High-resolution genomic analysis to investigate the impact of the invasive brushtail possum (<i>Trichosurus vulpecula</i>) and other wildlife on microbial water quality assessments

by Marie Moinet, Lynn Rogers, Patrick Biggs, Jonathan Marshall, Richard Muirhead, Megan Devane, Rebecca Stott, Adrian Cookson

Escherichia coli are routine indicators of fecal contamination in water quality assessments. Contrary to livestock and human activities, brushtail possums (Trichosurus vulpecula), common invasive marsupials in Aotearoa/New Zealand, have not been thoroughly studied as a source of fecal contamination in freshwater. To investigate their potential role, Escherichia spp. isolates (n = 420) were recovered from possum gut contents and feces and were compared to those from water, soil, sediment, and periphyton samples, and from birds and other introduced mammals collected within the Mākirikiri Reserve, Dannevirke. Isolates were characterized using E. coli-specific real-time PCR targeting the uidA gene, Sanger sequencing of a partial gnd PCR product to generate a gnd sequence type (gST), and for 101 isolates, whole genome sequencing. Escherichia populations from 106 animal and environmental sample enrichments were analyzed using gnd metabarcoding. The alpha diversity of Escherichia gSTs was significantly lower in possums and animals compared with aquatic environmental samples, and some gSTs were shared between sample types, e.g., gST535 (in 85% of samples) and gST258 (71%). Forty percent of isolates gnd-typed and 75% of reads obtained by metabarcoding had gSTs shared between possums, other animals, and the environment. Core-genome single nucleotide polymorphism (SNP) analysis showed limited variation between several animal and environmental isolates (Escherichia clones are shared between possums, other wildlife, water, and the wider environment. These findings support the potential role of possums as contributors to fecal contamination in Aotearoa/New Zealand freshwater. Our study deepens the current knowledge of Escherichia populations in under-sampled wildlife. It presents a successful application of high-resolution genomic methods for fecal source tracking, thereby broadening the analytical toolbox available to water quality managers. Phylogenetic analysis of isolates and profiling of Escherichia populations provided useful information on the source(s) of fecal contamination and suggest that comprehensive invasive species management strategies may assist in restoring not only ecosystem health but also water health where microbial water quality is compromised.

Risk of major myopia-associated non-communicable ocular health disorders in Ghana

by Samuel Kyei, Rexford Kwasi Gyaami, John Baptist Abowine, Ebenezer Zaabaar, Kofi Asiedu, Samuel Bert Boadi-Kusi, Jacob Mensah Mesuh, Frank Assiamah, Anthony Armah, Patience Ansomah Ayerakwah

Objective

To assess the differential association of myopia with major non-communicable ocular diseases in an African clinical cohort.

Methods

A five-year hospital-based retrospective study of myopia cases. Patients’ folders, Optical Coherence Tomography scans, and fundus photographs were reviewed for the abstraction of relevant data. Only records that employed recognized standards and classification systems for diagnosing and staging the various ocular conditions were included. Demographic characteristics, non-cycloplegic objective refractive findings, and non-communicable eye diseases were retrieved from the records. Myopia-associated risk factors were then determined using logistic regression and correlation.

Results

Some 16018 patients (32027 eyes) met the inclusion criteria for at least one eye comprising 50.8% males (n = 8137) and 49.2% females (n = 7881). The mean age of the patients was 43.14 ± 17.88 years (range: 2–98 years). The mean spherical equivalent± Standard deviation for myopia was -2.30±3.23 DS (range: -0.50 to -25DS). Binary logistic regression analysis showed that myopic eyes had a higher odd of AC (OR, 0.53; 95% CI, 0.50–0.57), POAG (OR, 6.0; 95% CI, 5.26–6.82), DR (OR, 10.70; 95% CI, 3.91–29.27) and cataracts (OR, 20; 95% CI, 15.32–26.20) but not dry eye (OR, 0.74, 95% CI, 0.68–0.81), macular degeneration and pterygium (OR, 0.36; 95% CI, 0.32–0.40).

Conclusion

Africans with myopia are more at risk of developing allergic conjunctivitis, cataracts, POAG, and DR but not for dry eye, macular degeneration, and pterygium.

