rate of SARS-CoV-2 in post-mortem cases. However, most deaths were not caused by SARS-CoV-2 but by cardiovascular complications. The high rate of bronchopulmonary positive results for SARS-CoV-2 requires that autopsies be done in suspicious cases with negative nasopharyngeal sampling.

Assessing infant sleep practices and other risk factors of SIDS in Zambia: a cross-sectional survey of mothers in Lusaka, Zambia.

BACKGROUND: Having infants sleep with their parents and sleeping face down or on their sides are the two most proximate and modifiable risk factors for sudden infant death syndrome (SIDS). Little is known about the burden of SIDS or the prevalence of these risk factors in Africa. Our primary objective was to determine the prevalence of modifiable risk factors of SIDS in Lusaka, Zambia. METHODS: We conducted cross-sectional surveys with recent mothers of infants aged < 1 year across two busy urban clinic sites in Lusaka, Zambia. We used log-binomial regression analysis to identify factors predictive of bedsharing and prone sleeping. RESULTS: Surveys were conducted with 478 mothers between April-May 2021. The sleep-related risk factors, bedsharing and side sleeping, were widely prevalent. 89.5% of respondents indicated that they share a bed with the infant during sleep, 73.0% preferred putting their baby on its side, and 19.9% preferred the prone position. Only 6.7% of respondents described using the safer, supine position. Age of infant was the only factor which was predictive of prone sleeping. Infants > 2 months old were twice as likely to be put to sleep in a prone position compared to infants aged less than 2 months old. Mothers reported that they rarely (24.1%) received advice from medical caregivers to use the supine position. Maternal use of alcohol (12.0%) and tobacco (0.8%) during pregnancy were uncommon. CONCLUSIONS: Bedsharing and placing the infant to sleep on the side were commonly reported among the mothers we interviewed. Whether this represents an opportunity to reduce SIDS in Zambia is unclear since accurate data on the burden of SIDS in Zambia is not available. There is a need for increased awareness of SIDS and more prospective data collection on its burden and related risk factors in these African populations.

Covalent and Noncovalent Loading of Doxorubicin by Folic Acid-Carbon Dot Nanoparticles for Cancer Theranostics.

With special properties such as excellent fluoresce features, low toxicity, good biocompatibility, permeability, and easy clearance from the body, carbon dot (CD)-based nanoparticles (NPs) have the potential to deliver drugs and use in vivo diagnostics through molecular imaging. In this work, folic acid-CD (FA-CD) NPs were prepared to deliver doxorubicin (Dox) covalently and noncovalently as cancer theranostics. FA was conjugated to the surface of CDs for targeting cancer cells with overexpressing folate receptors. CDs prepared with various amounts of precursors lead to their associated NPs with different photoluminescence properties and drug release profiles. The loading of Dox and its releasing data depends on the linkage of drug Dox to FA-CD and CD composition. All NPs were characterized by UV-vis, Fourier transform infrared spectroscopy, and dynamic light scattering. The noncovalent FA-CD-Dox NPs were preferred with a simple preparation process, excellent photoluminescence, and in vitro drug release properties. The noncovalent FA-CD-Dox showed the best efficacy against MDA-MB-231 compared to the CD-Dox and covalent FA-CD-Dox.

Response of three local chicken ecotypes of Ghana to lentogenic and velogenic Newcastle disease virus challenge.

This study was carried out to assess the response of three Ghanaian local chicken ecotypes to LaSota (lentogenic) and virulent field strains of Newcastle disease virus (NDV). Local chickens sampled from the Interior Savannah (IS), Forest (FO) and Coastal Savannah (CS) agro-ecological zones were bred and their offspring were challenged with LaSota NDV at 4 weeks of age. The LaSota challenge was replicated four times with different chicken groups. A total of 1438 chicks comprising 509 Coastal Savannah, 518 Forest and 411 Interior Savannah ecotypes were used. Pre- and post-challenge anti-NDV antibody titre levels were determined via ELISA assays. A second trial was conducted by introducing sick birds infected with virulent NDV to a flock of immunologically naïve chickens at 4 weeks old. Body weights were measured pre- and post-infection. Sex of the chickens was determined using a molecular method. In both trials, there was no significant difference among ecotypes in body weight and growth rate. In the LaSota trial, anti-NDV antibody titre did not differ by ecotype or sex. However, there was a positive linear relationship between body weight and antibody titre. In the velogenic NDV trial, survivability and lesion scores were similar among the three ecotypes. This study confirms that a relatively high dose of LaSota (NDV) challenge has no undesirable effect on Ghanaian local chicken ecotypes. All three Ghanaian local chicken ecotypes were susceptible to velogenic NDV challenge. Resistance to NDV by Ghanaian local chickens appears to be determined more by the individual's genetic makeup than by their ecotype.

Short regulatory DNA sequences to target brain endothelial cells for gene therapy.

