bluuebunny/crossref_metadata_2025 huggingface dataset:
A Systematic and Critical Review on the Anatomy of the Ethmoidal Foramina
Authors: Durante Miriam , Bonente Denise , Fagni Niccolò , Mandalà Marco , Barone Virginia , Nicoletti Claudio , Bertelli Eugenio
Published: July 2024

Purpose:

The osteologic anatomy of the orbit is still a field of intense research, particularly as far as vascular channels are concerned. Among them, ethmoidal foraminas (EFs) are certainly those that have more clinical importance and indeed have been deeply investigated. Unfortunately, the vast production of articles, far from clarifying their anatomy, generated a certain degree of confusion.

Methods:

A search on Pubmed and Scopus databases updated up to December 31, 2023, has been carried out with the keyword “ethmoidal foramen” yielding a list of 357 items. With a careful screening process, 31 articles were enlisted to be included in the present review.

Results:

A critical review process confirmed that many results published over the years appear inconsistent, particularly as far as EFs topography is concerned. The possible reasons for this lack of consistency can be traced back to inter-ethnical differences, uncertainty on the anterior bony landmarks employed in the investigations, and lack of a general consensus over EFs classification. A novel approach, based on the normalization of the distance of the anterior landmarks relative to the length of the orbit (relative depth index), should overcome some of the major problems encountered so far.

Conclusions:

Novel and clear guidelines to classify EFs and to locate them on the medial wall are required. Determining the relative depth index of EFs may be an interesting approach to solve the matter. Other methods can be also devised. However, direct measurements from bony landmarks, without any further analysis seem inadequate and possibly misleading
Intratarsal Keratinous Cyst at the Eyelid Margin: A Case Report
Authors: Tada Atsushi , Ono Yuko , Kojima Takayoshi , Machida Shigeki
Published: July 2024

An uncommon case of an intratarsal keratinous cyst at the lid margin is described in a 73-year-old Asian man using long-term antiglaucoma eye drops. There was no history of trauma or surgery of the upper eyelid. A yellow solid mass attached to the tarsal plate had been located there for about 3 years. It imitated a sebaceous gland carcinoma or steatocystoma simplex. Excision biopsy showed cystic formation and leaked yellow creamy substance without hair. Histopathological and immunological findings helped make the diagnosis of an intratarsal keratinous cyst. To the best of the authors’ knowledge, this is the first case report of an intratarsal keratinous cyst at the lid margin.
The effect of dexamethasone and bupivacaine on postoperative pain and nausea and vomiting by preperitoneal nerve blocking in laparoscopic cholecystectomy: a randomized clinical trial
Authors: Eslamian Mohammad , Sheikhbahaei Erfan , Esparham Ali , Zefreh Hamidreza , Fasahat Amirhossein , Firouzfar Alireza , Talebzadeh Hamid
Published: July 2024

Background:

This study aims to examine the effects of preperitoneal administration of dexamethasone and bupivacaine surrounding laparoscopic trocars on postoperative pain (POP) and nausea and vomiting (PONV) in patients undergoing laparoscopic cholecystectomy (LC).

Method:

In this randomized triple-blinded trial with a 1:1 randomization ratio, 104 patients with chronic cholecystitis were candidates for elective LC. A total of 40 mg (8 ml) of bupivacaine was mixed with 8 mg (2 ml) of dexamethasone or normal saline. The solution was injected preperitoneally via an 18G needle parallel and lateral to trocars until a bulge in the interior surface of the parietal peritoneum was observed by the camera. Primary outcomes were the severity of POP based on 0–10 Likert visual analog scale (VAS) and rates of PONV and secondary outcomes were rate of postoperative opioid usage and any side-effects.

Result:

The mean VAS score was significantly lower in the dexamethasone group (3.5 vs. 6.2, P<0.001). The dexamethasone group had 46.2% and 26.9% lower rates of nausea and vomiting after LC compared to the other group (P=0.001 and 0.015, respectively). Postoperative opioid use was lower in the dexamethasone group, but its difference was insignificant (P=0.3).

Conclusions:

Preperitoneal dexamethasone injection around laparoscopic trocars may lower the intensity of POP and PONV rates. Perioperative local corticosteroids can be used as an effective, available, and inexpensive analgesic and antiemetic prevention for laparoscopic procedures.
A cross-sectional study measuring the magnitude of depression and associated factors among patients attending orthopedic outpatient clinic at Ambo University Referral Hospital, Ambo Town, Oromia, Ethiopia, 2023
Authors: Duresa Daditau B. , Benti Tsegaye , Birhanu Adamu , Teshome Zenebe B. , Mulugeta Wondwossen
Published: July 2024

Background:

Depression is a leading cause of major public health problems globally, and its frequency has been increasing, particularly in low-income and middle-income countries. The prevalence of depression in sub-Saharan Africa ranges from 15 to 30%. In Ethiopia, depression is found to be the seventh leading cause of disease burden, yet no study was done in West Shewa, Ethiopia. Therefore, this study aimed to assess the magnitude of depression and associated factors among adult orthopedic outpatients getting treatment at Ambo University Referral Hospital, West Shewa, Oromia, Ethiopia, in 2023.

