bluuebunny/crossref_metadata_2025 huggingface dataset:
A systematic review and meta-analysis of the epidemiological characteristics of COVID-19 in children
Authors: Vosoughi Fardis , Makuku Rangarirai , Tantuoyir Marcarious M. , Yousefi Farbod , Shobeiri Parnian , Karimi Amirali , Alilou Sanam , LaPorte Ronald , Tilves Curtis , Nabian Mohammad Hossein , Yekaninejad Mir Saeed
Published: October 2022

Background

Several individual studies from specific countries have reported rising numbers of pediatric COVID-19 cases with inconsistent reports on the clinical symptoms including respiratory and gastrointestinal symptoms as well as diverse reports on the mean age and household exposure in children. The epidemiological characteristics of COVID-19 in children are not fully understood, hence, comprehensive meta-analyses are needed to provide a better understanding of these characteristics.

Methods

This review was conducted in Medline, Scopus, Cochrane library, Embase, Web of Science, and published reports on COVID-19 in children. Data were extracted by two independent researchers and a third researcher resolved disputes. STATA software and the random-effect model were used in the synthesis of our data. For each model, the heterogeneity between studies was estimated using the Q Cochrane test. Heterogeneity and publication bias were calculated using the I2 statistic and Egger’s/Begg’s tests.

Results

The qualitative systematic review was performed on 32 articles. Furthermore, the meta-analysis estimated an overall rate of involvement at 12% (95% CI: 9–15%) among children, with an I2 of 98.36%. The proportion of household exposure was calculated to be 50.99% (95% CI: 20.80%–80.80%) and the proportion of admitted cases was calculated to be 45% (95% CI: 24%–67%). Additionally, the prevalence of cough, fatigue, fever and dyspnea was calculated to be 25% (95% CI: 0.16–0.36), 9% (95% CI: 0.03–0.18), 33% (95% CI: 0.21–0.47) and 9% (95% CI: 0.04–0.15), respectively. It is estimated that 4% (95% CI: 1–8%) of cases required intensive care unit admission.

Conclusions

The pediatric clinical picture of COVID-19 is not simply a classic respiratory infection, but unusual presentations have been reported. Given the high incidence of household transmission and atypical clinical presentation in children, we strongly recommend their inclusion in research and population-based preventive measures like vaccination as well as clinical trials to ensure efficacy, safety, and tolerability in this age group.
Clinical effectiveness of patellar resurfacing, no resurfacing and selective resurfacing in primary total knee replacement: systematic review and meta-analysis of interventional and observational evidence
Authors: Grela Michal , Barrett Matthew , Kunutsor Setor K. , Blom Ashley W. , Whitehouse Michael R. , Matharu Gulraj S.
Published: October 2022

Background

Patellar resurfacing is optional during total knee replacement (TKR). Some surgeons always resurface the patella, some never resurface, and others selectively resurface. Which resurfacing strategy provides optimal outcomes is unclear. We assessed the effectiveness of patellar resurfacing, no resurfacing, and selective resurfacing in primary TKR.

Methods

A systematic review and meta-analysis was performed. MEDLINE, Embase, Web of Science, The Cochrane Library, and bibliographies were searched to November 2021 for randomised-control trials (RCTs) comparing outcomes for two or more resurfacing strategies (resurfacing, no resurfacing, or selective resurfacing) in primary TKR. Observational studies were included if limited or no RCTs existed for resurfacing comparisons. Outcomes assessed were patient reported outcome measures (PROMs), complications, and further surgery. Study-specific relative risks [RR] were aggregated using random-effects models. Quality of the evidence was assessed using GRADE.

Results

We identified 33 RCTs involving 5,540 TKRs (2,727 = resurfacing, 2,772 = no resurfacing, 41 = selective resurfacing). One trial reported on selective resurfacing. Patellar resurfacing reduced anterior knee pain compared with no resurfacing (RR = 0.65 (95% CI = 0.44–0.96)); there were no significant differences in PROMs. Resurfacing reduced the risk of revision surgery (RR = 0.63, CI = 0.42–0.94) and other complications (RR = 0.54, CI = 0.39–0.74) compared with no resurfacing. Quality of evidence ranged from high to very low. Limited observational evidence (5 studies, TKRs = 215,419) suggested selective resurfacing increased the revision risk (RR = 1.14, CI = 1.05–1.22) compared with resurfacing. Compared with no resurfacing, selective resurfacing had a higher risk of pain (RR = 1.25, CI = 1.04–1.50) and lower risk of revision (RR = 0.92, CI = 0.85–0.99).

Conclusions

Level 1 evidence supports TKR with patellar resurfacing over no resurfacing. Resurfacing has a reduced risk of anterior knee pain, revision surgery, and complications, despite PROMs being comparable. High-quality RCTs involving selective resurfacing, the most common strategy in the UK and other countries, are needed given the limited observational data suggests selective resurfacing may not be effective over other strategies.
A study comparing outcomes between obese and nonobese patients with lumbar disc herniation undergoing surgery: a study of the Swedish National Quality Registry of 9979 patients
Authors: Hareni Niyaz , Strömqvist Fredrik , Rosengren Björn E. , Karlsson Magnus K.
Published: October 2022

Background

This study aimed to evaluate whether an increasing grade of obesity is associated with inferior outcomes after lumbar disc herniation (LDH) surgery.

