Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents.

Leishmaniasis is a neglected tropical disease that is estimated to afflict over 12 million people. Current drugs for leishmaniasis suffer from serious deficiencies, including toxicity, high cost, modest efficacy, primarily parenteral delivery, and emergence of widespread resistance. We have discovered and developed a natural product-inspired tambjamine chemotype, known to be effective against Plasmodium spp, as a novel class of antileishmanial agents. Herein, we report in vitro and in vivo antileishmanial activities, detailed structure-activity relationships, and metabolic/pharmacokinetic profiles of a large library of tambjamines. A number of tambjamines exhibited excellent potency against both Leishmania mexicana and Leishmania donovani parasites with good safety and metabolic profiles. Notably, tambjamine 110 offered excellent potency and provided partial protection to leishmania-infected mice at 40 and/or 60 mg/kg/10 days of oral treatment. This study presents the first account of antileishmanial activity in the tambjamine family and paves the way for the generation of new oral antileishmanial drugs.

Consideration for alpha-gal syndrome in two critically ill persons with group O blood who received group B plasma.

BACKGROUND: The U.S. Centers for Disease Control and Prevention (CDC) has reported increasing rates of alpha-gal syndrome, an allergic response after meat ingestion (AGS). AGS has been associated with prior exposure to tick bites or other biologics characterized by a life-threatening immunoglobulin E (IgE)-mediated hypersensitivity to galactose-alpha-1,3-galactose (alpha-gal) an oligosaccharide structurally similar to the group B antigen on red blood cells (RBC) found in most non-primate mammalian meat and products derived from these mammals. In 2023, Transfusion reported 3 group O recipients of group B plasma in the Washington, D.C. metropolitan area with no history of meat allergy who had anaphylactic transfusion reactions compatible with AGS. AIMS: We investigated allergic reactions in 2 additional patients who received ABO minor-incompatible blood products at 2 hospitals in the D.C. area during fall 2023. METHODS: For both patients, a medical chart review was performed and IgE levels to alpha-gal were measured. RESULTS: The first patient, a 64-year-old, O-positive patient status post heart transplant with no known allergies, was admitted with acute COVID-19 induced antibody-mediated transplant rejection and placed on extracorporeal membrane oxygenation (ECMO). While undergoing plasma exchange (PLEX) (50% albumin/50% fresh frozen plasma (FFP)), the patient tolerated 2 units of group O FFP and 1 unit of group A FFP before becoming hemodynamically unstable during transfusion of 1 unit of B-positive FFP. PLEX was stopped. The patient later died of sepsis from underlying causes. The second patient, a 57-year-old O-positive man with a history of melanoma and neuro fibromatosis type 1, was undergoing an abdominal resection including transfusion of 3 units of O-positive RBC when he suffered hypotension and ventricular tachycardia requiring intraoperative code after receiving 2 units of group B FFP. Hiveswere noted after resuscitation. The patient had a history of tick bites but no known allergies. He is alive 5 months after the possible allergic event. Both patients had full transfusion reaction evaluations and immunology testing results above the positive cutoff for anti-alpha-gal IgE. DISCUSSION AND CONCLUSION: Two patients with O-positive blood and no known allergies experience danaphyl axis after transfusion with group B FFP. The symptoms cannot definitively be imputed to an allergic transfusion reaction, but the presence of IgE against alpha-gal supports an association. Medicating patients with antihistamines and IV steroids pre-transfusion may prevent allergic reactions. Restricting group B plasma-containing products (plasma, platelets, cryoprecipitate) for patients who experience AGS-like symptoms may be considered.

Relationship between workplace violence and mental/physical health of security guards during the COVID-19 pandemic in Taiwan.