Methods:

An institution-based cross-sectional study was conducted among 391 adult orthopedic patients from January 1–30, 2023. A systematic random sampling technique was used to select the study subjects. The data were collected by using a structured questionnaire and checklist through face-to-face interviews and chart review techniques. The collected data were entered into Epi-data, version 4.6, and then exported to SPSS, version 26.0, for statistical analysis. The binary logistic regression model was fitted, and both bivariable and multivariable logistic regression analyses were employed.

Result:

The magnitude of depression was found to be 38.9% (95% CI: 34.5%, 43.9%), being female [adjusted odds ratio (AOR)=2.41; 95% confidence interval (CI): 1.45–4.00], chewing chat (AOR=2.39; 95% CI: 1.29–4.43), and no disorder on the lower limb (AOR=0.24; 95% CI: 0.07–0.85), had ligament injury (AOR=2.62; 95% CI: 1.23–5.59), had no complication (AOR=0.07; 95% CI: 0.01–0.52), and had amputation (AOR=3.83; 95% CI: 2.09–7.00) were significantly associated with depression.

Conclusion and recommendation:

The study found that the prevalence of depression among orthopedic patients was considerable; nearly half of the participants developed depression at Ambo University Referral Hospital, and being female, chewing chat, having no disorder on the lower limb, having a ligament injury, having a complication, and being amputated were significantly associated with depression. Therefore, due attention is needed from concerned bodies in order to tackle this problem.
Assessment of predictive value of thyromental height in predicting difficult laryngoscopy compared with Mallampati, and thyromental distance among surgical patient who will take general anesthesia at selected governmental hospital cross-sectional study: Ethiopia, 2022
Authors: Ashebir Zewetir , Fentie Fissiha , Mohammed Zebiba
Published: July 2024

Background:

Anesthesiologists must always perform a preoperative airway examination to identify individuals who will have challenging laryngoscopy. In an effort to identify the most accurate airway predictor, numerous authors have evaluated a number of predictive assays. Thyromental height test (TMHT), a new airway predictor, has recently been demonstrated to have good predictive value in determining difficult airways. This study’s main objective was to assess the diagnostic effectiveness of the TMHT and compare it to other known airway predictors, such as the modified Mallampati test (MMT) and the thyromental distance (TMD).

Objective:

To assess the predictive value of TMHT in predicting difficult laryngoscopy compared to modified MMT and TMD among patients who will take general anesthesia.

Method:

In this prospective, observational study, which took place from March 2021 to May 2021, 247 people of either sex who were older than 18 but not more than 65 and scheduled for elective surgery under general anesthesia participated. The receiver operating characteristic (ROC) curve was used to identify the proper cut-off values for TMHT, and the Fisher exact test was used to calculate the correlation.

Result:

Incidence of Difficult laryngoscopy was 13.4%. For TMHT the cut-off values were 4.9 cm and it had a sensitivity of 78.8%, a specificity of 89.7%, a positive predictive value (PPV) of 54.2%, and a negative predictive value (NPV) of 96.5%, respectively. When compared to other parameters, like TMD, and MMT. TMHT had the highest sensitivity, specificity, PPV, and NPV. (P<0.000)

Conclusion and recommendation:

Of all the airway assessments, the TMHT had the highest accuracy and odds ratio for predicting difficult laryngoscopy with the highest odds ratio and accuracy. TMHT has to be validated in broader patient groups because it appears to be a possible single anatomical marker for predicting the likelihood of a difficult laryngoscopy. It needs more research because it isn’t assessed in pediatrics and pregnant women.
Feasibility and Acceptability of a Prospective Syphilis Sexual Network Study for Sexual Minority Men
Authors: Ricks JaNelle M. , Spahnie Morgan , Endres-Dighe Stacy , Conroy Sara , Miller William C. , Turner Abigail N.
Published: July 2024

Background

In preparation for a prospective syphilis network study of sexual minority men, we conducted a mixed-methods formative study with the following objectives: (a) assess acceptability of respondent-driven sampling, (b) assess acceptability of study procedures, (c) social network seed selection, and (d) pilot an ecological momentary assessment (EMA) study to assess social networking, sexual, and substance use behaviors.

Methods

We conducted in-depth interviews with 8 providers serving sexual minority men and 5 focus group discussions with 34 sexual minority men, prioritizing 4 target populations: (1) young Black sexual minority men, (2) on preexposure prophylaxis, (3) living with HIV, and (4) not engaged in care. The 4-week EMA pilot was conducted with 40 sexual minority men. Ecological momentary assessment survey responses were analyzed to evaluate how different compensation levels influenced response rates. Brief exit surveys were used to assess EMA app acceptability.

Results

Primary themes identified through qualitative data collection: (1) importance of developing trust and maintaining confidentiality during proposed recruitment activities, (2) importance of compensating participants appropriately for study activities, and (3) cultural considerations for increasing visibility and participation of young Black sexual minority men. All EMA participants reported being “completely comfortable” reporting sexual behavior through the app. Most (78%) preferred the app to in-person interviews. Several participants identified technical issues with the app, including not receiving push notifications and spontaneous closure.

