bluuebunny/crossref_metadata_2025 huggingface dataset:
Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination
Authors: Zirngibl Martin , Assinck Peggy , Sizov Anastasia , Caprariello Andrew V. , Plemel Jason R.
Published: May 2022

Background

The dietary consumption of cuprizone – a copper chelator – has long been known to induce demyelination of specific brain structures and is widely used as model of multiple sclerosis. Despite the extensive use of cuprizone, the mechanism by which it induces demyelination are still unknown. With this review we provide an updated understanding of this model, by showcasing two distinct yet overlapping modes of action for cuprizone-induced demyelination; 1) damage originating from within the oligodendrocyte, caused by mitochondrial dysfunction or reduced myelin protein synthesis. We term this mode of action ‘intrinsic cell damage’. And 2) damage to the oligodendrocyte exerted by inflammatory molecules, brain resident cells, such as oligodendrocytes, astrocytes, and microglia or peripheral immune cells – neutrophils or T-cells. We term this mode of action ‘extrinsic cellular damage’. Lastly, we summarize recent developments in research on different forms of cell death induced by cuprizone, which could add valuable insights into the mechanisms of cuprizone toxicity. With this review we hope to provide a modern understanding of cuprizone-induced demyelination to understand the causes behind the demyelination in MS.
Elimination of porcine reproductive and respiratory syndrome virus infection using an inactivated vaccine in combination with a roll-over method in a Hungarian large-scale pig herd
Authors: Pertich Attila , Barna Zoltán , Makai Orsolya , Farkas János , Molnár Tamás , Bálint Ádám , Szabó István , Albert Mihály
Published: May 2022

Background

Porcine reproductive and respiratory syndrome virus (PRRSV) causes severe economic losses worldwide and only four countries in Europe are free from PRRSV. Complete depopulation–repopulation is the safest and fastest, but also the most expensive method for eradicating PRRSV from a population. Another possible way to eliminate an endemic PRRSV infection is to replace the infected breeding stock by gilts reared isolated and protected from PRRSV on an infected farm. With this method it is possible to maintain continuous production on the farm. The authors report the first successful elimination of PRRSV in a Hungarian large-scale pig farm by using an inactivated vaccine and performing segregated rearing of the offspring.

Case presentation

The study was performed on a PRRSV infected farm (Farm A) with 1475 sows. The clinical signs of reproductive failure had been eliminated previously by using an inactivated vaccine (Progressis®, Ceva). At the beginning of the elimination programme, gilts intended for breeding were vaccinated at 60 and 90–100 days of age. After that, gilts selected for breeding were vaccinated at 6 months of age, on the 60–70th day of pregnancy and at weaning.

Approximately 1200 piglets from vaccinated sows were transported at 7 weeks of age to a closed, empty farm (Farm B) after being tested negative for PRRSV by a polymerase chain reaction (PCR) method, and then were reared here until 14 weeks of age. At this age, all pigs were tested by PRRS ELISA. Seronegative gilts (n = 901) were subsequently transported from Farm B to a third, closed and empty farm (Farm C), and (having reached the breeding age) they were inseminated here after a second negative serological test (ELISA). At the same time, Farm A was depopulated, cleaned and disinfected. All pregnant gilts were transported from Farm C to Farm A after being re-tested negative for antibodies against PRRSV. Follow-up serology tests were performed after farrowing and results yielded only seronegative animals. Based on the subsequent negative test results, the herd was declared PRRSV free by the competent authority.

Conclusions

The presented farm was the first during the National PRRS Eradication Programme of Hungary to eradicate PRRSV successfully by vaccinating the sows with an inactivated vaccine and performing segregated rearing of the offspring. Production was almost continuous during the whole process of population replacement.
Short-term survival rates of 1397 horses referred for colic from 2010 to 2018
Authors: Dybkjær Emma , Steffensen Kirstine Fleng , Honoré Marie Louise , Dinesen Mathias Ankjær , Christophersen Mogens Teken , Pihl Tina Holberg
Published: May 2022

Background

Up-to-date and hospital-specific knowledge of prognoses for horses with various forms of colic is essential for helping to guide owners’ decisions on costly treatments, and for assessing the continuous development of standards of care in the hospital. This study aimed to determine the short-term survival rates of horses admitted with colic to the University Hospital for Large Animals (UHLA), University of Copenhagen, Denmark, from 2010 to 2018, and to compare these to a previous local study as well as recent, comparable international studies.