Objectives: To investigate the relationship between workplace violence (WPV) and mental and physical health (MPH) of security guards during the COVID-19 pandemic in Taiwan. Methods: A cross-sectional survey was conducted in 15 representative security companies across northern, central, and southern Taiwan, and outlying islands from July 2021 to June 2022 during the COVID-19 pandemic. 1,200 questionnaires were distributed. A total of 1,032 valid questionnaires were collected. Results: 13.18% of the participants reported that they had experienced WPV during the COVID-19 pandemic, including physical violence (PhV), psychological violence (PsV), verbal violence (VV), and sexual harassment (SH). The most common violence was VV (54.19%), followed by PsV (20.69%). Community residents and property owners were the primary perpetrators, followed by strangers. The study showed that the security guards who had experienced WPV had higher scores on the 12-item Chinese Health Questionnaire (Taiwan version) (CHQ-12), indicating poorer MPH than those who had never experienced WPV. The result showed that VV had strong correlations with the lack of effective communication, dissatisfaction with treatment and service attitude, and work stress. PsV was strongly associated with excessive waiting times. Conclusion: There were correlations among PhV, VV, and PsV and they had adverse impacts on MPH, except for SH. The study found that the primary perpetrators of WPV against security guards were community residents and property owners. The causes were the lack of effective communication, dissatisfaction with treatment and service attitude, excessive waiting times, and work stress, which further led to turnover intention and poor MPH. The findings of this study have useful implications and it is recommended to enhance the understanding of workplace violence against security guards and to formulate appropriate local and international strategies to address it.

From TgO/GABA-AT, GABA, and T-263 Mutant to Conception of Toxoplasma.

Toxoplasma gondii causes morbidity, mortality, and disseminates widely via cat sexual stages. Here, we find T. gondii ornithine aminotransferase (OAT) is conserved across phyla. We solve TgO/GABA-AT structures with bound inactivators at 1.55 Å and identify an inactivator selective for TgO/GABA-AT over human OAT and GABA-AT. However, abrogating TgO/GABA-AT genetically does not diminish replication, virulence, cyst-formation, or eliminate cat's oocyst shedding. Increased sporozoite/merozoite TgO/GABA-AT expression led to our study of a mutagenized clone with oocyst formation blocked, arresting after forming male and female gametes, with "Rosetta stone"-like mutations in genes expressed in merozoites. Mutations are similar to those in organisms from plants to mammals, causing defects in conception and zygote formation, affecting merozoite capacitation, pH/ionicity/sodium-GABA concentrations, drawing attention to cyclic AMP/PKA, and genes enhancing energy or substrate formation in TgO/GABA-AT-related-pathways. These candidates potentially influence merozoite's capacity to make gametes that fuse to become zygotes, thereby contaminating environments and causing disease.

Evaluation of Real and Perceived Risk to Health Care Workers Caring for Patients With the Omicron Variant of the SARS-CoV-2 Virus in Surgery and Obstetrics.

OBJECTIVES: The Omicron variant of the SARS-CoV-2 virus is described as more contagious than previous variants. We sought to assess risk to health care workers (HCWs) caring for patients with COVID-19 in surgical/obstetrical settings, and the perception of risk among this group. METHODS: From January to April 2022, reverse transcription polymerase chain reaction was used to detect the presence of SARS-CoV-2 viral ribonucleic acid in patient, environmental (floor, equipment, passive air) samples, and HCWs' masks (inside surface) during urgent surgery or obstetrical delivery for patients with SARS-CoV-2 infection. The primary outcome was the proportion of HCWs' masks testing positive. Results were compared with our previous cross-sectional study involving obstetrical/surgical patients with earlier variants (2020-2021). HCWs completed a risk perception electronic questionnaire. RESULTS: Eleven patients were included: 3 vaginal births and 8 surgeries. In total, 5/108 samples (5%) tested positive (SARS-CoV-2 Omicron) viral ribonucleic acid: 2/5 endotracheal tubes, 1/22 floor samples, 1/4 patient masks, and 1 nasal probe. No samples from the HCWs' masks (0/35), surgical equipment (0/10), and air (0/11) tested positive. No significant differences were found between the Omicron and 2020/21 patient groups' positivity rates (Mann-Whitney U test, P = 0.838) or the level of viral load from the nasopharyngeal swabs (P = 0.405). Nurses had a higher risk perception than physicians (P = 0.038). CONCLUSION: No significant difference in contamination rates was found between SARS-CoV-2 Omicron BA.1 and previous variants in surgical/obstetrical settings. This is reassuring as no HCW mask was positive and no HCW tested positive for COVID-19 post-exposure.