Conclusions

This mixed-methods formative study allowed for adjustments to and tailoring of the planned network study, including recruitment protocols, compensation type and amount, and EMA survey wording and response items.
Usability Testing Via Simulation
Authors: Wing Robyn , Goldman Michael P. , Prieto Monica M. , Miller Kelsey A. , Baluyot Mariju , Tay Khoon-Yen , Bharath Anita , Patel Deepa , Greenwald Emily , Larsen Ethan P. , Polikoff Lee A. , Kerrey Benjamin T. , Nishisaki Akira , Nagler Joshua
Published: July 2024

Objectives

To inform development of a preintubation checklist for pediatric emergency departments via multicenter usability testing of a prototype checklist.

Methods

This was a prospective, mixed methods study across 7 sites in the National Emergency Airway Registry for Pediatric Emergency Medicine (NEAR4PEM) collaborative. Pediatric emergency medicine attending physicians and senior fellows at each site were first oriented to a checklist prototype, including content previously identified using a modified Delphi approach. Each site used the checklist in 2 simulated cases: an “easy airway” and a “difficult airway” scenario. Facilitators recorded verbalization, completion, and timing of checklist items. After each simulation, participants completed an anonymous usability survey. Structured debriefings were used to gather additional feedback on checklist usability. Comments from the surveys and debriefing were qualitatively analyzed using a framework approach. Responses informed human factors-based optimization of the checklist.

Results

Fifty-five pediatric emergency medicine physicians/fellows (4–13 per site) participated. Participants found the prototype checklist to be helpful, easy to use, clear, and of appropriate length. During the simulations, 93% of checklist items were verbalized and more than 80% were completed. Median time to checklist completion was 6.2 minutes (interquartile range, 4.8–7.1) for the first scenario and 4.2 minutes (interquartile range, 2.7–5.8) for the second. Survey and debriefing data identified the following strengths: facilitating a shared mental model, cognitively offloading the team leader, and prompting contingency planning. Suggestions for checklist improvement included clarifying specific items, providing more detailed prompts, and allowing institution-specific customization. Integration of these data with human factors heuristic inspection resulted in a final checklist.

Conclusions

Simulation-based, human factors usability testing of the National Emergency Airway Registry for Pediatric Emergency Medicine Preintubation Checklist allowed optimization prior to clinical implementation. Next steps involve integration into real-world settings utilizing rigorous implementation science strategies, with concurrent evaluation of the impact on patient outcomes and safety.
Immune responses and severe dengue: what have we learned?
Authors: Malavige Gathsaurie Neelika , Ogg Graham S.
Published: July 2024

Purpose of review

With the marked rise in dengue globally, developing well tolerated and effective vaccines and therapeutics is becoming more important. Here we discuss the recent developments in the understanding of immune mechanisms that lead to severe dengue and the learnings from the past, that can help us to find therapeutic targets, prognostic markers, and vaccines to prevent development of severe disease.

Recent findings

The extent and duration of viraemia often appears to be associated with clinical disease severity but with some variability. However, there also appear to be significant differences in the kinetics of viraemia and nonstructural protein 1 (NS1) antigenemia and pathogenicity between different serotypes and genotypes of the DENV. These differences may have significant implications for development of treatments and in inducing robust immunity through dengue vaccines. Although generally higher levels of neutralizing antibodies are thought to protect against infection and severe disease, there have been exceptions and the specificity, breadth and functionality of the antibody responses are likely to be important.

Although there have been many advances in our understanding of dengue pathogenesis, viral and host factors associated with occurrence of severe dengue, vascular leak and the immune correlates of protection remain poorly understood.
Elevated levels of KLF12 impair trophoblast syncytialization via GCM1 downregulation
Authors: Shi Qing-Qing , Wu Xing , Kang Nan-Nan , Zhou Ji-Dong , Zhen Xin , Li Ze-Wu , Yan Gui-Jun , Sun Hai-Xiang , Liu Jing-Yu , Liu Yang
Published: July 2024

Objective:

Placental dysfunction is a major contributor to miscarriages in humans. We observed elevated expression of Kruppel-like factor 12 (KLF12) in placental villi of women who experienced miscarriage compared to that in women with healthy pregnancies. This study aimed to elucidate the role of KLF12 in maintaining a successful pregnancy.

Methods:

To investigate the role of KLF12 in placentation, we employed a model of forskolin-induced syncytialization in BeWo cells.

Results:

Our findings revealed that KLF12 expression is downregulated during normal syncytialization. Conversely, we observed that abnormally high KLF12 levels directly suppressed glial cells missing-1 (GCM1) expression. This suppression of GCM1 expression subsequently impaired BeWo cell syncytialization. Furthermore, we observed placental deformities in KLF12-overexpressing mouse fetuses.

Conclusion:

This study demonstrated that elevated levels of KLF12 disrupt trophoblast syncytialization by downregulating GCM1 expression. These findings suggest that KLF12 may be a novel candidate gene contributing to unexplained miscarriages.
Revolutionizing Liver Transplantation
Authors: Li Zhihao , Pfister Matthias , Huwyler Florian , Hoffmann Waldemar , Tibbitt Mark W. , Dutkowski Philipp , Clavien Pierre-Alain
Published: July 2024

Objective:

To assess the impact of normothermic machine perfusion (NMP) on patients, medical teams, and costs by gathering global insights and exploring current limitations.