Methods

We retrieved data from the Swedish register for spine surgery regarding patients aged 20–64 who underwent LDH surgery from 2006–2016 and had preoperative and one-year postoperative data. A total of 4156 patients were normal weight, 4063 were overweight, 1384 had class I obesity, 317 had class II obesity and 59 had class III obesity (“morbid obesity”). Data included patient satisfaction, improvement in leg pain (assessed using the National Rating Scale; NRS; rating 0–10), disability (assessed using the Oswestry Disability Index; ODI; rating 0–100) and complications.

Results

At one year postsurgery, 80% of normal-weight patients, 77% of overweight patients and 74% of obese patients (class I-III evaluated together) were satisfied (p < 0.001) [75%, 71%, 75% in obesity classes I, II, and III, respectively (p = 0.43)]. On average, all groups improved by more than the minimal clinically important difference (MCID) in both NRS leg pain (> 3.5) and ODI (> 20). NRS leg pain improved by 4.8 in normal weight patients (95% CI 4.7–4.9), by 4.5 in overweight patients (4.5–4.6) and by 4.3 in obese patients (4.2–4.4) (p < 0.001) [4.4 (4.3–4.6), 3.8 (3.5–4.1) and 4.6 (3.9–5.3) in obesity classes I, II, and III, respectively (p < 0.001)]. The ODI improved by 30 in normal weight patients (30–31), by 29 in overweight patients (28–29) and by 26 in obese patients (25–27) (p < 0.001) [29 (28–29), 25 (22–27) and 27 (22–32) in obesity classes I, II, and III, respectively (p < 0.01)]. A total of 3.0% of normal-weight patients, 3.9% of overweight patients and 3.9% of obese patients suffered complications (p = 0.047) [3.8%, 4.4%, 3.5% in obesity classes I, II, and III, respectively (p = 0.90)].

Conclusions

LDH surgery is also generally associated with favourable outcomes and few complications in patients with morbid obesity.
Do patients want clinicians to ask about social needs and include this information in their medical record?
Authors: Albert Steven M , McCracken Polly , Bui Thuy , Hanmer Janel , Fischer Gary S , Hariharan Jaishree , James Alton Everette
Published: October 2022

Background

Social needs screening in primary care may be valuable for addressing non-medical health-related factors, such as housing insecurity, that interfere with optimal medical care. Yet it is unclear if patients welcome such screening and how comfortable they are having this information included in electronic health records (EHR).

Objective

To assess patient attitudes toward inclusion of social needs information in the EHR and key correlates, such as sociodemographic status, self-rated health, and trust in health care.

Design, participants, and main measures

In a cross-sectional survey of patients attending a primary care clinic for annual or employment exams, 218/560 (38%) consented and completed a web survey or personal interview between 8/20/20-8/23/21. Patients provided social needs information using the Accountable Care Communities Screening Tool. For the primary outcome, patients were asked, “Would you be comfortable having these kinds of needs included in your health record (also known as your medical record or chart)?”

Analyses

Regression models were estimated to assess correlates of patient comfort with including social needs information in medical records.

Key results

The median age was 45, 68.8% were female, and 78% were white. Median income was $75,000 and 84% reported education beyond high school. 85% of patients reported they were very or somewhat comfortable with questions about social needs, including patients reporting social needs. Social need ranged from 5.5% (utilities) to 26.6% (housing), and nonwhite and gender-nonconforming patients reported greater need. 20% reported “some” or “complete” discomfort with social needs information included in the EHR. Adjusting for age, gender, race, education, trust, and self-rated health, each additional reported social need significantly increased discomfort with the EHR for documenting social needs.

Conclusions

People with greater social needs were more wary of having this information placed in the EHR. This is a concerning finding, since one rationale for collecting social need data is to use this information (presumably in the EHR) for addressing needs.
The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures
Authors: Bouzón-Arnáiz Inés , Avalos-Padilla Yunuen , Biosca Arnau , Caño-Prades Omar , Román-Álamo Lucía , Valle Javier , Andreu David , Moita Diana , Prudêncio Miguel , Arce Elsa M. , Muñoz-Torrero Diego , Fernàndez-Busquets Xavier
Published: October 2022

Background

By 2016, signs of emergence of Plasmodium falciparum resistance to artemisinin and partner drugs were detected in the Greater Mekong Subregion. Recently, the independent evolution of artemisinin resistance has also been reported in Africa and South America. This alarming scenario calls for the urgent development of new antimalarials with novel modes of action. We investigated the interference with protein aggregation, which is potentially toxic for the cell and occurs abundantly in all Plasmodium stages, as a hitherto unexplored drug target in the pathogen.

Results

Attempts to exacerbate the P. falciparum proteome’s propensity to aggregation by delivering endogenous aggregative peptides to in vitro cultures of this parasite did not significantly affect their growth. In contrast, protein aggregation inhibitors clearly reduced the pathogen’s viability. One such compound, the bis(styrylpyridinium) salt YAT2150, exhibited potent antiplasmodial activity with an in vitro IC50 of 90 nM for chloroquine- and artemisinin-resistant lines, arresting asexual blood parasites at the trophozoite stage, as well as interfering with the development of both sexual and hepatic forms of Plasmodium. At its IC50, this compound is a powerful inhibitor of the aggregation of the model amyloid β peptide fragment 1-40, and it reduces the amount of aggregated proteins in P. falciparum cultures, suggesting that the underlying antimalarial mechanism consists in a generalized impairment of proteostasis in the pathogen. YAT2150 has an easy, rapid, and inexpensive synthesis, and because it fluoresces when it accumulates in its main localization in the Plasmodium cytosol, it is a theranostic agent.