Short-term survival rates were calculated for horses grouped by treatment (surgical, medical) and diseases. Results were compared to the selected studies using Chi-square tests.

Results

A total of 1752 horses were admitted with colic during the period, of which 355 were excluded for reasons such as economic restrictions or immediate euthanasia. Short-term survival of the remaining 1397 cases was significantly higher (83.0% (95% CI 81.1–85.0%)) than a previous local study (76%) and a recent Dutch study (80%). Medical treatment was carried out in 77.1% of cases, and surgery in 22.9% of the cases. Short-term survival for medically (89.7%) and surgically (60.6%) treated horses was significantly higher in the present study compared to the previous study (87% and 42%, respectively), but was similar to that found in the Dutch study. Significantly fewer horses were euthanised during surgery than in the previous study (17.2 vs. 40%), and significantly more horses recovered from surgery (79.1 vs. 56%). Short-term survival rate of surgically treated horses (60.6%) did not differ from other European studies (55–62%).

Conclusions

Short-term survival rates have increased since the previous study at UHLA, mainly due to a decrease in intraoperative euthanasia. Survival rates in this study are similar to those found in recent comparable colic studies.
Implementation of maternal and perinatal death surveillance and response (MPDSR) in humanitarian settings: insights and experiences of humanitarian health practitioners and global technical expert meeting attendees
Authors: Russell Neal , Tappis Hannah , Mwanga Jean Paul , Black Benjamin , Thapa Kusum , Handzel Endang , Scudder Elaine , Amsalu Ribka , Reddi Jyoti , Palestra Francesca , Moran Allisyn C.
Published: May 2022

Background

Maternal and perinatal death surveillance and response (MPDSR) is a system of identifying, analysing and learning lessons from such deaths in order to respond and prevent future deaths, and has been recommended by WHO and implemented in many low-and-middle income settings in recent years. However, there is limited documentation of experience with MPDSR in humanitarian settings. A meeting on MPDSR in humanitarian settings was convened by WHO, UNICEF, CDC and Save the Children, UNFPA and UNHCR on 17th–18th October 2019, informed by semi-structured interviews with a range of professionals, including expert attendees.

Consultation findings

Interviewees revealed significant obstacles to full implementation of the MPDSR process in humanitarian settings. Many obstacles were familiar to low resource settings in general but were amplified in the context of a humanitarian crisis, such as overburdened services, disincentives to reporting, accountability gaps, a blame approach, and politicisation of mortality. Factors more unique to humanitarian contexts included concerns about health worker security and moral distress. There are varying levels of institutionalisation and implementation capacity for MPDSR within humanitarian organisations. It is suggested that if poorly implemented, particularly with a punitive or blame approach, MPDSR may be counterproductive. Nevertheless, successes in MPDSR were described whereby the process led to concrete actions to prevent deaths, and where death reviews have led to improved understanding of complex and rectifiable contextual factors leading to deaths in humanitarian settings.

Conclusions

Despite the challenges, examples exist where the lessons learnt from MPDSR processes have led to improved access and quality of care in humanitarian contexts, including successful advocacy. An adapted approach is required to ensure feasibility, with varying implementation being possible in different phases of crises. There is a need for guidance on MPDSR in humanitarian contexts, and for greater documentation and learning from experiences.
Rebuilding child health in South Kivu, Democratic Republic of Congo (DRC): evaluating the Asili social enterprise program
Authors: Behl Rasika , Ali Sofia , Altamirano Jonathan , Leno Abraham , Maldonado Yvonne , Sarnquist Clea
Published: May 2022

Background

The Democratic Republic of Congo (DRC) has a long history of conflict and ongoing local instability; the eastern provinces, including South Kivu, have been especially affected. Health systems and livelihoods have been undermined, contributing to massive inequities in access to health services and high rates of internal displacement. Asili, an innovative social enterprise program, aimed to provide essential community services and improve the health of under-five children in two South Kivu communities, Mudaka and Panzi, via provision of small-format, franchisable health clinics and clean water services.