Background:

NMP for ex situ liver graft perfusion is gaining increasing attention for its capability to extend graft preservation. It has the potential to transform liver transplantation (LT) from an urgent to a purely elective procedure, which could revolutionize LT logistics, reduce burden on patients and health care providers, and decrease costs.

Methods:

A 31-item survey was sent to international transplant directors to gather their NMP experiences and vision. In addition, we performed a systematic review on cost-analysis in LT and assessed studies on cost-benefit in converting urgent-to-elective procedures. We compared the costs of available NMPs and conducted a sensitivity analysis of NMP’s cost benefits.

Results:

Of 120 transplant programs contacted, 64 (53%) responded, spanning North America (31%), Europe (42%), Asia (22%), and South America (5%). Of the total, 60% had adopted NMP, with larger centers (>100 transplants/year) in North America and Europe more likely to use it. The main NMP systems were OrganOx-metra (39%), XVIVO (36%), and TransMedics-OCS (15%). Despite NMP adoption, 41% of centers still perform >50% of LTs at nights/weekends. Centers recognized NMP’s benefits, including improved work satisfaction and patient outcomes, but faced challenges like high costs and machine complexity. 16% would invest $100,000 to 500’000, 33% would invest $50,000 to 100’000, 38% would invest $10,000 to 50’000, and 14% would invest <$10,000 in NMP. These results were strengthened by a cost analysis for NMP in emergency-to-elective LT transition. Accordingly, while liver perfusions with disposables up to $10,000 resulted in overall positive net balances, this effect was lost when disposables’ cost amounted to >$40,000/organ.

Conclusions:

The adoption of NMP is hindered by high costs and operational complexity. Making LT elective through NMP could reduce costs and improve outcomes, but overcoming barriers requires national reimbursements and simplified, automated NMP systems for multiday preservation.
Differential gene expression underpinning the production of distinct sperm morphs in the wax moth
Galleria mellonella
Authors: Moth Emma , Messer Fiona , Chaudhary Saurabh , White-Cooper Helen
Published: July 2024

Male Lepidoptera produce two distinct sperm types; each ejaculate contains both eupyrene sperm, which can fertilize the egg, and apyrene sperm, which are not fertilization competent. These sperm have distinct morphologies, unique functions and different proteomes. Their production is highly regulated, however, very few genes with specific roles in the production of one or other morph have been described. We present the first comparative transcriptomics study of precursors of eupyrene and apyrene sperm to identify genes potentially implicated in regulating or enacting the distinct differentiation programmes. Differentially expressed genes included genes with potential roles in transcriptional regulation, cell cycle and sperm morphology. We identified gene duplications generating paralogues with functions restricted to one or other morph. However, phylogenetic analysis also revealed evolutionary flexibility in expression patterns of duplicated genes between different lepidopteran species. An improved understanding of lepidopteran reproduction will be vital in targeting prevalent pests in agriculture, and on the flip side, ensuring the fertility and thus survival of pollinator populations in response to environmental stress.
Belowground plant competition: uncoupling root response strategies of peas
Authors: Gottlieb Ruth , Gruntman Michal
Published: July 2024

Belowground plant competition has been shown to induce varying responses, from increases to decreases in root biomass allocation or in directional root placement. Such inconsistencies could result from the fact that root allocation and directional growth were seldom studied together, even though they might represent different strategies. Moreover, variations in belowground responses might be due to different size hierarchies between plants, but this hypothesis has not been studied previously. In a greenhouse rhizobox experiment, we examined the way both root allocation and directional root placement of
Pisum sativum
are affected by the size and density of
Festuca glauca
neighbours, and by nutrient distribution. We found that root allocation of
P. sativum
increased with the density and size of
F. glauca
. By contrast, directional root placement was unaffected by neighbour size and increased either towards or away from neighbours when nutrients were patchily or uniformly distributed, respectively. These results demonstrate that directional root placement under competition is contingent on the distribution of soil resources. Interestingly, our results suggest that root allocation and directional placement might be uncoupled strategies that simultaneously provide stress tolerance and spatial responsiveness to neighbours, thus highlighting the importance of measuring both when studying belowground plant competition.
Ant social network structure is highly conserved across species
Authors: Kay Tomas , Motes-Rodrigo Alba , Royston Arthur , Richardson Thomas O. , Stroeymeyt Nathalie , Keller Laurent
Published: July 2024

The ecological success of social insects makes their colony organization fascinating to scientists studying collective systems. In recent years, the combination of automated behavioural tracking and social network analysis has deepened our understanding of many aspects of colony organization. However, because studies have typically worked with single species, we know little about interspecific variation in network structure. Here, we conduct a comparative network analysis across five ant species from five subfamilies, separated by more than 100 Myr of evolution. We find that social network structure is highly conserved across subfamilies. All species studied form modular networks, with two social communities, a similar distribution of individuals between the two communities, and equivalent mapping of task performance onto the communities. Against this backdrop of organizational similarity, queens of the different species occupied qualitatively distinct network positions. The deep conservation of the two community structure implies that the most fundamental behavioural division of labour in social insects is between workers that stay in the nest to rear brood, and those that leave the nest to forage. This division has parallels across the animal kingdom in systems of biparental care and probably represents the most readily evolvable form of behavioural division of labour.
Insights into the evolution of photoreceptor oil droplets in frogs and toads
Authors: Cervino Nadia G. , Elias-Costa Agustín J. , Iglesias Patricia P. , Yovanovich Carola A. M. , Faivovich Julián
Published: July 2024