Conclusions

Inhibiting protein aggregation in Plasmodium significantly reduces the parasite’s viability in vitro. Since YAT2150 belongs to a novel structural class of antiplasmodials with a mode of action that potentially targets multiple gene products, rapid evolution of resistance to this drug is unlikely to occur, making it a promising compound for the post-artemisinin era.
Leptospira seroprevalence and associated risk factors in healthy Swedish dogs
Authors: Scahill Karolina , Windahl Ulrika , Boqvist Sofia , Pelander Lena
Published: October 2022

Background

Leptospirosis is an emerging zoonotic infection worldwide and a cause of life-threatening disease in dogs. Seroprevalence in Swedish dogs is unknown. The aims of the present study were to estimate seroprevalence of pathogenic Leptospira in healthy dogs in Sweden using the microagglutination test (MAT) and a rapid point-of-care enzyme-linked immunosorbent assay (ELISA), and to evaluate risk factors of Leptospira exposure in Swedish dogs.

Results

Positive MAT titres (≥ 1:50) were detected in 27/369 (7.3%) of included dogs. Five different serovars were represented of which the Saxkoebing serovar was the most common (64.3%), followed by Copenhagi (14.3%), Bratislava (10.7%), Icterohaemorrhagiae (7.1%), and Canicola (3.6%). The ELISA test (SNAP® Lepto) was positive in 3/316 (0.9%) dogs. Living in urban areas and contact with stagnant water were found to be risk factors for Leptospira seropositivity (p < 0.05) in a multivariable logistic regression model.

Conclusion

In this first seroprevalence study of Leptospira in Swedish dogs, it was shown that healthy dogs without recent (24 months) travel history and antileptospira vaccination had been exposed to pathogenic Leptospira interrogans serovars. Contact with stagnant water and living in urban areas were independent risk factors for seropositivity.
Tetrandrine ameliorates cognitive deficits and mitigates tau aggregation in cell and animal models of tauopathies
Authors: Tong Benjamin Chun-Kit , Huang Alexis Shiying , Wu Aston Jiaxi , Iyaswamy Ashok , Ho Olivia Ka-Yi , Kong Anna Hau-Yee , Sreenivasmurthy Sravan Gopalkrishnashetty , Zhu Zhou , Su Chengfu , Liu Jia , Song Juxian , Li Min , Cheung King-Ho
Published: October 2022

Background

Tauopathies are neurodegenerative diseases that are associated with the pathological accumulation of tau-containing tangles in the brain. Tauopathy can impair cognitive and motor functions and has been observed in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The aetiology of tauopathy remains mysterious; however, recent studies suggest that the autophagic-endolysosomal function plays an essential role in the degradation and transmission of pathological tau. We previously demonstrated that tetrandrine could ameliorate memory functions and clear amyloid plaques in transgenic AD mice by restoring autophagic-endolysosomal function. However, the efficacy of tetrandrine and the associated therapeutic mechanism in tauopathies have not been evaluated and elucidated.

Methods

Novel object recognition, fear conditioning and electrophysiology were used to evaluate the effects of tetrandrine on memory functions in transgenic tau mice. Western blotting and immunofluorescence staining were employed to determine the effect of tetrandrine on autophagy and tau clearance in vivo. Calcium (Ca2+) imaging and flow cytometry were used to delineate the role of pathological tau and tetrandrine in lysosomal Ca2+ and pH homeostasis. Biochemical BiFC fluorescence, Western blotting and immunofluorescence staining were used to evaluate degradation of hyperphosphorylated tau in vitro, whereas coculture of brain slices with isolated microglia was used to evaluate tau clearance ex vivo.

Results

We observed that tetrandrine treatment mitigated tau tangle development and corrected memory impairment in Thy1-hTau.P301S transgenic mice. Mechanistically, we showed that mutant tau expression disrupts lysosome pH by increasing two-pore channel 2 (TPC2)-mediated Ca2+ release, thereby contributing to lysosome alkalinization. Tetrandrine inhibits TPC2, thereby restoring the lysosomal pH, promotes tau degradation via autophagy, and ameliorates tau aggregation. Furthermore, in an ex vivo assay, we demonstrated that tetrandrine treatment promotes pathological tau clearance by microglia.

Conclusions

Together, these findings suggest that pathological tau disturbs endolysosomal homeostasis to impair tau clearance. This impairment results in a vicious cycle that accelerates disease pathogenesis. The success of tetrandrine in reducing tau aggregation suggests first, that tetrandrine could be an effective drug for tauopathies and second, that rescuing lysosomal Ca2+ homeostasis, thereby restoring ALP function, could be an effective general strategy for the development of novel therapies for tauopathies.
Clinical characteristics of Plasmodium falciparum infection among symptomatic patients presenting to a major urban military hospital in Cameroon
Authors: Hodson Daniel Z. , Mbarga Etoundi Yannick , Mbatou Nghokeng Narcisse , Mohamadou Poulibe Raïhana , Magne Djoko Sonia , Goodwin Justin , Cheteug Nguesta Glwadys , Nganso Tatiana , Armstrong Jillian N. , Andrews John J. , Zhang Elizabeth , Wade Martina , Eboumbou Moukoko Carole Else , Boum Yap , Parikh Sunil
Published: October 2022

Background

Urban malaria has received insufficient attention in the literature. The prevalence and clinical characteristics of Plasmodium falciparum infection amongst patients presenting with suspected malaria were investigated at a major urban hospital in Douala, Cameroon with a particular focus on anaemia.

Methods

A cross-sectional, 18-week demographic and clinical survey was conducted of patients presenting to the Emergency Department of Douala Military Hospital with suspected malaria, largely defined by the presence or recent history of fever. Venous samples were tested for P. falciparum using rapid diagnostic tests and PCR, and anaemia was defined by haemoglobin level according to WHO definitions. Likelihood ratios (LR), odds ratios (OR), and population attributable risk percent (PARP) were calculated.