<i>Metarhizium</i> spp. isolates effective against Queensland fruit fly juvenile life stages in soil

by Madita Prince, Aimee C. McKinnon, Diana Leemon, Tim Sawbridge, John Paul Cunningham

Queensland fruit fly, Bactrocera tryoni, Froggatt (Diptera: Tephritidae) is Australia’s primary fruit fly pest species. Integrated Pest Management (IPM) has been adopted to sustainably manage this polyphagous species with a reduced reliance on chemical pesticides. At present, control measures are aimed at the adult stages of the fly, with no IPM tools available to target larvae once they exit the fruit and pupate in the soil. The use of entomopathogenic fungi may provide a biologically-based control method for these soil-dwelling life stages. The effectiveness of fungal isolates of Metarhizium and Beauveria species were screened under laboratory conditions against Queensland fruit fly. In bioassays, 16 isolates were screened for pathogenicity following exposure of third-instar larvae to inoculum-treated vermiculite used as a pupation substrate. The best performing Metarhizium sp. isolate achieved an average percentage mortality of 93%, whereas the best performing Beauveria isolate was less efficient, with an average mortality of 36%. Susceptibility to infection during different development stages was investigated using selected fungal isolates, with the aim of assessing all soil-dwelling life stages from third-instar larvae to final pupal stages and emerging adults. Overall, the third larval instar was the most susceptible stage, with average mortalities between 51–98% depending on the isolate tested. Moreover, adult mortality was significantly higher when exposed to inoculum during pupal eclosion, with mortalities between 56–76% observed within the first nine days post-emergence. The effect of temperature and inoculum concentration on insect mortality were assessed independently with candidate isolates to determine the optimum temperature range for fungal biological control activity and the rate required for application in field conditions. Metarhizium spp. are highly efficacious at killing Queensland fruit fly and have potential for use as biopesticides to target soil-dwelling and other life stages of B. tryoni.

The incredible shrinking puffin: Decreasing size and increasing proportional bill size of Atlantic puffins nesting at Machias Seal Island

by Heather L. Major, Joy E. Rivers, Quinn B. Carvey, Antony W. Diamond

Climate change imposes physiological constraints on organisms particularly through changing thermoregulatory requirements. Bergmann’s and Allen’s rules suggest that body size and the size of thermoregulatory structures differ between warm and cold locations, where body size decreases with temperature and thermoregulatory structures increase. However, phenotypic plastic responses to malnutrition during development can result in the same patterns while lacking fitness benefits. The Gulf of Maine (GOM), located at the southern end of the Labrador current, is warming faster than most of the world’s oceans, and many of the marine species that occupy these waters exist at the southern edge of their distributions including Atlantic puffins (Fratercula arctica; hereafter “puffin”). Monitoring of puffins in the GOM, at Machias Seal Island (MSI), has continued annually since 1995. We asked whether changes in adult puffin body size and the proportional size of bill to body have changed with observed rapid ocean warming. We found that the size of fledgling puffins is negatively related to sea surface temperature anomalies (warm conditions = small fledgers), adult puffin size is related to fledgling size (small fledgers = small adults), and adult puffins have decreased in size in recent years in response to malnutrition during development. We found an increase in the proportional size of bill to wing chord, likely in response to some mix of malnutrition during development and increasing air temperatures. Although studies have assessed clinal variation in seabird morphology with temperature, this is the first study addressing changes in seabird morphology in relation to ocean warming. Our results suggest that puffins nesting in the GOM have morphological plasticity that may help them acclimate to ocean warming.

Convergence and divergence in mortality: A global study from 1990 to 2030

by David Atance, M. Mercè Claramunt, Xavier Varea, Jose Manuel Aburto

An empirical question that has motivated demographers is whether there is convergence or divergence in mortality/longevity around the world. The epidemiological transition is the starting point for studying a global process of mortality convergence. This manuscript aims to provide an update on the concept of mortality convergence/divergence. We perform a comprehensive examination of nine different mortality indicators from a global perspective using clustering methods in the period 1990-2030. In addition, we include analyses of projections to provide insights into prospective trajectories of convergence clubs, a dimension unexplored in previous work. The results indicate that mortality convergence clubs of 194 countries by sex resemble the configuration of continents. These five clubs show a common steady upward trend in longevity indicators, accompanied by a progressive reduction in disparities between sexes and between groups of countries. Furthermore, this paper shows insights into the historical evolution of the convergence clubs in the period 1990-2020 and expands their scope to include projections of their expected future evolution in 2030.