'It's really important to be collaborating': Experiences of participatory research for Chinese and Vietnamese parents of autistic children.

Background and aims: Participatory research involves academic partners working together with the community that is affected by research to make decisions about that research. Such approaches often result in research that is more respectful of, and responsive to, community preferences - and is vital in the context of autism research with culturally and linguistically diverse (CALD) communities. Whilst participatory approaches are becoming more commonplace within CALD autism research, no studies have explored the experiences of being involved in autism research from the perspectives of CALD community partners over the course of a study. This paper intended to address this gap by reporting on the experiences of CALD parents of autistic children who were community partners in a 1-year Australian research project exploring home-school partnerships for CALD parents of autistic children. We aimed to: (1) report on how parents' involvement in the research process shaped the home-school partnerships study over time and (2) understand their experiences of being community partners on the home-school partnerships project. Methods: Using key principles of participatory approaches, we established Chinese and Vietnamese parent advisory groups to contribute to a project exploring home-school partnerships for parents of autistic children from CALD backgrounds in Australia. Advisory groups included parents of autistic children from Chinese/Vietnamese backgrounds, as well as interpreters, professionals and researchers. We documented how parents' participation as community partners shaped the home-school partnerships study over the course of the project. We also elicited parents' own views and experiences of being community partners through informal, open-ended questions at the beginning and end of the study. Results: We found that parents' input fundamentally shaped the broader home-school partnership study, from meaningful, accurate translation of interview schedules through to making decisions regarding community-specific recommendations and dissemination plans. Parents themselves reported being keen to collaborate and to hear and share opinions for the purpose of the home-school partnership study - although they noted how emotionally difficult sharing their stories could be. While they initially had some concerns about combining being involved as a community partner with their existing responsibilities, ultimately, parents were surprised by the scope of the home-school partnership study and their level of involvement as community partners. Through hearing others' stories and sharing their own in advisory group meetings, parents reported ancillary benefits of their involvement, including increased self-advocacy and well-being. Conclusions: These findings show how research that is conducted in partnership with diverse members of the autism community has the capacity to improve the quality of the research and benefit community partners. Implications: This study clearly documents the benefits and potential challenges of participatory approaches with CALD communities. These findings emphasise to researchers and funders the importance of including extra time and money within budgets in order to produce meaningful research that is respectful and responsive to communities.

Prevalence and shared risk factors of HIV in three key populations in Vietnam: A systematic review and meta-analysis.

This study aims to estimate the prevalence of HIV among each of the three key populations in Vietnam: people who inject drugs (PWID), female sex workers (FSW), and men who have sex with men (MSM) and quantify their shared risk factors for HIV infection through a systematic review and meta-analysis of recent literature (published in 2001-2017) in the relevant topics. A total of 17 studies consisting of 16,304 participants were selected in this review. The meta-analysis results revealed that the pooled prevalence estimates with 95% confidence intervals (CIs) among PWID, FSW, and MSM were: 0.293 (0.164, 0.421), 0.075 (0.060, 0.089), and 0.085 (0.044, 0.126), respectively. The findings also indicated that injecting drug use (OR: 9.88, 95%CI: 4.47-15.28), multiperson use of injecting equipment (OR: 2.91, 95%CI: 1.69, 4.17), and inconsistent condom use (OR: 2.11, 95%CI: 1.33, 2.90) were the shared risk factors for HIV infection among these population groups. The findings highlighted the importance of HIV prevention approaches to addressing the shared sexual and drug-related practices among the key populations in consideration of their overlapping social networks.

Thalassemia carrier status and groundwater iron: Implication for iron supplementation program for children in Bangladesh.