Gene vectors targeting CNS endothelial cells allow to manipulate the blood-brain barrier and to correct genetic defects in the CNS. Because vectors based on the adeno-associated virus (AAV) have a limited capacity, it is essential that the DNA sequence controlling gene expression is short. In addition, it must be specific for endothelial cells to avoid off-target effects. To develop improved regulatory sequences with selectivity for brain endothelial cells, we tested the transcriptional activity of truncated promoters of eleven (brain) endothelial-specific genes in combination with short regulatory elements, i.e., the woodchuck post-transcriptional regulatory element (W), the CMV enhancer element (C), and a fragment of the first intron of the Tie2 gene (S), by transfecting brain endothelial cells of three species. Four combinations of regulatory elements and short promoters (Cdh5, Ocln, Slc2a1, and Slco1c1) progressed through this in-vitro pipeline displaying suitable activity. When tested in mice, the regulatory sequences C-Ocln-W and C-Slc2a1-S-W enabled a stronger and more specific gene expression in brain endothelial cells than the frequently used CAG promoter. In summary, the new regulatory elements efficiently control gene expression in brain endothelial cells and may help to specifically target the blood-brain barrier with gene therapy vectors.

Causes of death and post-mortem testing for SARS-CoV-2 in a tertiary hospital during the COVID-19 pandemic in Ghana

Background: Causes of death during the coronavirus disease 2019 (COVID-19) pandemic ranhttp://crossmark.crossref.org/dialog/?doi=10.4102/ajlm.v11i1.1766=pdf&date_stamp=2022-11-23ge from direct consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to deaths unrelated to SARS-CoV-2. Another feature of the pandemic is the post-mortem testing for SARS-CoV-2. Understanding these aspects of COVID-19 are essential in planning and limiting the impact of SARS-CoV-2 virus on healthcare systems. Objective: This study investigated the underlying causes of death and the presence of SARS-CoV-2 in bodies received at the 37 Military Hospital, Accra, Ghana, during the COVID-19 pandemic. Methods: The study was conducted from 4­27 May 2020. Deceased patients that met the inclusion criteria were prospectively selected during the expanded surveillance period for SARS-CoV-2 testing, autopsy and determination of underlying and immediate cause of death. Results: A total of 161 deceased patients were analysed with 53 autopsies. The overall positive test rate for SARS-CoV-2 was 14.9% (24/161 patients), with a positive rate of 5.0% (8/161 patients) for nasopharyngeal samples and 30.2% (16/161 patients) for bronchopulmonary samples. The underlying causes of death were not related to SARS-CoV-2 infection in 85.1% (137/161) of patients, SARS-CoV-2-associated 12.4% (20/161) and SARS-CoV-2-induced in 2.5% (4/161). Cardiovascular complications formed the most common cause of death in patients with or without SARS-CoV-2. Conclusion: There was a high positive rate of SARS-CoV-2 in post-mortem cases. However, most deaths were not caused by SARS-CoV-2 but by cardiovascular complications. The high rate of bronchopulmonary positive results for SARS-CoV-2 requires that autopsies be done in suspicious cases with negative nasopharyngeal sampling.

Evaluation of the Efficacy of Doxycycline, Ciprofloxacin, Levofloxacin, and Co-trimoxazole Using In Vitro and In Vivo Models of Q Fever.

Q fever, caused by the intracellular pathogen Coxiella burnetii, is traditionally treated using tetracycline antibiotics, such as doxycycline. Doxycycline is often poorly tolerated, and antibiotic-resistant strains have been isolated. In this study, we have evaluated a panel of antibiotics (doxycycline, ciprofloxacin, levofloxacin, and co-trimoxazole) against C. burnetii using in vitro methods (determination of MIC using liquid and solid media; efficacy assessment in a THP cell infection model) and in vivo methods (wax moth larvae and mouse models of infection). In addition, the schedule for antibiotic treatment has been evaluated, with therapy initiated at 24 h pre- or postchallenge. Both doxycycline and levofloxacin limited overt clinical signs during treatment in the AJ mouse model of aerosol infection, but further studies are required to investigate the possibility of disease relapse or incomplete bacterial clearance after the antibiotics are stopped. Levofloxacin was well tolerated and therefore warrants further investigation as an alternative to the current recommended treatment with doxycycline.

Discovery of Orally Active Isofuranones as Potent, Selective Inhibitors of Hematopoetic Progenitor Kinase 1.

While the discovery of immune checkpoint inhibitors has led to robust, durable responses in a range of cancers, many patients do not respond to currently available therapeutics. Therefore, an urgent need exists to identify alternative mechanisms to augment the immune-mediated clearance of tumors. Hematopoetic progenitor kinase 1 (HPK1) is a serine-threonine kinase that acts as a negative regulator of T-cell receptor (TCR) signaling, to dampen the immune response. Herein we describe the structure-based discovery of isofuranones as inhibitors of HPK1. Optimization of the chemotype led to improvements in potency, selectivity, plasma protein binding, and metabolic stability, culminating in the identification of compound 24. Oral administration of 24, in combination with an anti-PD1 antibody, demonstrated robust enhancement of anti-PD1 efficacy in a syngeneic tumor model of colorectal cancer.