Genetic profiling of rat gliomas and cardiac schwannomas from life-time radiofrequency radiation exposure study using a targeted next-generation sequencing gene panel

by Ashley M. Brooks, Andrea Vornoli, Ramesh C. Kovi, Thai Vu T. Ton, Miaofei Xu, Ahmed Mashal, Eva Tibaldi, Federica Gnudi, Jian-Liang Li, Robert C. Sills, John R. Bucher, Daniele Mandrioli, Fiorella Belpoggi, Arun R. Pandiri

The cancer hazard associated with lifetime exposure to radiofrequency radiation (RFR) was examined in Sprague Dawley (SD) rats at the Ramazzini Institute (RI), Italy. There were increased incidences of gliomas and cardiac schwannomas. The translational relevance of these rare rat tumors for human disease is poorly understood. We examined the genetic alterations in RFR-derived rat tumors through molecular characterization of important cancer genes relevant for human gliomagenesis. A targeted next-generation sequencing (NGS) panel was designed for rats based on the top 23 orthologous human glioma-related genes. Single-nucleotide variants (SNVs) and small insertion and deletions (indels) were characterized in the rat gliomas and cardiac schwannomas. Translational relevance of these genetic alterations in rat tumors to human disease was determined through comparison with the Catalogue of Somatic Mutations in Cancer (COSMIC) database. These data suggest that rat gliomas resulting from life-time exposure to RFR histologically resemble low grade human gliomas but surprisingly no mutations were detected in rat gliomas that had homology to the human IDH1 p.R132 or IDH2 p.R172 suggesting that rat gliomas are primarily wild-type for IDH hotspot mutations implicated in human gliomas. The rat gliomas appear to share some genetic alterations with IDH1 wildtype human gliomas and rat cardiac schwannomas also harbor mutations in some of the queried cancer genes. These data demonstrate that targeted NGS panels based on tumor specific orthologous human cancer driver genes are an important tool to examine the translational relevance of rodent tumors resulting from chronic/life-time rodent bioassays.

Morphological and ultrastructural investigation of the posterior atlanto-occipital membrane: Comparing children with Chiari malformation type I and controls

by Vijay M. Ravindra, Lorraina Robinson, Hailey Jensen, Elena Kurudza, Evan Joyce, Allison Ludwick, Russell Telford, Osama Youssef, Justin Ryan, Robert J. Bollo, Rajiv R. Iyer, John R. W. Kestle, Samuel H. Cheshier, Daniel S. Ikeda, Qinwen Mao, Douglas L. Brockmeyer

Introduction

The fibrous posterior atlanto-occipital membrane (PAOM) at the craniocervical junction is typically removed during decompression surgery for Chiari malformation type I (CM-I); however, its importance and ultrastructural architecture have not been investigated in children. We hypothesized that there are structural differences in the PAOM of patients with CM-I and those without.

Methods

In this prospective study, blinded pathological analysis was performed on PAOM specimens from children who had surgery for CM-I and children who had surgery for posterior fossa tumors (controls). Clinical and radiographic data were collected. Statistical analysis included comparisons between the CM-I and control cohorts and correlations with imaging measures.

Results

A total of 35 children (mean age at surgery 10.7 years; 94.3% white) with viable specimens for evaluation were enrolled: 24 with CM-I and 11 controls. There were no statistical demographic differences between the two cohorts. Four children had a family history of CM-I and five had a syndromic condition. The cohorts had similar measurements of tonsillar descent, syringomyelia, basion to C2, and condylar-to-C2 vertical axis (all p>0.05). The clival-axial angle was lower in patients with CM-I (138.1 vs. 149.3 degrees, p = 0.016). Morphologically, the PAOM demonstrated statistically higher proportions of disorganized architecture in patients with CM-I (75.0% vs. 36.4%, p = 0.012). There were no differences in PAOM fat, elastin, or collagen percentages overall and no differences in imaging or ultrastructural findings between male and female patients. Posterior fossa volume was lower in children with CM-I (163,234 mm³ vs. 218,305 mm³, p Conclusions

In patients with CM-I, the PAOM demonstrates disorganized architecture compared with that of control patients. This likely represents an anatomic adaptation in the presence of CM-I rather than a pathologic contribution.