Results

Participants were ages 8 months to 86 years, 51% were women (257/503), and all districts of Douala were represented. Overall, 38.0% (n = 189/497) were anaemic, including 5.2% (n = 26/497) with severe anaemia. Anaemia prevalence was significantly higher (OR: 2.20, 95% CI 1.41–3.45) among children < 15 years (53.1%, n = 52/98) compared to adults (34%, n = 133/392). Plasmodium falciparum was detected in 37.2% by nested PCR. Among all participants, several factors were associated with clinically significant LR for P. falciparum infection, including age 10–14 years (positive LR: 3.73), living in the island district of Douala VI (positive LR: 3.41), travel to any of three northern regions (positive LR: 5.11), and high fever > 40 °C at presentation (positive LR: 4.83). Among all participants, 8.7% of anaemia was associated with P. falciparum infection, while the PARP was 33.2% among those < 15 years of age and 81.0% among 10–14-year-olds.

Conclusions

The prevalence of P. falciparum infection in the urban hospital was high. Mirroring trends in many rural African settings, older children had the highest positivity rate for P. falciparum infection. Anaemia was also common in all age groups, and for those 10–14 years of age, 80% of the risk for anaemia was associated with P. falciparum infection. Malaria rates in major urban population centres can be high, and more research into the multifactorial causes of anaemia across the age spectrum are needed.
The consumption of culinary preparations and ultra-processed food is associated with handgrip strength in teenagers
Authors: Confortin Susana Cararo , Barbosa Aline Rodrigues , de Oliveira Bianca Rodrigues , da Silva Magalhães Elma Izze , Bragança Maylla Luanna Barbosa Martins , de Britto e Alves Maria Teresa Seabra Soares , Levy Renata Bertazzi , Batista Rosângela Fernandes Lucena , de Almeida Fonseca Viola Poliana Cristina , da Silva Antônio Augusto Moura
Published: October 2022

Background

A nutrient-poor and hypocaloric diet may be associated with lower handgrip strength (HGS), whereas a high-quality or balanced diet may be associated with higher HGS. However, no study has used the NOVA system for classifying food by their degree of processing.

Objective

To analyze the association between food consumption according to the degree of food processing and HGS in Brazilian teenagers.

Methods

This cross-sectional study included teenagers aged 18 and 19 years old from the 1997/98 São Luís’ birth cohort, Maranhão, Brazil. HGS (kilogram-force) was measured via a Jamar Plus + dynamometer. Food consumption was assessed using a semiquantitative food frequency questionnaire. The energy intake of culinary preparations (unprocessed or minimally processed food and processed culinary ingredients), processed, and ultra-processed foods was evaluated in percentages and categorized in tertiles. The associations between each food group intake and HGS was estimated via crude and adjusted linear regression models. A directed acyclic graph was used to identify confounding factors.

Results

We evaluated 2,433 teenagers, 52.1% of which were girls. For boys, adjusted analysis showed an association between the highest HGS and the 3rd tertile of culinary preparation consumption (β: 1.95; 95%CI: 0.80; 3.10) and between the lowest HGS and the 3rd tertile of ultra-processed food consumption (β: -2.25; 95%CI: -3.40; -1.10). Among girls, the consumption of culinary preparations in the 3rd tertile was associated with higher HGS (β: 0.76; 95%CI: 0.05; 1.46).

Conclusions

Higher consumption of culinary preparations and lower consumption of ultra-processed foods can contribute to reduce the chance of lower HGS in adult life. Interventions to promote the development and preservation of muscle strength should include dietary recommendations.
Association between triglyceride-to-high-density lipoprotein cholesterol ratio and prediabetes: a cross-sectional study in Chinese non-obese people with a normal range of low-density lipoprotein cholesterol
Authors: Wu Liling , Wu Xiaodan , Hu Haofei , Wan Qijun
Published: October 2022

Background

Evidence about the relationship between triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-C) ratio and prediabetes (Pre-DM) in Chinese non-obese people with a normal range of low-density lipoprotein cholesterol (LDL-c) is limited. Therefore, the present study was undertaken to explore the link of the TG/HDL-C ratio on Pre-DM among non-obese Chinese population with a normal range of LDL-c.

Methods

This study was a cross-sectional study that enrolled 153163 non-obese individuals with a normal range of low-density lipoprotein cholesterol in a Chinese hospital from January 2010 to December 2014. Logistic regression model, generalized additive model (GAM), smooth curve fitting and a series of sensitivity analyses was used to evaluate the association between TG/HDL-C ratio and Pre-DM.

Result

The prevalence of Pre-DM was 9.77%.The median TG/HDL-C ratio was 0.671 (interquartile range, 0.468–1.010). After adjusting covariates, the results showed that TG/HDL-C ratio was positively associated with Pre-DM ((OR = 1.185, 95%CI 1.145–1.226). In addition, the TG/HDL-C ratio level has a non-linear relationship with the incidence of Pre-DM, in which the inflection point was 1.617. The effect sizes (OR) on the left and right sides of the inflection point were 1.312 (95%CI 1.242–1.386) and 0.980 (95%CI 0.898–1.070), respectively. And the sensitive analysis demonstrated the robustness of the results. Subgroup analysis showed a stronger association between TG/HDL-C ratio and Pre-DM in females and the population with 30 years  < age  < 40 years, 18.5 kg/m2 < body mass index  < 24 kg/m2, and ALT < 40U/L.