Methods

We evaluated utilization and acceptance of Asili services in two study sites, Mudaka and Panzi. Data collected included questions on housing conditions, food security, and at follow up, Asili membership and use, satisfaction with services, and recommendations for improvement. Structured pre- and post-interviews with primary caregivers of families with under-five children were the primary source of data with additional community input collected through focus group discussions.

Results

At baseline, we enrolled 843 households in Mudaka and 890 in Panzi. Market segmentation analysis illuminated service usage patterns, showing Asili services were well received overall in both Mudaka and Panzi. Families reporting higher levels of proxy measures of socioeconomic status (SES), such as electricity, land ownership, and education, were more likely to use Asili services, findings that were further supported by focus group discussions among community members.

Conclusions

Rebuilding health infrastructure in post-conflict settings, especially those that continue to be conflict-affected and very low SES, is a challenging prospect. Focus group results for this study highlighted the positive community response to Asili, while also underscoring challenges related to cost of services. Programs may need, in particular, to have different levels of costs for different SES groups. Additionally, longer follow-up periods and increased stability may be needed to assess the potential of social enterprise interventions such as Asili to improve health outcomes, especially in children.

Trial registration

Institutional Review Board approval for this study was obtained at Stanford University (IRB 35216) and the University of Kinshasa, DRC. Further, this study has been registered on Clinicaltrials.gov (record NCT03536286), retrospectively registered as of 4/23/2018.
Antiallodynic effects of KDS2010, a novel MAO-B inhibitor, via ROS-GABA inhibitory transmission in a paclitaxel-induced tactile hypersensitivity model
Authors: Park Su Eun , Neupane Chiranjivi , Noh Chan , Sharma Ramesh , Shin Hyun Jin , Pham Thuy Linh , Lee Gyu-Seung , Park Ki Duk , Lee C. Justin , Kang Dong-Wook , Lee So Yeong , Kim Hyun-Woo , Park Jin Bong
Published: May 2022

Monoamine oxidase (MAO) inhibitors have been investigated for the treatment of neuropathic pain. Here, we assessed the antiallodynic effects of a novel MAO-B inhibitor, KDS2010, on paclitaxel (PTX)-induced mechanical hypersensitivity. Oral administration of KDS2010 effectively relieved PTX-induced mechanical hypersensitivity in a dose-dependent manner. KDS2010 (25 mg/Kg) significantly prevented and suppressed PTX-induced pain responses with minimal effects on the body weight, motor activity, and working memory. KDS2010 significantly reduced reactive astrocytosis and reactive oxygen species (ROS) level in the L4–L6 spinal cord of PTX-treated mice. Furthermore, KDS2010 reversed the attenuation of GABAergic spontaneous inhibitory postsynaptic current (sIPSC) frequency in spinal dorsal horn neurons, although it failed to restore the reduced tonic GABAA inhibition nor the increased GABA transporter 1 (GAT1) expression in PTX-treated mice. In addition, bath application of a reactive oxygen species (ROS) scavenger (PBN) restored the sIPSC frequency in PTX-treated mice but not in control and PTX + KDS2010-treated mice. These results indicated that the antiallodynic effect of KDS2010 is not due to a MAO-B-dependent GABA production. Finally, PBN alone also exerted a similar analgesic effect as KDS2010, but a co-treatment of PBN with KDS2010 showed no additive effect, suggesting that inhibition of MAO-B-dependent ROS production is responsible for the analgesic effect by KDS2010 on PTX-induced allodynia. Overall, KDS2010 attenuated PTX-induced pain behaviors by restoring the altered ROS level and GABAergic inhibitory signaling in the spinal cord, suggesting that KDS2010 is a promising therapeutic strategy for chemotherapy-induced peripheral neuropathy.
The dual role of autophagy in acute myeloid leukemia
Authors: Seo Wonhyoung , Silwal Prashanta , Song Ik-Chan , Jo Eun-Kyeong
Published: May 2022