Patterns in refractive error and treatment delay in keratoconus–An Australian study

by Samantha Bobba, Alanna Wood, John Males, Yves Kerdraon

Keratoconus is the most common primary corneal ectasia and is associated with significant morbidity. In its early stages, keratoconus is often asymptomatic, making the identification of subclinical disease challenging. Refractive error is a parameter that is documented at most routine optometry visits, yet interestingly, changes in refraction of keratoconic patients over time have not yet been studied and compared with the general population. Early diagnosis of keratoconus facilitates timely referral for treatments such as corneal collagen cross-linking, which has been shown to slow disease progression. In this context, documenting delays between initial presentation to the optometrist and referral for collagen-cross-linking as well as comparing the trends in visual acuity and refractive error between keratoconic and non-keratoconic patients over time are particularly relevant.

Cytomegalovirus detection is associated with ICU admission in non-AIDS and AIDS patients with <i>Pneumocystis jirovecii</i> pneumonia

by Alexandre Perret, Marion Le Marechal, Raphaele Germi, Daniele Maubon, Cécile Garnaud, Johan Noble, Aude Boignard, Loïc Falque, Mathieu Meunier, Théophile Gerster, Olivier Epaulard

Objectives

Cytomegalovirus (CMV) is frequently detected in lung and/or blood samples of patients with Pneumocystis jirovecii pneumonia (PJP), although this co-detection is not precisely understood. We aimed to determine whether PJP was more severe in case of CMV detection.

Methods

We retrospectively included all patients with a diagnosis of PJP between 2009 and 2020 in our centre and with a measure of CMV viral load in blood and/or bronchoalveolar lavage (BAL). PJP severity was assessed by the requirement for intensive care unit (ICU) admission.

Results

The median age of the 249 patients was 63 [IQR: 53–73] years. The main conditions were haematological malignancies (44.2%), solid organ transplantations (16.5%), and solid organ cancers (8.8%). Overall, 36.5% patients were admitted to ICU. CMV was detected in BAL in 57/227 patients; the 37 patients with viral load ≥3 log copies/mL were more frequently admitted to ICU (78.4% vs 28.4%, p Conclusions

PJP is more severe in the case of concomitant CMV detection. This may reflect either the deleterious role of CMV itself, which may require antiviral therapy, or the fact that patients with CMV reactivation are even more immunocompromised.

Efficacy of early cardiac rehabilitation after acute myocardial infarction: Randomized clinical trial protocol

by Caroline Schon, Amanda Felismino, Joceline de Sá, Renata Corte, Tatiana Ribeiro, Selma Bruno

The acute myocardial infarction (AMI) present high mortality rate that may be reduced with cardiac rehabilitation. Despite its good establishment in outpatient care, few studies analyzed cardiac rehabilitation during hospitalization. Thus, this study aims to clarify the safety and efficacy of early cardiac rehabilitation after AMI. This will be a clinical, controlled, randomized trial with blind outcome evaluation and a superiority hypothesis. Twenty-four patients with AMI will be divided into two groups (1:1 allocation ratio). The intervention group will receive an individualized exercise-based cardiac rehabilitation protocol during hospitalization and a semi-supervised protocol after hospital discharge; the control group will receive conventional care. The primary outcomes will be the cardiac remodeling assessed by cardiac magnetic resonance imaging, functional capacity assessed by maximal oxygen consumption, and cardiac autonomic balance examined via heart rate variability. Secondary outcomes will include safety and the total exercise dose provided during the protocol. Statistical analysis will consider the intent-to-treat analysis. Trial registration. Trial registration number: Brazilian Registry of Clinical Trials (ReBEC) (RBR- 9nyx8hb).