Conclusion

This study demonstrates a positive and non-linear relationship between TG/HDL-C ratio and Pre-DM in Chinese non-obese people with a normal range of low-density lipoprotein cholesterol. TG/HDL-C ratio is strongly related to Pre-DM when TG/HDL-C ratio is less than 1.617. It makes sense to reduce the TG/HDL-C ratio level below the inflection point from a treatment perspective.
Mitochondrial transplantation: opportunities and challenges in the treatment of obesity, diabetes, and nonalcoholic fatty liver disease
Authors: Chen Yifei , Yang Fuji , Chu Ying , Yun Zhihua , Yan Yongmin , Jin Jianhua
Published: October 2022

Metabolic diseases, including obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD), are rising in both incidence and prevalence and remain a major global health and socioeconomic burden in the twenty-first century. Despite an increasing understanding of these diseases, the lack of effective treatments remains an ongoing challenge. Mitochondria are key players in intracellular energy production, calcium homeostasis, signaling, and apoptosis. Emerging evidence shows that mitochondrial dysfunction participates in the pathogeneses of metabolic diseases. Exogenous supplementation with healthy mitochondria is emerging as a promising therapeutic approach to treating these diseases. This article reviews recent advances in the use of mitochondrial transplantation therapy (MRT) in such treatment.
Exploiting DNA Ligase III addiction of multiple myeloma by flavonoid Rhamnetin
Authors: Caracciolo Daniele , Juli Giada , Riillo Caterina , Coricello Adriana , Vasile Francesca , Pollastri Sara , Rocca Roberta , Scionti Francesca , Polerà Nicoletta , Grillone Katia , Arbitrio Mariamena , Staropoli Nicoletta , Caparello Basilio , Britti Domenico , Loprete Giovanni , Costa Giosuè , Di Martino Maria Teresa , Alcaro Stefano , Tagliaferri Pierosandro , Tassone Pierfrancesco
Published: October 2022

Background

DNA ligases are crucial for DNA repair and cell replication since they catalyze the final steps in which DNA breaks are joined. DNA Ligase III (LIG3) exerts a pivotal role in Alternative-Non-Homologous End Joining Repair (Alt-NHEJ), an error-prone DNA repair pathway often up-regulated in genomically unstable cancer, such as Multiple Myeloma (MM). Based on the three-dimensional (3D) LIG3 structure, we performed a computational screening to identify LIG3-targeting natural compounds as potential candidates to counteract Alt-NHEJ activity in MM.

Methods

Virtual screening was conducted by interrogating the Phenol Explorer database. Validation of binding to LIG3 recombinant protein was performed by Saturation Transfer Difference (STD)—nuclear magnetic resonance (NMR) experiments. Cell viability was analyzed by Cell Titer-Glo assay; apoptosis was evaluated by flow cytometric analysis following Annexin V-7AAD staining. Alt-NHEJ repair modulation was evaluated using plasmid re-joining assay and Cytoscan HD. DNA Damage Response protein levels were analyzed by Western blot of whole and fractionated protein extracts and immunofluorescence analysis. The mitochondrial DNA (mtDNA) copy number was determined by qPCR. In vivo activity was evaluated in NOD-SCID mice subcutaneously engrafted with MM cells.

Results

Here, we provide evidence that a natural flavonoid Rhamnetin (RHM), selected by a computational approach, counteracts LIG3 activity and killed Alt-NHEJ-dependent MM cells. Indeed, Nuclear Magnetic Resonance (NMR) showed binding of RHM to LIG3 protein and functional experiments revealed that RHM interferes with LIG3-driven nuclear and mitochondrial DNA repair, leading to significant anti-MM activity in vitro and in vivo.

Conclusion

Taken together, our findings provide proof of concept that RHM targets LIG3 addiction in MM and may represent therefore a novel promising anti-tumor natural agent to be investigated in an early clinical setting.
FoxP3 expression by retinal pigment epithelial cells: transcription factor with potential relevance for the pathology of age-related macular degeneration
Authors: Alfaar Ahmad Samir , Stürzbecher Lucas , Diedrichs-Möhring Maria , Lam Marion , Roubeix Christophe , Ritter Julia , Schumann Kathrin , Annamalai Balasubramaniam , Pompös Inga-Marie , Rohrer Bärbel , Sennlaub Florian , Reichhart Nadine , Wildner Gerhild , Strauß Olaf
Published: October 2022

Background

Forkhead-Box-Protein P3 (FoxP3) is a transcription factor and marker of regulatory T cells, converting naive T cells into Tregs that can downregulate the effector function of other T cells. We previously detected the expression of FoxP3 in retinal pigment epithelial (RPE) cells, forming the outer blood–retina barrier of the immune privileged eye.

Methods

We investigated the expression, subcellular localization, and phosphorylation of FoxP3 in RPE cells in vivo and in vitro after treatment with various stressors including age, retinal laser burn, autoimmune inflammation, exposure to cigarette smoke, in addition of IL-1β and mechanical cell monolayer destruction. Eye tissue from humans, mouse models of retinal degeneration and rats, and ARPE-19, a human RPE cell line for in vitro experiments, underwent immunohistochemical, immunofluorescence staining, and PCR or immunoblot analysis to determine the intracellular localization and phosphorylation of FoxP3. Cytokine expression of stressed cultured RPE cells was investigated by multiplex bead analysis. Depletion of the FoxP3 gene was performed with CRISPR/Cas9 editing.