Acute myeloid leukemia (AML) is a severe hematologic malignancy prevalent in older patients, and the identification of potential therapeutic targets for AML is problematic. Autophagy is a lysosome-dependent catabolic pathway involved in the tumorigenesis and/or treatment of various cancers. Mounting evidence has suggested that autophagy plays a critical role in the initiation and progression of AML and anticancer responses. In this review, we describe recent updates on the multifaceted functions of autophagy linking to genetic alterations of AML. We also summarize the latest evidence for autophagy-related genes as potential prognostic predictors and drivers of AML tumorigenesis. We then discuss the crosstalk between autophagy and tumor cell metabolism into the impact on both AML progression and anti-leukemic treatment. Moreover, a series of autophagy regulators, i.e., the inhibitors and activators, are described as potential therapeutics for AML. Finally, we describe the translation of autophagy-modulating therapeutics into clinical practice. Autophagy in AML is a double-edged sword, necessitating a deeper understanding of how autophagy influences dual functions in AML tumorigenesis and anti-leukemic responses.
A novel role of lysophosphatidic acid (LPA) in human myeloma resistance to proteasome inhibitors
Authors: Su Pan , Xiao Liuling , Ye Lingqun , Wang Zhuo , Xiong Wei , Wang Qiang , Ma Xingzhe , Xian Miao , Yang Maojie , Zu Youli , Pingali Sai Ravi , Qian Jianfei , Yi Qing
Published: May 2022

Lysophosphatidic acid (LPA) is a naturally occurring phospholipid that regulates cell proliferation, survival, and migration. However, its role on human multiple myeloma (MM) cells is largely unknown. In this study, we show that LPA, which is highly elevated in MM patients, plays an important role in protecting human MM cells against proteasome inhibitor (PI)-induced apoptosis. LPA bound to its receptor LPAR2 activated its downstream MEK1/2-ERK1/2 signaling pathway and enhanced oxidative phosphorylation (OXPHOS) in mitochondria in MM cells. Increased OXPHOS activity produced more NAD+ and ATP, reduced proteasome activity, and enhanced protein folding and refolding in endoplasmic reticulum (ER), leading to induction of MM resistance to PIs. Importantly, inhibiting LPAR2 activity or knocking out LPAR2 in MM cells significantly enhanced MM sensitivity to PI-induced apoptosis in vitro and in vivo. Interestingly, primary MM cells from LPA-high patients were more resistant to PI-induced apoptosis than MM cells from LPA-low patients. Thus, our study indicates that LPA-LPAR2-mediated signaling pathways play an important role in MM sensitivity to PIs and targeting LPA or LPAR2 may potentially be used to (re)sensitize patients to PI-based therapy.
A novel tRNA-derived fragment AS-tDR-007333 promotes the malignancy of NSCLC via the HSPB1/MED29 and ELK4/MED29 axes
Authors: Yang Wenhan , Gao Kaiping , Qian Youhui , Huang Yongyi , Xiang Qin , Chen Cheng , Chen Qianqian , Wang Yiling , Fang Fuyuan , He Qihan , Chen Siqi , Xiong Juan , Chen Yangchao , Xie Ni , Zheng Duo , Zhai Rihong
Published: May 2022

Background

Transfer RNA-derived fragments (tRFs) are a new class of small non-coding RNAs. Recent studies suggest that tRFs participate in some pathological processes. However, the biological functions and mechanisms of tRFs in non-small cell lung cancer (NSCLC) are largely unknown.

Methods

Differentially expressed tRFs were identified by tRF and tiRNA sequencing using 9 pairs of pre- and post-operation plasma from patients with NSCLC. Quantitative real-time PCR (qRT-PCR) and fluorescence in situ hybridization (FISH) were used to determine the levels of tRF in tissues, plasma, and cells. Gain- and loss-of-function experiments were implemented to investigate the oncogenic effects of tRF on NSCLC cells in vitro and in vivo. Chromatin immunoprecipitation (ChIP), luciferase reporter, RNA pulldown, mass spectrum, RNA immunoprecipitation (RIP), Western blot, co-immunoprecipitation (Co-IP) assays, and rescue experiments were performed to explore the regulatory mechanisms of tRF in NSCLC.