Cost and utilization analysis of concurrent versus staged testicular prosthesis implantation for radical orchiectomy

by Vi Nguyen, Arman Walia, Joshua J. Horns, Niraj Paudel, Aditya Bagrodia, Darshan P. Patel, Tung-Chin Hsieh, James M. Hotaling

Purpose

American Urological Association guidelines recommend testicular prosthesis discussion prior to orchiectomy. Utilization may be low. We compared outcomes and care utilization between concurrent implant (CI) and staged implant (SI) insertion after radical orchiectomy.

Materials & methods

The MarketScan Commercial claims database (2008–2017) was queried for men ages >18 years who underwent radical orchiectomy for testicular mass, stratified as orchiectomy with no implant, CI, or SI. 90-day outcomes included rate of reoperation, readmission, emergency department (ED) presentation, and outpatient visits. Regression models provided rate ratio comparison.

Results

8803 patients (8564 no implant, 190 CI, 49 SI; 2.7% implant rate) were identified with no difference in age, Charlson Comorbidity Index, insurance plan, additional cancer treatment, or metastasis. Median perioperative cost at orchiectomy (+/- implant) for no implant, CI, and SI were $5682 (3648–8554), $7823 (5403–10973), and $5380 (4130–10521), respectively (p Conclusions

CI placement has less total perioperative cost, lower explant rate, and similar postoperative utilization to SI.

Screening for antibacterial and cytotoxic activities of Sri Lankan marine sponges through microfractionation: Isolation of bromopyrrole alkaloids from <i>Stylissa massa</i>

by Lakmini Kosgahakumbura, Jayani Gamage, Luke P. Robertson, Taj Muhammad, Björn Hellman, Ulf Göransson, Prabath Jayasinghe, Chamari Hettiarachchi, Paco Cárdenas, Sunithi Gunasekera

Sri Lanka is a biodiversity hotspot and one of the richest geographical locations of marine sponges in the Indian ocean. However, the most extensive taxonomical study on Sri Lankan sponge biodiversity dates back ~100 years and only a limited number of studies have been conducted on sponge natural products. In the current study, 35 marine sponge specimens (collected from 16 sponge habitats around Sri Lanka) were identified, microfractionated and evaluated for antibacterial and anticancer assays. In total, 30 species were characterized, of which 19 species gave extracts with antibacterial and/or cytotoxic activities. Microfractionated organic extract of Aciculites orientalis gave the most potent antibacterial activity against Staphylococcus aureus and strongest lymphoma cell toxicity was exhibited by the organic extract of Acanthella sp. Guided by the molecular ion peaks in the bioactive fractions, large-scale extraction of Stylissa massa led to the isolation of three bromopyrrole alkaloids, sceptrin, hymenin and manzacidin A/C. Of these, sceptrin exhibited broad spectrum antibacterial activity against both Escherichia coli and S. aureus (MIC of 62.5 μM against both species). Based on natural product literature, seven promising species were identified as understudied. Their further exploration may lead to the discovery of structurally novel compounds.

Endorsement of COVID-19 misinformation among criminal legal involved individuals in the United States: Prevalence and relationship with information sources

by Xiaoquan Zhao, Aayushi Hingle, Cameron C. Shaw, Amy Murphy, Breonna R. Riddick, Rochelle R. Davidson Mhonde, Bruce G. Taylor, Phoebe A. Lamuda, Harold A. Pollack, John A. Schneider, Faye S. Taxman

Criminal legal system involvement (CLI) is a critical social determinant of health that lies at the intersection of multiple sources of health disparities. The COVID-19 pandemic exacerbates many of these disparities, and specific vulnerabilities faced by the CLI population. This study investigated the prevalence of COVID-19-related misinformation, as well as its relationship with COVID-19 information sources used among Americans experiencing CLI. A nationally representative sample of American adults aged 18+ (N = 1,161), including a subsample of CLI individuals (n = 168), were surveyed in February-March 2021. On a 10-item test, CLI participants endorsed a greater number of misinformation statements (M = 1.88 vs. 1.27) than non-CLI participants, p

Comorbidities in heart failure patients that predict cardiovascular readmissions within 100 days—An observational study

by Mia Scholten, Jason Davidge, Björn Agvall, Anders Halling

Background

Heart failure (HF) commonly arises as a complication to cardiovascular diseases and is closely associated with various comorbidities. The impacts of these comorbidities in patients with HF are diverse. We aimed to analyze the increased risk for cardiovascular-related readmission within 100 days after discharge in patients with HF depending on their different comorbidities.