Results

RPE in vivo displayed increased nuclear FoxP3-expression with increases in age and inflammation, long-term exposure of mice to cigarette smoke, or after laser burn injury. The human RPE cell line ARPE-19 constitutively expressed nuclear FoxP3 under non-confluent culture conditions, representing a regulatory phenotype under chronic stress. Confluently grown cells expressed cytosolic FoxP3 that was translocated to the nucleus after treatment with IL-1β to imitate activated macrophages or after mechanical destruction of the monolayer. Moreover, with depletion of FoxP3, but not of a control gene, by CRISPR/Cas9 gene editing decreased stress resistance of RPE cells.

Conclusion

Our data suggest that FoxP3 is upregulated by age and under cellular stress and might be important for RPE function.
Impact of random outliers in auto-segmented targets on radiotherapy treatment plans for glioblastoma
Authors: Poel Robert , Rüfenacht Elias , Ermis Ekin , Müller Michael , Fix Michael K. , Aebersold Daniel M. , Manser Peter , Reyes Mauricio
Published: October 2022

Aims

To save time and have more consistent contours, fully automatic segmentation of targets and organs at risk (OAR) is a valuable asset in radiotherapy. Though current deep learning (DL) based models are on par with manual contouring, they are not perfect and typical errors, as false positives, occur frequently and unpredictably. While it is possible to solve this for OARs, it is far from straightforward for target structures. In order to tackle this problem, in this study, we analyzed the occurrence and the possible dose effects of automated delineation outliers.

Methods

First, a set of controlled experiments on synthetically generated outliers on the CT of a glioblastoma (GBM) patient was performed. We analyzed the dosimetric impact on outliers with different location, shape, absolute size and relative size to the main target, resulting in 61 simulated scenarios. Second, multiple segmentation models where trained on a U-Net network based on 80 training sets consisting of GBM cases with annotated gross tumor volume (GTV) and edema structures. On 20 test cases, 5 different trained models and a majority voting method were used to predict the GTV and edema. The amount of outliers on the predictions were determined, as well as their size and distance from the actual target.

Results

We found that plans containing outliers result in an increased dose to healthy brain tissue. The extent of the dose effect is dependent on the relative size, location and the distance to the main targets and involved OARs. Generally, the larger the absolute outlier volume and the distance to the target the higher the potential dose effect. For 120 predicted GTV and edema structures, we found 1887 outliers. After construction of the planning treatment volume (PTV), 137 outliers remained with a mean distance to the target of 38.5 ± 5.0 mm and a mean size of 1010.8 ± 95.6 mm3. We also found that majority voting of DL results is capable to reduce outliers.

Conclusions

This study shows that there is a severe risk of false positive outliers in current DL predictions of target structures. Additionally, these errors will have an evident detrimental impact on the dose and therefore could affect treatment outcome.
Use of cryotherapy to treat obstructing papilloma of an accessory tracheal bronchus: case report
Authors: Adams Alexandra E. , Steiner Federico A.
Published: October 2022

Background

Tracheal papillomatosis is a relatively rare condition with limited data on successful treatment modalities. To our knowledge, this is the first report to describe a papilloma arising from an accessory bronchus. Furthermore, this case report demonstrates successful treatment with clinical and patient-centered improvements after use of Spray Cryotherapy.

Case presentation

A 71-year-old woman presented with one year history of recurrent fevers and intermittent hemoptysis. Imaging and video bronchoscopy revealed an obstructing papilloma of an accessory tracheal bronchus to the right upper lobe. She was treated with debridement followed by multiple cryotherapy treatments resulting in complete clinical and radiographic resolution of her post-obstructive pneumonia.

Conclusions

This case report not only supports existing literature on the use of cryotherapy for airway diseases but also presents a unique form of obstructing papilloma confined to an accessory bronchus, the only report of its kind based on extensive literature review.
The role of triggering receptor expressed on myeloid cells-1 (TREM-1) in central nervous system diseases
Authors: Zhang Chunyan , Kan Xugang , Zhang Baole , Ni Haibo , Shao Jianfeng
Published: October 2022

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily and is mainly expressed on the surface of myeloid cells such as monocytes, macrophages, and neutrophils. It plays an important role in the triggering and amplification of inflammatory responses, and it is involved in the development of various infectious and non-infectious diseases, autoimmune diseases, and cancers. In recent years, TREM-1 has also been found to participate in the pathological processes of several central nervous system (CNS) diseases. Targeting TREM-1 may be a promising strategy for treating these diseases. This paper aims to characterize TREM-1 in terms of its structure, signaling pathway, expression, regulation, ligands and pathophysiological role in CNS diseases.
The effects of laparoscopic Roux-en-Y gastric bypass and one-anastomosis gastric bypass on glycemic control and remission of type 2 diabetes mellitus: study protocol for a multi-center randomized controlled trial (the DIABAR-trial)
Authors: van Rijswijk A. , van Olst N. , Meijnikman A. S. , Acherman Y. I. Z. , Bruin S. C. , van de Laar A. W. , van Olden C. C. , Aydin O. , Borger H. , Beuers U. H. W. , Herrema H. , Verheij J. , Apers J. A. , Bäckhed F. , Gerdes V. E. A. , Nieuwdorp M. , de Brauw L. M.
Published: October 2022

Background

Metabolic surgery induces rapid remission of type 2 diabetes mellitus (T2DM). There is a paucity of high level evidence comparing the efficacy of the laparoscopic Roux-en-Y gastric bypass (RYGB) and the laparoscopic one-anastomosis gastric bypass (OAGB) in glycemic control. Also, the mechanisms that drive the conversion of T2DM in severe obese subjects to euglycemia are poorly understood.