Background: Thalassemia, a congenital disorder of hemoglobin synthesis is characterized by low hemoglobin and high iron status, is prevalent in Bangladesh. Iron, consumed through drinking groundwater also increases the population iron status in Bangladesh. The study examined the effect of iron containing micronutrient powder (MNP) on the hemoglobin and ferritin status in Bangladeshi children with thalassemia and their non-thalassemia peers exposed to a high concentration of iron from drinking groundwater. Design and methods: Three hundred twenty-seven children aged 2-5 years were recruited for an MNP efficacy trial. A sub sample (n = 222) were screened for thalassemia. Hemoglobin and ferritin levels were measured in children with and without thalassemia. Intake of iron from the key sources-diet, groundwater and MNP was measured. Mann Whitney and t-test were employed to compare the groups. Results: Hemoglobin concentration of the children with thalassemia at the endpoint remained unchanged relative to the baseline; 11.56 ± 0.59 g/dL (Endpoint) versus 11.6 ± 0.54 g/dL (Baseline), p = 0.83. In children without thalassemia hemoglobin tended to increase; 12.54 ± 0.72 g/dL (Endpoint) versus 12.41 ± 0.72 g/dL (baseline), p = 0.06. Baseline reserve of body iron was significantly (p = 0.03) higher in thalassemia carriers (594 gm) compared to their non-carrier peers (558 gm). The increase of the infection-adjusted ferritin from baseline to the endpoint was 7.37% (p = 0.7) and 10.17% (p = 0.009) in the carrier and non-carrier groups respectively. Conclusions: In Bangladesh, the coexistence of thalassemia and the exposure to a high concentration of iron from drinking groundwater renders anemia prevention program with a low iron MNP potentially lesser hazardous to the thalassemia carriers.

Neuronal tau pathology worsens late-phase white matter degeneration after traumatic brain injury in transgenic mice.

Traumatic brain injury (TBI) causes diffuse axonal injury which can produce chronic white matter pathology and subsequent post-traumatic neurodegeneration with poor patient outcomes. Tau modulates axon cytoskeletal functions and undergoes phosphorylation and mis-localization in neurodegenerative disorders. The effects of tau pathology on neurodegeneration after TBI are unclear. We used mice with neuronal expression of human mutant tau to examine effects of pathological tau on white matter pathology after TBI. Adult male and female hTau.P301S (Tg2541) transgenic and wild-type (Wt) mice received either moderate single TBI (s-TBI) or repetitive mild TBI (r-mTBI; once daily × 5), or sham procedures. Acutely, s-TBI produced more extensive axon damage in the corpus callosum (CC) as compared to r-mTBI. After s-TBI, significant CC thinning was present at 6 weeks and 4 months post-injury in Wt and transgenic mice, with homozygous tau expression producing additional pathology of late demyelination. In contrast, r-mTBI did not produce significant CC thinning except at the chronic time point of 4 months in homozygous mice, which exhibited significant CC atrophy (- 29.7%) with increased microgliosis. Serum neurofilament light quantification detected traumatic axonal injury at 1 day post-TBI in Wt and homozygous mice. At 4 months, high tau and neurofilament in homozygous mice implicated tau in chronic axon pathology. These findings did not have sex differences detected. Conclusions: Neuronal tau pathology differentially exacerbated CC pathology based on injury severity and chronicity. Ongoing CC atrophy from s-TBI became accompanied by late demyelination. Pathological tau significantly worsened CC atrophy during the chronic phase after r-mTBI.

Using LC-MS/MS to Determine Salivary Steroid Reference Intervals in a European Older Adult Population.

A number of steroids, including glucocorticoids and sex hormones, have been associated with neurodegenerative and cardiovascular conditions common in aging populations. The application of liquid chromatography tandem mass spectrometry (LC-MS/MS) steroid analysis offers an opportunity to conduct simultaneous multiplex steroid analysis within a given sample. In this paper, we describe the application of an LC-MS/MS steroid analysis method for the assessment of reference ranges of steroids in human saliva samples (200 µL) collected from older adults (age 50 years and above) enrolled in a European cohort investigating the risk for Alzheimer's dementia. Saliva samples were prepared using supported liquid extraction (SLE) along with a calibration curve and analysed using a Waters I-Class UPLC (Ultra Performance Liquid Chromatography) and a Sciex QTrap 6500+ mass spectrometer. Mass spectrometry parameters of steroids were optimised for each steroid and a method for the chromatographic separation of 19 steroids was developed. Lower limits of quantitation (LLOQs), linearity and other method criteria were assessed. In total, data from 125 participants (500 samples) were analysed and assessed for reference ranges (64 male, 61 female). A total of 19 steroids were detected in saliva within the range of the method. There were clear diurnal patterns in most of the steroid hormones detected. Sex differences were observed for androstenedione (A4), testosterone (T), cortisone (E) and aldosterone (Aldo). In the first sample of the day, dehydroepiandrosterone (DHEA) was significantly higher in healthy volunteers compared to those with Alzheimer's disease biomarkers. This LC-MS/MS method is suitable for the analysis of 19 steroids in saliva in adults.