Methods

A population-based retrospective study was conducted in Region Halland with 5029 patients admitted to hospital with a diagnosis of HF during 2017–2019. The occurrence and number of comorbidities were recorded. Competing risk regression was employed to analyze the hazard ratio (HR) of 10 comorbidities for cardiovascular-related readmission within 100 days after discharge. A composite measure of the 10 common comorbidities was constructed with the comorbidities as dichotomous indicator variables and Rasch analysis. Receiver operating characteristic (ROC) and area under curve (AUC) after logistic regression were used to estimate how well the model explained the probability of death or readmission within 100 days after discharge according to their individual comorbidity level.

Results

HF patients with atrial fibrillation, chronic obstructive pulmonary disease, chronic kidney disease, peripheral artery disease or diabetes mellitus as comorbidities had an increased HR for readmission within 100 days after discharge. When these comorbidities were adjusted together, only atrial fibrillation, chronic kidney disease and chronic obstructive pulmonary disease had an increased HR for readmission. ROC analysis after the most complete models using logistic regression with the comorbidities as dichotomous indicator variables or Rasch analysis had a low AUC.

Conclusions

Atrial fibrillation, chronic kidney disease or chronic obstructive pulmonary disease were significantly associated with increased risk for readmission in HF patients, but ROC analysis showed a low AUC, which indicates that other factors are more important for predicting the increased risk of readmission.

The role of basic psychological needs in the relationships between identity orientations and adolescent mental health: A protocol for a longitudinal study

by Veljko Jovanović, Aleksandar Tomašević, Dušana Šakan, Milica Lazić, Vesna Gavrilov-Jerković, Marija Zotović-Kostić, Vojana Obradović

Research into the role of identity orientations (the relative importance an individual places on different personal and social attributes and characteristics when defining her or his identity) in adolescent mental health is extremely limited. Furthermore, the potential mechanisms that might explain the associations between identity orientations and adolescent mental health are poorly understood. This study protocol describes a one-year longitudinal study across three time points to be initiated with the purpose of investigating the mediating role of basic psychological needs satisfaction and frustration in the relationship between identity orientations and various mental health indicators in adolescence. We aim to recruit a large sample of Serbian adolescents (N = 2,000 at Time 1), using a two-stage stratified random sampling. The data will be analyzed using the random intercept cross-lagged panel model (RI-CLPM), and the results will be contrasted with the traditional CLPM. The goal of this study is to make a theoretical contribution to research in the fields of identity, self-determination theory, and adolescent mental health, as well as to provide insights towards the development of evidence-based recommendations for creating prevention and promotion programs aimed at improving the well-being of adolescents.

Atrial fibrillation as a novel risk factor for retinal stroke: A protocol for a population-based retrospective cohort study

by Jay B. Lusk, Lauren Wilson, Vinit Nalwade, Ailin Song, Matthew Schrag, Valerie Biousse, Fan Li, Sven Poli, Jonathan Piccini, Ying Xian, Emily O’Brien, Brian Mac Grory

Central retinal artery occlusion (CRAO; retinal stroke or eye stroke) is an under-recognized, disabling form of acute ischemic stroke which causes severe visual loss in one eye. The classical risk factor for CRAO is ipsilateral carotid stenosis; however, nearly half of patients with CRAO do not have high-grade carotid stenosis, suggesting that other cardiovascular risk factors may exist for CRAO. Specifically, prior studies have suggested that cardioembolism, driven by underlying atrial fibrillation, may predispose patients to CRAO. We describe the design of an observational, population-based study in this protocol. We evaluate two specific objectives: 1) To determine if atrial fibrillation is an independent risk factor for CRAO after adjusting for medical and cardiovascular risk; 2) To determine if use of oral anticoagulation can modify the risk of CRAO for patients with atrial fibrillation. This protocol lays out our strategy for cohort definition, case and control definition, comorbidity ascertainment, and statistical methods.