Photoreceptor oil droplets (ODs) are spherical organelles placed most commonly within the inner segment of the cone photoreceptors. Comprising neutral lipids, ODs can be either non-pigmented or pigmented and have been considered optically functional in various studies. Among living amphibians, ODs were only reported to occur in frogs and toads (Anura), while they are absent in salamanders and caecilians. Nonetheless, the limited understanding of their taxonomic distribution in anurans impedes a comprehensive assessment of their evolution and relationship with visual ecology. We studied the retinae of 134 anuran species, extending the knowledge of the distribution of ODs to 46 of the 58 currently recognized families, and providing a new perspective on this group that complements the available information from other vertebrates. The occurrence of ODs in anurans shows a strong phylogenetic signal, and our findings revealed that ODs evolved at least six times during the evolutionary history of the group, independently from other vertebrates. Although no evident correlation was found between OD occurrence, adult habits and diel activity, it is inferred that each independent origin involves distinct scenarios in the evolution of ODs concerning photic habits. Furthermore, our results revealed significant differences in the size of the ODs between nocturnal and arrhythmic anurans relative to the length of the cones’ outer segment.
Identification of potential SARS-CoV-2 genetic markers resulting from host domestication
Authors: Wiśniewski Janusz , Chen Heng-Chang
Published: July 2024

We developed ak-mer-based pipeline, namely the Pathogen Origin Recognition Tool using EnrichedK-mers (PORT-EK) to identify genomic regions enriched in the respective hosts after the comparison of metagenomes of isolates between two host species. Using it we identified thousands ofk-mers enriched in US white-tailed deer and betacoronaviruses in bat reservoirs while comparing them with human isolates. We demonstrated different coverage landscapes ofk-mers enriched in deer and bats and unraveled 148 mutations in enrichedk-mers yielded from the comparison of viral metagenomes between bat and human isolates. We observed that the third position within a genetic codon is prone to mutations, resulting in a high frequency of synonymous mutations of amino acids harboring the same physicochemical properties as unaltered amino acids. Finally, we classified and predicted the likelihood of host species based on the enrichedk-mer counts. Altogether, PORT-EK showcased its feasibility for identifying enriched viral genomic regions, illuminating the different intrinsic tropisms of coronavirus after host domestication.

Teaser

A measure of enriched viral genomic correlates resulting from host domestication as a potential predictor of zoonotic risk.
Analysis of Factors Determining Success in FFPE Based NGS Panel Testing For Lung & Ovarian Cancer
Authors: Bhattacharya P. , Bishop P. , Gokhale D. , Rowlston S. , Eggington B. , Burghel G. J. , Schlecht H.
Published: July 2024

The identification of oncogenic variants in both lung and ovarian cancer is central to personalised treatment. NGS approaches using formalin-fixed paraffin-embedded (FFPE) tissue samples are routinely implemented for variant detection, but optimisation of pre-analytic factors is critical for success. We performed a large multi-cohort retrospective audit assessing pre-analytic factors related to Qiagen in house custom designed NGS panel testing for lung (n=801 from 23 referring hospitals) and ovarian (n=882 from 85 referring hospitals) FFPE cancer samples, sequenced at the NHS Northwest Genomic Laboratory Hub (NWGLH). A further detailed analysis of a cohort of lung samples (n=461) submitted from a single high-volume referral centre was also undertaken. Overall NGS cohort success ranged from 74-85% with large variation amongst referring laboratories. Multivariate logistic regression analysis revealed DNA yield and quality to be significant predictors of NGS success (p<0.001) alongside sample type for lung (p=0.035) and use of macrodissection for ovarian (p=0.025). Univariate analysis revealed specific poor lung performance within biopsy samples and associated with number and length of core biopsy samples. Furthermore, excessive fixation time for lung cytology and ovarian samples was associated with NGS failure (p<0.05), with only 49.5% of lung endoscopic bronchial ultrasound (EBUS) cytology samples meeting existing local guidelines for fixation time <24 hours, with 2/3 of prolonged fixation samples being received in the lab the following day. Variation in key identified pre-analytic factors amongst referring centres and variable adherence to best practice guidelines is likely to be responsible for the wide variation in NGS success. Improved collaboration between NHS genomic hubs and referring pathology laboratories through the establishment of a regional interactive collaborative network, facilitating guideline sharing and assessing adherence to pre-analytic optimisation of sample collection and processing for genomic testing, is crucial to improve future NGS genomic cancer testing.
PREDICTORS OF VIRAL REBOUND AMONG ADOLESCENTS AT AN URBAN CLINIC IN KAMPALA USING REPEATED EVENTS SURVIVAL ANALYSIS
Authors: Kirabira Anthony , Bukenya Justine , Ssenkusu John , Ssekamatte Noah K , Tumwesigye Nazarius M , Kiwanuka Noah
Published: July 2024

Background

A suppressed HIV viral load below 1000 copies/ml is mark of HIV treatment success because it is associated with reduced risk of transmission of HIV. However, following viral suppression, some people experience viral rebound which may occur multiple times. We used repeated events survival analysis to assess the predictors of viral rebound among adolescents (aged 10-19 years) at an urban clinic in Kampala, Uganda.