Methods

The DIABAR-trial is an open, multi-center, randomized controlled clinical trial with 10 years follow-up which will be performed in 220 severely obese patients, diagnosed with T2DM and treated with glucose-lowering agents. Patients will be randomized in a 1:1 ratio to undergo RYGB or OAGB. The primary outcome is glycemic control at 12 months follow-up. Secondary outcome measures are diverse and include weight loss, surgical complications, psychologic status and quality of life, dietary behavior, gastrointestinal symptoms, repetitive bloodwork to identify changes over time, glucose tolerance and insulin sensitivity as measured by mixed meal tests, remission of T2DM, presence of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in liver biopsy, oral and fecal microbiome, cardiovascular performance, composition of bile acids, and the tendency to develop gallstones.

Discussion

The DIABAR-trial is one of the few randomized controlled trials primarily aimed to evaluate the glycemic response after the RYGB and OAGB in severe obese patients diagnosed with T2DM. Secondary aims of the trial are to contribute to a deeper understanding of the mechanisms that drive the remission of T2DM in severe obese patients by identification of microbial, immunological, and metabolic markers for metabolic response and to compare complications and side effects of RYGB and OAGB.

Trial registration

ClinicalTrials.govNCT03330756; date first registered: October 13, 2017.
Interactions in the 2×2×2 factorial randomised clinical STEPCARE trial and the potential effects on conclusions: a protocol for a simulation study
Authors: Olsen Markus Harboe , Jensen Aksel Karl Georg , Dankiewicz Josef , Skrifvars Markus B. , Reinikainen Matti , Tiainen Marjaana , Saxena Manoj , Aneman Anders , Gluud Christian , Ullén Susann , Nielsen Niklas , Jakobsen Janus Christian
Published: October 2022

Background

Randomised clinical trials with a factorial design may assess the effects of multiple interventions in the same population. Factorial trials are carried out under the assumption that the trial interventions have no interactions on outcomes. Here, we present a protocol for a simulation study investigating the consequences of different levels of interactions between the trial interventions on outcomes for the future 2×2×2 factorial designed randomised clinical Sedation, TEmperature, and Pressure after Cardiac Arrest and REsuscitation (STEPCARE) trial in comatose patients after out-of-hospital cardiac arrest.

Methods

By simulating a multisite trial with 50 sites and 3278 participants, and a presumed six-month all-cause mortality of 60% in the control population, we will investigate the validity of the trial results with different levels of interaction effects on the outcome. The primary simulation outcome of the study is the risks of type-1 and type-2 errors in the simulated scenarios, i.e. at what level of interaction is the desired alpha and beta level exceeded. When keeping the overall risk of type-1 errors ≤ 5% and the risk of type-2 errors ≤ 10%, we will quantify the maximum interaction effect we can accept if the planned sample size is increased by 5% to take into account possible interaction between the trial interventions. Secondly, we will assess how interaction effects influence the minimal detectable difference we may confirm or reject to take into account 5% (small interaction effect), 10% (moderate), or 15% (large) positive interactions in simulations with no ‘true’ intervention effect (type-1 errors) and small (5%), moderate (10%), or large negative interactions (15%) in simulations with ‘true’ intervention effects (type-2 errors). Moreover, we will investigate how much the sample size must be increased to account for a small, moderate, or large interaction effects.

Discussion

This protocol for a simulation study will inform the design of a 2×2×2 factorial randomised clinical trial of how potential interactions between the assessed interventions might affect conclusions. Protocolising this simulation study is important to ensure valid and unbiased results.

Trial registration

Not relevant
Effect of vitamin D supplementation on brain waves, behavioral performance, nitric oxide, malondialdehyde, and high-sensitivity C-reactive protein in children with attention deficit/hyperactivity disorder: study protocol for a randomized clinical trial
Authors: Sangouni Abbas Ali , Mirhosseini Hamid , Hosseinzadeh Mahdieh
Published: October 2022

Background

Attention deficit/hyperactivity disorder (ADHD) is the most common chronic mental and behavioral disorder among children. Some studies showed the lower levels of vitamin D in patients with ADHD compared with the healthy people. Few clinical trials were conducted in this field. The present study will be performed to examine the effect of vitamin D supplementation in children with ADHD.

Methods

We will conduct a double-blind, randomized controlled clinical trial to investigate the effect of vitamin D supplementation on brain waves, behavioral performance, serum nitric oxide, malondialdehyde, and high-sensitivity C-reactive protein in 50 patients with ADHD. The intervention group will receive one capsule 50,000 IU vitamin D every week, for 8 weeks. The control group will receive one placebo capsule containing 1000 mg olive oil every week. Electroencephalography will be performed for 10 min using Brain Master Discovery from 19 scalp sites both before the first intervention and the 10 sessions of the therapy. The artifact-free periods of 1-min electroencephalography data will be analyzed for quantitative electroencephalography measures.

Discussion

For the first time, this clinical trial will evaluate the effect of vitamin D supplementation on brain waves, serum nitric oxide, malondialdehyde, and high-sensitivity C-reactive protein in patients with ADHD. The results of the present clinical trial will provide a better vision about the vitamin D efficacy in patients with ADHD.