Anakinra or tocilizumab in patients admitted to hospital with severe covid-19 at high risk of deterioration (IMMCoVA): A randomized, controlled, open-label trial

by Jonas Sundén-Cullberg, Puran Chen, Henrike Häbel, Paul Skorup, Helena Janols, Johan Rasmuson, Katarina Niward, Åse Östholm Balkhed, Katerina Chatzidionysiou, Hilmir Asgeirsson, Ola Blennow, Åsa Parke, Anna-Karin Svensson, Jagadeeswara Rao Muvva, Hans-Gustav Ljunggren, Karolinska KI/K COVID-19 Treatment Working Group , Anna-Carin Horne, Ulrika Ådén, Jan-Inge Henter, Anders Sönnerborg, Jan Vesterbacka, Piotr Nowak, Jon Lampa

Background

Anakinra and tocilizumab are used for severe Covid-19, but only one previous randomized controlled trial (RCT) has studied both. We performed a multi-center RCT comparing anakinra or tocilizumab versus usual care (UC) for adults at high risk of deterioration.

Methods

The study was conducted June 2020 to March 2021. Eligibility required ≥ 5 liters/minute of Oxygen to maintain peripheral oxygen saturation at ≥ 93%, CRP > 70 mg/L, ferritin > 500 μg/L and at least two points where one point was awarded for lymphocytes 9/L; D-dimer ≥ 0.5 mg/L and; lactate dehydrogenase ≥ 8 microkatal/L. Patients were randomly assigned 1:1:1 to receive either a single dose of tocilizumab (8 mg/kg) or anakinra 100 mg IV QID for seven days or UC alone. The primary outcome was time to recovery.

Results

Recruitment was ended prematurely when tocilizumab became part of usual care. Out of a planned 195 patients, 77 had been randomized, 27 to UC, 28 to anakinra and 22 to tocilizumab. Median time to recovery was 15, 15 and 11 days. Rate ratio for recovery for UC vs anakinra was 0.91, 0.47 to 1.78, 95% [CI], p = 0.8 and for UC vs tocilizumab 1.13, 0.55 to 2.30; p = 0.7. There were non-significant trends favoring tocilizumab (and to limited degree anakinra) vs UC for some secondary outcomes. Safety profiles did not differ significantly.

Conclusion

Premature closure of trial precludes firm conclusions. Anakinra or tocilizumab did not significantly shorten time to clinical recovery compared to usual care. (IMMCoVA, NCT04412291, EudraCT: 2020–00174824).

ROS mediated anticandidal efficacy of 3-Bromopyruvate prevents vulvovaginal candidiasis in mice model

by Ravi Jothi, Seong-Tshool Hong, Munkhtur Enkhtsatsral, Shunmugiah Karutha Pandian, Shanmugaraj Gowrishankar

Candidal infections, particularly vulvovaginal candidiasis (VVC), necessitate effective therapeutic interventions in clinical settings owing to their intricate clinical nature and elusive understanding of their etiological mechanisms. Given the challenges in developing effective antifungal therapies, the strategy of repurposing existing pharmaceuticals has emerged as a promising approach to combat drug-resistant fungi. In this regard, the current study investigates molecular insights on the anti-candidal efficacy of a well-proven anticancer small molecule -3-bromopyruvate (3BP) against three clinically significant VVC causing Candida species viz., C. albicans, C. tropicalis and C. glabrata. Furthermore, the study validates 3BP’s therapeutic application by developing it as a vaginal cream for the treatment of VVC. 3BP exhibited phenomenal antifungal efficacy (killing >99%) with minimum inhibitory concentrations (MIC) and minimum fungicidal concentrations (MFC) of 256 μg/mL against all tested Candida spp. Time killing kinetics experiment revealed 20 min as the minimum time required for 3BP at 2XMIC to achieve complete-killing (99.9%) in all Candida strains. Moreover, the ergosterol or sorbitol experiment explicated that the antifungal activity of 3BP does not stem from targeting the cell wall or the membrane component ergosterol. Instead, 3BP was observed to instigate a sequence of pre-apoptotic cascade events, such as phosphatidylserine (PS) externalization, nuclear condensation and ROS accumulations, as evidenced by PI, DAPI and DCFH-DA staining methods. Furthermore, 3BP demonstrated a remarkable efficacy in eradicating mature biofilms of Candida spp., achieving a maximum eradication level of 90%. Toxicity/safety profiling in both in vitro erythrocyte lysis and in vivo Galleria mellonella survival assay authenticated the non-toxic nature of 3BP up to 512 μg/mL. Finally, a vaginal cream formulated with 3BP was found to be effective in VVC-induced female mice model, as it significantly decreasing fungal load and protecting vaginal mucosa. Concomitantly, the present study serves as a clear demonstration of antifungal mechanistic action of anticancer drug -3BP, against Candida species. This finding holds significant potential for mitigating candidal infections, particularly VVC, within healthcare environments.