Methods

The study was a retrospective cohort design conducted at Baylor-Uganda, an HIV care facility. The Lognormal model was used to estimate time from viral suppression to viral rebound (in months) and to determine factors associated with time to first viral rebound. The Prentice, Williams, and Peterson (PWP) model was used to determine the factors associated with repetitive viral rebound.

Results

Data from 219 participants were included in the study; 160 (73.06%) were female, and 117 (53.42%) were aged 15-19 years. The overall proportion of viral rebound was 31.5% (31.51/100); 23.29% (23.29/100) experienced one rebound whereas 8.22% (8.22/100) had multiple rebounds. The probability of viral rebound did not reach 50%, so the median time from viral suppression to viral rebound could not be estimated. The 25thpercentile survival time to first viral rebound was 34.1 months. The incidence rate of first viral rebound was 84.7 (95%CI, 66.9 - 107.2) per 10,000-person months of observation. The predictors of first viral rebound included; duration on ART (adjusted Time Ratio (TR), 1.04; 95%CI, 1.04-1.05; p<0.001), having psychosocial issues (adjusted TR, 0.67; 95%CI, 0.58-0.77; p<0.001), baseline viral load of <1000 (adjusted TR, 0.85; 95%CI, 0.72-0.99; p=0.008) and protease inhibitors (PI) based ART regimens (adjusted TR, 0.67; 95%CI, 0.49-0.92; p=0.012). The predictors of multiple rebounds included duration on ART (adjusted Hazard Ratio (HR), 0.86, 95%CI, 0.84-0.89; p<0.001), having psychosocial issues (adjusted HR, 11.04, 95%CI, 6.09-20.0; p<0.001), WHO clinical stage II (adjusted HR, 2.28, 95%CI, 1.22-4.25; p=0.002), and WHO clinical stage III (adjusted HR, 2.17, 95%CI, 1.14-4.14; p=0.005)

Conclusion

In an urban HIV care facility in Kampala, we found an overall proportion of viral rebound among the adolescents of 31.5%. Occurrence of multiple viral rebounds was associated with duration on ART, psychosocial issues, and WHO clinical staging. Therefore, there is need to incorporate screening of adolescents for psychosocial challenges into the routine programming of HIV care and treatment so as identify and appropriately support those affected in time.
Financial Feasibility Study and policy recommendations of Incremental Modified Drugs Development by the Domestic Pharmaceutical Industry
Authors: Laichapis Manthana , Sakulbumrungsil Rungpetch , Udomaksorn Khunjira , Kessomboon Nusaraporn , Nerapusee Osot , Hongthong Charkkrit , Poonpolsub Sitanun
Published: July 2024

The Thai pharmaceutical industry aims to strengthen its drug system in accordance with the National Strategic Master Plan, emphasizing sustainable development, particularly in biologics and herbal products, to achieve self-reliance. Current efforts are mainly focused on generic drug production, but there’s a significant need for Research and Development (R&D) in Innovative Medicines (IMDs). This study explores the financial feasibility of locally developing an IMDs dosage form. To assess this feasibility, a mixed-methods approach was used, incorporating a literature review, surveys, and interviews. This process involved selecting types of IMDs, constructing financial models, determining cost structures, and conducting a thorough feasibility analysis. The results indicated that a sustained-release dosage form was the most viable option. The analysis took into account total development costs, payback periods, growth rates, and the revenue required to recoup investments. It was found that IMD development is associated with higher costs and longer durations compared to new generic drugs.The study identified several challenges, such as the high cost of clinical studies, extended development times, market feasibility, and drug selection difficulties. Policy recommendations were made to address these challenges, including incentives for clinical studies and fostering industry expertise through collaborative efforts and supportive government policies.In conclusion, the financial feasibility of developing IMDs requires strategic policies and collaboration to overcome these challenges and ensure sustainability. The findings of this study are intended to aid stakeholders in making informed R&D investment decisions.
Long-lived chondroprogenitors are generated by fetal-limb Gli1+ cells and are replenished upon mosaic cell-cycle arrest in the cartilage
Authors: Qu Xinli , Razmara Ehsan , H'ng Chee Ho , Vinu Kailash Kumar , Martelotto Luciano Gaston , Zethoven Magnus , Rossello Fernando J. , Johnstone Ricky W , Amarasinghe Shanika L. , Powell David Richard , Rosello-Diez Alberto
Published: July 2024