Trial registration

Registered on 5 November 2020 at Iranian Registry of Clinical Trials with code number IRCT20200922048802N1 (https://www.irct.ir/trial/51410).
Synthetic methylotrophic yeasts for the sustainable fuel and chemical production
Authors: Wegat Vanessa , Fabarius Jonathan T. , Sieber Volker
Published: October 2022

Global energy-related emissions, in particular carbon dioxide, are rapidly increasing. Without immediate and strong reductions across all sectors, limiting global warming to 1.5 °C and thus mitigating climate change is beyond reach. In addition to the expansion of renewable energies and the increase in energy efficiency, the so-called Carbon Capture and Utilization technologies represent an innovative approach for closing the carbon cycle and establishing a circular economy. One option is to combine CO2capture with microbial C1fermentation. C1-molecules, such as methanol or formate are considered as attractive alternative feedstock for biotechnological processes due to their sustainable production using only CO2, water and renewable energy. Native methylotrophic microorganisms can utilize these feedstock for the production of value-added compounds. Currently, constraints exist regarding the understanding of methylotrophic metabolism and the available genetic engineering tools are limited. For this reason, the development of synthetic methylotrophic cell factories based on the integration of natural or artificial methanol assimilation pathways in biotechnologically relevant microorganisms is receiving special attention. Yeasts likeSaccharomyces cerevisiaeandYarrowia lipolyticaare capable of producing important products from sugar-based feedstock and the switch to produce these in the future from methanol is important in order to realize a CO2-based economy that is independent from land use. Here, we review historical biotechnological applications, the metabolism and the characteristics of methylotrophic yeasts. Various studies demonstrated the production of a broad set of promising products from fine chemicals to bulk chemicals by applying methylotrophic yeasts. Regarding synthetic methylotrophy, the deep understanding of the methylotrophic metabolism serves as the basis for microbial strain engineering and paves the way towards a CO2-based circular bioeconomy. We highlight design aspects of synthetic methylotrophy and discuss the resulting chances and challenges using non-conventional yeasts as host organisms. We conclude that the road towards synthetic methylotrophic yeasts can only be achieved through a combination of methods (e.g., metabolic engineering and adaptive laboratory evolution). Furthermore, we presume that the installation of metabolic regeneration cycles such as supporting carbon re-entry towards the pentose phosphate pathway from C1-metabolism is a pivotal target for synthetic methylotrophy.
Interleukin-33 deficiency prevents biliary injuries and repairments caused by Clonorchis sinensis via restraining type 2 cytokines
Authors: Yan Chao , Xu Na , Liu Man , Jiang Zhihua , Wu Jing , Koda Stephane , Chen Yu , Zhang Beibei , Yu Qian , Xu Yin-Hai , Wu Jian-Lin , Zheng Kui-Yang
Published: October 2022

Background

Clonorchiasis caused by Clonorchis sinensis is a zoonotic parasitic disease characterized by cholangitis, biliary proliferation, biliary fibrosis, and even cholangiocarcinoma. Our previous study showed that the expression of interleukin (IL)-33 is increased in both humans and mice infected by C. sinensis, suggesting that IL-33 is potentially involved in the pathogenesis of clonorchiasis. However, the roles and potential mechanism of IL-33 underlying remain unknown.

Methods

Wild-type (WT) and IL-33 knockout (KO) mice (BALB/c female mice) were orally infected with 45 metacercariae of C. sinensis for 8 weeks. Biliary injuries and fibrosis were extensively evaluated. Hepatic type II cytokines (IL-4, IL-13, and IL-10) were detected by ELISA.

Results

For wild-type mice, we found that the mice infected with C. sinensis showed severe biliary injuries and fibrosis compared with the normal mice that were free from worm infection. In addition, the levels of type II cytokines such as IL-4, IL-13, and IL-10 in infected wild-type mice were significantly higher than in the control mice without infection (P < 0.05). However, IL-33 deficiency (IL-33 KO) prevents the augmentation of biliary injuries and fibrosis caused by C. sinensis infection. Furthermore, the increased levels of these type II cytokines induced by worm infection were also reversed in IL-33 KO mice.

Conclusion

Our present study demonstrates that IL-33 contributes to the pathogenesis of C. sinensis-induced biliary injuries and repair, which can potentially orchestrate type 2 responses. These findings highlight the pathophysiological role of IL-33 in the progression of clonorchiasis.
Linear and conformational determinants of visceral leishmaniasis diagnostic antigens rK28 and rK39
Authors: Simonson Poppy , Bhattacharyya Tapan , El-Safi Sayda , Miles Michael A.
Published: October 2022

Background

Recombinant antigens rK39 (based on kinesin sequence) and rK28 (comprising kinesin and HASPB sequences) are a mainstay of serological diagnosis for visceral leishmaniasis (VL). However, their key epitopes and the significance of their structural conformation are not clearly defined, particularly in relation to reported cross-reactivity with sera from patients with malaria, schistosomiasis, and tuberculosis.

Methods

To assess the effect of conformation on antigenicity with Sudanese VL sera, antigens rK39 and rK28 were heat-denatured at 95 °C for 10 min and then assayed by enzyme-linked immunosorbent assay (ELISA). Amino acid sequences of rK39 and rK28 were submitted to NCBI BLASTp to assess homology with Plasmodium, Schistosoma, and Mycobacterium.

Results

Heat denaturation significantly diminished the antigenicity of rK39 compared to non-denatured antigen (P = 0.001), but not for rK28 (P = 0.275). In BLASTp searches, HASPB sequences from rK28 had similarities with sequences from Plasmodium, encompassing software-predicted B-cell epitopes.

Conclusions

The antigenicity of rK39 appears to be dependent on structural conformation, whereas that of rK28 depends on linear sequence. HASPB sequence homology with Plasmodium may be responsible for the reported cross-reactivity of rK28 with malaria sera. Further work is warranted to refine the specificity of these antigens.

Graphical Abstract