Comparing undergraduate research experiences before, during, and after the COVID-19 quarantine: The successful adaptation of the BUILD PODER Summer JumpStart program

by Patricia Escobedo, Daniel Garcia, Liam Cascelli, Gabriela Chavira, Gilberto E. Flores, Jodi L. Constantine Brown, David Boyns, Andrew T. Ainsworth

In March 2020, the COVID-19 pandemic forced many in person undergraduate research experiences (UREs) to pivot to remote online training. To investigate how the COVID-19 quarantine disrupted student URE outcomes over time, the current study examines Building Infrastructure Leading to Diversity (BUILD) Promoting Opportunities for Diversity in Education and Research (PODER) URE outcomes across different platforms (in-person, remote, and hybrid models) by comparing student survey data from 2019 to 2021. Participants consisted of three cohorts: 2019 (n = 26 students), 2020 (n = 33), 2021 (n = 34). The BUILD PODER Summer JumpStart program (SJS), which aims to increase diversity in Science, Technology, Engineering, and Mathematics (STEM) by recruiting mostly underrepresented students, was conducted in person in 2019, remotely in 2020 and using a hybrid model in 2021. All students completed an online survey on the first and last day of the four-week SJS program. We used one-way and mixed ANOVA models to analyze Cohort, Time (pre-test vs. post-test scores), and interaction of Cohort and Time for Research Self-Efficacy, Sense of Belonging, Mentor Relationship, Mentee Knowledge, Health, Stress, and Student Program Satisfaction measures. Despite the platform changes, student scores increased significantly over time for all measures. There was a significant main effect of Time for Research Self-Efficacy, Sense of Belonging, Mentor Relationship, Mentee Knowledge, Health Assessment, and Stress Management. Findings indicate that URE programs that are implemented remotely and using a hybrid format can provide students with experiences similar to in-person URE programs. In addition, remote UREs may provide added benefits compared to in-person programs. For instance, remote UREs could engage more historically minoritized students, who may experience barriers to access, such as work/family commitments, financial constraints, and geographic limitations.

Systematic review of end stage renal disease in Pakistan: Identifying implementation research outcomes

by Hamad AlRashed, Johanna Miele, Joshua Prasad, Deborah Adenikinju, Chukwuemeka Iloegbu, John Patena, Dorice Vieira, Joyce Gyamfi, Emmanuel Peprah

Aim and objectives

The aim of this study was to conduct a systematic review analysis to identify and evaluate the available literature on implementation science outcomes research in relation to End Stage Renal Disease (ESRD) in Pakistan.

Methods

A systematic database search of PubMed, Web of Science, EMBASE, Cochrane Library, CINAHL, and Ovid was conducted through October 22^nd, 2022, without any restrictions on publication dates. A screening and data extraction tool, Covidence, was used to evaluate the literature against our inclusion and exclusion criteria. Furthermore, a Mixed Methods Appraisal Tool (MMAT) was used to evaluate the selected studies.

Results

We identified four studies that presented findings of implementation outcomes research which were related to appropriateness, feasibility, and acceptability. Appropriateness was examined using knowledge scores (p = 0.022) and medication adherence scores (p Conclusion

The preliminary results of this review indicate a gap in the availability of implementation research studies about ESRD in Pakistan. The burden of ESRD, and the implementation methods by which it is treated is notable in Pakistan and requires evidence-based measures to be implemented to support the critical healthcare delivery platforms that provide treatment.