Evidence of adult male scarcity associated with female-skewed offspring sex ratios in sea turtles.

Climate change is a clear and present threat to species survival. For species with temperature-dependent sex determination, including all sea turtles, it has been hypothesised that climate change may drive the creation of sex-ratio biases leading to population extinctions1. Through a global analysis across multiple species, we present the first direct empirical evidence for a demographic consequence of male scarcity in sea turtle populations, with a lower incidence of multiple paternity being found in populations with more extreme female-biased hatchling sex-ratio skews. For green turtles, when the female bias in hatchling sex ratio was >90%, the incidence of multiple paternity was low compared to other nesting sites, being 24.5% in the eastern Mediterranean (Cyprus), 36.4% on Redang Island (Malaysia) and 15.4% on the southern Great Barrier Reef (Heron Island, Australia) compared to higher values (range 61.1-91.7%) at other sites globally. These results suggest that a low incidence of multiple paternity may serve as a harbinger of future problems with egg fertility if males become even scarcer. Assessments of the incidence of multiple paternity at sites where adult males are expected to become scarce, such as Raine Island on the northern Great Barrier Reef in Australia, may help to identify when a lack of males raises the threat of local extinctions. In such cases, intervention to increase the production of male hatchlings may be needed.

Spesolimab, an anti-interleukin-36 receptor antibody, in patients with moderate-to-severe atopic dermatitis: Results from a multicentre, randomized, double-blind, placebo-controlled, phase IIa study.

BACKGROUND: Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease, and there is increasing evidence that the interleukin (IL)-36 pathway may play a role in the pathogenesis of AD. OBJECTIVES: To evaluate the efficacy and safety of spesolimab, a novel anti-IL-36 receptor antibody, in adult patients with moderate-to-severe AD. METHODS: In this phase IIa study, 51 eligible patients were randomized 2:1 to receive intravenous doses of spesolimab 600 mg or placebo every 4 weeks. The primary endpoint was the percentage change from baseline in Eczema Area and Severity Index (EASI) score at Week 16. RESULTS: The decrease in EASI score from baseline to Week 16 was -37.9% for spesolimab versus -12.3% for placebo (adjusted mean difference -25.6%, p = 0.149). A predefined sensitivity analysis, excluding data from patients who used restricted corticosteroids, resulted in an adjusted mean difference of -48.3% (nominal p = 0.024). Spesolimab was well tolerated, with no clinically relevant safety signals. CONCLUSIONS: This is the first study to evaluate the IL-36 pathway inhibition in AD. Although not statistically significant, numerical improvements were observed in the primary endpoint of change from baseline in the EASI score. Spesolimab had an acceptable safety profile, with no unexcepted safety concerns.

Vision screening outcomes of 4-5 year-olds reflect the social gradient.

CLINICAL RELEVANCE: Children in socioeconomically disadvantaged communities often do not access follow-up eye care services when referred from vision screenings; whether this is due to lack of availability is not known. This paper highlights the need for vision and eye care for vulnerable children with practicing clinical optometrists well placed to provide vision care. BACKGROUND: Vision impairments develop from a young age and may inhibit learning experiences and impact life outcomes. Vision screening to detect and refer vision abnormalities supports children in their education and prevents minor vision impairments from worsening. This research describes outcomes from a vision screening programme for 4- to 5-year-olds delivered in Queensland, Australia. METHODS: The programme involved all prep children from participating schools in Queensland. Vision screening was conducted with the Parr 4 m Visual Acuity Test and Welch Allyn Spot Vision Screener. A cross-sectional study design was adopted. Descriptive data analyses explored the frequency of vision screening and referral outcomes. Inferential analyses examined associations between vision screening and referral outcomes with socio-economic indexes for areas (SEIFA) scores . RESULTS: Of 71,003 prep students screened, 4,855 (6.8%) received a referral recommendation. A higher proportion of children who received a referral recommendation was from more disadvantaged locations (?2 = 109.16, p < 0.001). Of the students referred, 3,017 were seen by an eye health professional. Further vision assessment of students by an eye health professional revealed that 43.3% of the referred children were diagnosed with a vision abnormality, 18.9% had no vision abnormality and 37.7% had an 'undetermined' diagnosis. A higher proportion of children confirmed with a vision abnormality were from more disadvantaged locations (?2 = 52.27, p < 0.001). CONCLUSION: It is important that vision screening programmes target disadvantaged populations and support families of children who require further health assessment to access health services.