Key questions in organ development and regeneration revolve around the origin and regulation factors of the progenitor cells that fuel organ growth. The cartilage progenitors that drive long-bone growth display a postnatal switch in their behaviour, from short-lived progenitors to self-renewing, long-lived ones. However, it is unclear whether these are distinct populations with different origins, or the same population changes over time due to intrinsic/extrinsic factors, or there is no real behavioural switch, just differential proximity to a supportive niche. The multiple candidates of cartilage stem-cell/progenitors that have been recently described add more complexity to this field, as it is unclear how much spatio-temporal overlap there is between these populations. Here, using lineage tracing, single-cell transcriptomics and label-retention assays during normal and compensatory growth, we show that Gli1+ cells in fetal cartilage are long-lived chondroprogenitors that remain dormant until postnatal stages. Moreover, Pdgfra+ cells outside the cartilage contribute only to short-term chondroprogenitors in normal conditions, but become Gli1-expressing and increase their cartilage contribution in response to cartilage cell-cycle arrest. These findings shed light on the long-standing question of the origin and regulation of long-lived cartilage progenitors, laying the groundwork for potential future approaches to generate cartilage reparative cells in vivo
Unraveling the Web of Life: Incomplete lineage sorting and hybridization as primary mechanisms over polyploidization in the evolutionary dynamics of pear species
Authors: Jin Ze-Tao , Lin Xiao-Hua , Ma Dai-Kun , Hodel Richard G.J. , Ren Chen , Zhao Liang , Duan Lei , Xu Chao , Wu Jun , Liu Bin-Bin
Published: July 2024

In contrast to the traditional Tree of Life (ToL) paradigm, the Web of Life (WoL) model provides a more nuanced and precise depiction of organismal phylogeny, particularly considering the prevalent incongruence observed among gene/species trees. The lack of a generalized pipeline for teasing apart potential evolutionary mechanisms—such as Incomplete Lineage Sorting (ILS), hybridization, introgression, polyploidization, and Whole-Genome Duplication—poses significant challenges to the delineation of the WoL. The pear genusPyrus, characterized by extensive hybridization events, serves as an excellent model for investigating the WoL. This study introduces a novel Step-by-Step Exclusion (SSE) approach to deciphering the complexities inherent in the WoL. Our findings indicate: 1) ILS, rather than polyploidization, is identified as the primary driver behind the origin ofPyrusfrom the arid regions of the Himalayas-Central Asia; 2) the two subgenera ofPyrushave independent evolutionary trajectories, facilitated by the geographical barriers that arose via the uplift of the Tibetan Plateau and increased aridity in Central Asia; 3) ILS and hybridization have facilitated the diversification of Oriental pears, while hybridization alone has driven the reticulate evolution of Occidental pears; 4) the establishment of the Silk Road during the Han Dynasty acted as a conduit for genetic exchange between Occidental and Oriental pears. The novel SSE approach provides a universally applicable framework for investigating evolutionary mechanisms defining the WoL paradigm.
Brown Adipose Tissue undergoes pathological perturbations and shapes C2C12 myoblast homeostasis in the SOD1-G93A mouse model of Amyotrophic Lateral Sclerosis
Authors: Rosina Marco , Scaricamazza Silvia , Riggio Flaminia , Fenili Gianmarco , Giannessi Flavia , Matteocci Alessandro , Nesci Valentina , Salvatori Illari , Angelini Daniela F. , Aquilano Katia , Chiurchiù Valerio , Barbato Daniele Lettieri , Mercuri Nicola Biagio , Valle Cristiana , Ferri Alberto
Published: July 2024

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of motor neurons. While the contribution of peripheral organs remains incompletely understood, recent evidence suggests that brown adipose tissue (BAT) and its secreted extracellular vesicles (EVs) could play a role in diseased context as ALS. In this study, we employed a multi-omics approach, including RNA sequencing (GEO identifier GSE273052) and proteomics (ProteomeXchange identifier PXD054147), to investigate the alterations in BAT and its EVs in the SOD1-G93A mouse model of ALS. Our results revealed significant changes in the proteomic and transcriptomic profiles of BAT from SOD1-G93A mice, highlighting ALS-related features such as mitochondrial dysfunction and impaired differentiation capacity. Specifically, primary brown adipocytes (PBAs) from SOD1-G93A mice exhibited differentiation impairment, respiratory defects, and alterations in mitochondrial dynamics. Furthermore, the BAT-derived EVs from SOD1-G93A mice displayed distinct changes in size distribution and cargo content, which negatively impacted the differentiation and homeostasis of C2C12 murine myoblasts, as well as induced atrophy in C2C12-derived myotubes. These findings suggest that BAT undergoes pathological perturbations in ALS, contributing to skeletal muscle degeneration through the secretion of dysfunctional EVs. This study provides novel insights into the role of BAT in ALS pathogenesis and highlights potential therapeutic targets for mitigating muscle wasting in ALS patients.
Using flux theory in dynamic omics data sets to identify differentially changing signals using DPoP
Authors: Edwards Harley , Zavorskas Joseph , Huso Walker , Doan Alexander G. , Silbiger Caton , Harris Steven , Srivastava Ranjan , Marten Mark R.
Published: July 2024

Derivative profiling (DP) is a novel approach to identify differential signals from dynamic omics data sets. This approach applies variable step-size differentiation to time dynamic omics data. This work assumes that there is a general omics derivative that is a useful and descriptive feature of dynamic omics experiments. We assert that this omics derivative, or omics flux, is a valuable descriptor that can be used instead of, or with, fold change calculations. The results of derivative profiling are compared to established methods such as Multivariate Adaptive Regression Splines (MARS), significance versus fold change analysis (Volcano), and an adjusted ratio over intensity (M/A) analysis to find that there is a statistically significant similarity between the results. This comparison is repeated for transcriptomic and phosphoproteomic expression profiles previously characterized inAspergillus nidulans. This method has been packaged in an open-source, GUI-based MATLAB app, the Derivative Profiling omics Package (DPoP). Gene Ontology (GO) term enrichment has been included in the app so that a user can automatically/programmatically describe the over/under-represented GO terms in the derivative profiling results using domain specific knowledge found in their organism’s specific GO database file. The advantage of the DPoP analysis is that it is computationally inexpensive, it does not require fold change calculations, it describes both instantaneous as well as overall behavior, and it achieves statistical confidence with signal trajectories of a single bio-replicate over four or more points. While we apply this method to time dynamic transcriptomic and phosphoproteomic datasets, it is a numerically generalizable technique that can be applied to any organism and any field interested in time series data analysis. The app described in this work enables omics researchers with no computer science background to apply derivative profiling to their data sets, while also allowing multidisciplined users to build on the nascent idea of profiling derivatives in omics.
The ability of human TIM1 to bind phosphatidylethanolamine enhances viral uptake and efferocytosis compared to rhesus and mouse orthologs
Authors: Zhang Lizhou , Kitzmiller Claire E. , Richard Audrey S. , Popli Sonam , Choe Hyeryun
Published: July 2024

T-cell Immunoglobulin and Mucin (TIM)-family proteins facilitate the clearance of apoptotic cells, are involved in immune regulation, and promote infection of enveloped viruses. These processes are frequently studied in experimental animals such as mice or rhesus macaques, but functional differences among the TIM orthologs from these species have not been described. Previously, we reported that while all three human TIM proteins bind phosphatidylserine (PS), only human TIM1 (hTIM1) binds phosphatidylethanolamine (PE), and that this PE-binding ability contributes to both phagocytic clearance of apoptotic cells and virus infection. Here we show that rhesus macaque TIM1 (rhTIM1) and mouse TIM1 (mTIM1) bind PS but not PE and that their inability to bind PE makes them less efficient than hTIM1. We also show that alteration of only two residues of mTIM1 or rhTIM1 enables them to bind both PE and PS, and that these PE-binding variants are more efficient at phagocytosis and mediating viral entry. Further, we demonstrate that the mucin domain also contributes to the binding of the virions and apoptotic cells, although it does not directly bind phospholipid. Interestingly, contribution of the hTIM1 mucin domain is more pronounced in the presence of a PE-binding head domain. These results demonstrate that rhTIM1 and mTIM1 are inherently less functional than hTIM1, owing to their inability to bind PE and their less functional mucin domains. They also imply that mouse and macaque models underestimate the activity of hTIM1.

SIGNIFICANCE

We previously reported that human T-cell Immunoglobulin and Mucin protein 1 (TIM1) binds phosphatidylethanolamine (PE) as well as phosphatidylserine (PS) and that PE is exposed on the apoptotic cells and viral envelopes. Moreover, TIM1 recognition of PE contributes to phagocytic clearance of apoptotic cells and virus uptake. Here we report that unlike human TIM1, murine and rhesus TIM1 orthologs bind only PS, and as a result, their ability to clear apoptotic cells or promote virus infection is less efficient. These findings are significant because they imply that the activity of TIM1 in humans is greater than what the studies conducted in common animal models would indicate.
Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62
Authors: Amponsah Prince Saforo , Bökenkamp Jan-Eric , Lenhard Svenja , Behrends Christian , Herrmann Johannes Martin , Räschle Markus , Storchová Zuzana
Published: July 2024

Aberrant chromosomal content, or aneuploidy, profoundly affects cellular physiology. Even a gain of a single chromosome disrupts proteostasis due to overexpression of numerous proteins. Consequently, cells accumulate SQSTM1/p62-positive cytosolic bodies and show altered proteasomal and lysosomal activity. To elucidate the p62 interaction network in aneuploid cells, we conducted p62 immunoprecipitation and proximity labeling assays followed by mass spectrometry analysis. Our investigation revealed the enrichment of mitochondrial proteins within the cytosolic p62 interactome and proxitome in aneuploid cells, but not in the proxitome spatially confined to autophagosomes. Immunofluorescence microscopy confirmed increased colocalization of p62 with novel interactors and with mitochondrial proteins in polysomic cells. Moreover, we observed mitochondrial defects characterized by increased perinuclear clustering, reduced oxygen consumption, and reduced mitochondrial DNA abundance in polysomic cells. Furthermore, we demonstrate that polysomic cells exhibit reduced import of mitochondrial proteins and accumulation of mitochondrial precursor proteins in the cytosol. Our data suggest that proteotoxic stress induced by chromosome gains leads to the sequestration of mitochondrial precursor proteins into cytosolic p62-bodies and compromises mitochondrial function.