Synthesis and In vitro Efficacy of Tetracyclic Benzothiazepines Against Blood-Stage Plasmodium falciparum and Liver-Stage P. berghei.

OBJECTIVE: A series of novel, substituted tetracyclic benzothiazepines were designed and prepared in an effort to optimize the potency of this chemical class against drug-resistant strains of the malaria parasite. METHODS: Tetracyclic benzothiazepines bearing structural modification at seven distinct positions within the structure were synthesized in Knoevenagel condensation reactions followed by sequential intermolecular thio-Michael and then intramolecular imine formation reactions. Following purification and chemical characterization, the novel compounds were tested for in vitro efficacy against blood-stage P. falciparum and liver-stage P. berghei and also for in vivo efficacy against P. berghei. RESULTS: Benzothiazepines bearing structural modification at the sulfur atom and at the three carbocycles within the molecule were successfully synthesized. The majority of analogs inhibited bloodstage P. falciparum with submicromolar IC50 values. The potency of an 8-methoxy-substituted analog 12 exceeded that of chloroquine in all three P. falciparum strains tested. The parent benzothiazepine 1 possessed liver-stage activity, inhibiting P. berghei sporozoites infecting HepG2 cells with an IC50 of 106.4 nM and an IC90 of 408.9 nM, but failed to enhance the longevity of P. berghei infected mice compared to the controls. Compounds displayed modest toxicity toward HepG2 cells and were tolerated by mice at the highest dose tested, 640 mg/kg/dose once daily for three days. CONCLUSION: The tetracyclic benzothiazepine described, which inhibits P. berghei infected hepatic cells with an IC50 of 106.4 nM, would appear to warrant further investigation. Optimization of ADME properties may be required since the most active analogs are probably excessively lipophilic.

"They Were Saying That I Was a Typical Chinese Mum" : Chinese Parents' Experiences of Parent-Teacher Partnerships for Their Autistic Children.

Effective parent-teacher partnerships improve outcomes for autistic students. Yet, we know little about what effective partnerships look like for parents of autistic children from different backgrounds. We conducted interviews with 17 Chinese parents of autistic children attending Australian kindergartens/schools to understand their experiences. Parents appreciated the acceptance, opportunities and supports they received in Australia. They had high expectations of children; expectations not often shared by educators. Parents were respectful of teachers' expertise and polite and undemanding in interactions. Nevertheless, parents were frustrated by inconsistent teaching quality and inadequate communication. Navigating systems was also challenging and parents faced discrimination from teachers and their community. Recommendations include fostering open home-school communication, proactively seeking parents' expertise about children and explicitly scaffolding parents' self-advocacy.

Intimate Partner Violence in the Sub-Saharan African Immigrant Community in Chicago: A Changing Landscape.

The challenges of conducting research on intimate partner violence (IPV) in immigrant communities means little is known about the occurrence of various forms of IPV, making it difficult to address in these populations. This research draws on data gathered in Chicago's large and varied African immigrant communities. This research used a mixed methods approach: collection of quantitative survey data on occurrence, followed by qualitative interviews to explain the results. Missing quantitative data and contradicting qualitative responses made it difficult to draw definite conclusions on physical IPV; however, verbal abuse and controlling behaviours appear to be relatively widespread and normalised, and not always viewed as violence. Particularly with the probability of future pandemics and natural disasters, which are known to increase prevalence, it is important to raise awareness of less visible controlling behaviours and verbal abuse as forms of violence, and to implement appropriate prevention programs to minimise a concomitant rise in IPV within African immigrant communities.