Results

AS-tDR-007333 was an uncharacterized tRF and significantly up-regulated in NSCLC tissues, plasma, and cells. Clinically, AS-tDR-007333 overexpression could distinguish NSCLC patients from healthy controls and associated with poorer prognosis of NSCLC patients. Functionally, overexpression of AS-tDR-007333 enhanced proliferation and migration of NSCLC cells, whereas knockdown of AS-tDR-007333 resulted in opposite effects. Mechanistically, AS-tDR-007333 promoted the malignancy of NSCLC cells by activating MED29 through two distinct mechanisms. First, AS-tDR-007333 bound to and interacted with HSPB1, which activated MED29 expression by enhancing H3K4me1 and H3K27ac in MED29 promoter. Second, AS-tDR-007333 stimulated the expression of transcription factor ELK4, which bound to MED29 promoter and increased its transcription. Therapeutically, inhibition of AS-tDR-007333 suppressed NSCLC cell growth in vivo.

Conclusions

Our study identifies a new oncogenic tRF and uncovers a novel mechanism that AS-tDR-007333 promotes NSCLC malignancy through the HSPB1-MED29 and ELK4-MED29 axes. AS-tDR-007333 is a potential diagnostic or prognostic marker and therapeutic target for NSCLC.
LncRNA-PACERR induces pro-tumour macrophages via interacting with miR-671-3p and m6A-reader IGF2BP2 in pancreatic ductal adenocarcinoma
Authors: Liu Yihao , Shi Minmin , He Xingfeng , Cao Yizhi , Liu Pengyi , Li Fanlu , Zou Siyi , Wen Chenlei , Zhan Qian , Xu Zhiwei , Wang Jiancheng , Sun Baofa , Shen Baiyong
Published: May 2022

Background

LncRNA-PACERR plays critical role in the polarization of tissue-associated macrophages (TAMs). In this study, we found the function and molecular mechanism of PACERR in TAMs to regulate pancreatic ductal adenocarcinoma (PDAC) progression.

Methods

We used qPCR to analyse the expression of PACERR in TAMs and M1-tissue-resident macrophages (M1-NTRMs) which were isolated from 46 PDAC tissues. The function of PACERR on macrophages polarization and PDAC proliferation, migration and invasion were confirmed through in vivo and in vitro assays. The molecular mechanism of PACERR was discussed via fluorescence in situ hybridization (FISH), RNA pull-down, ChIP-qPCR, RIP-qPCR and luciferase assays.

Results

LncRNA-PACERR was high expression in TAMs and associated with poor prognosis in PDAC patients. Our finding validated that LncRNA-PACERR increased the number of M2-polarized cells and facilized cell proliferation, invasion and migration in vitro and in vivo. Mechanistically, LncRNA-PACERR activate KLF12/p-AKT/c-myc pathway by binding to miR-671-3p. And LncRNA-PACERR which bound to IGF2BP2 acts as an m6A-dependent manner to enhance the stability of KLF12 and c-myc in cytoplasm. In addition, the promoter of LncRNA-PACERR was a target of KLF12 and LncRNA-PACERR recruited EP300 to increase the acetylation of histone by interacting with KLF12 in nucleus.

Conclusions

This study found that LncRNA-PACERR functions as key regulator of TAMs in PDAC microenvironment and revealed the novel mechanisms in cytoplasm and in nucleus.
SARS-CoV-2 vaccine response and rate of breakthrough infection in patients with hematological disorders
Authors: Piñana José Luis , López-Corral Lucia , Martino Rodrigo , Vazquez Lourdes , Pérez Ariadna , Martin-Martin Gabriel , Gago Beatriz , Sanz-Linares Gabriela , Sanchez-Salinas Andrés , Villalon Lucia , Conesa-Garcia Venancio , Olave María T. , Corona Magdalena , Marcos-Corrales Sara , Tormo Mar , Hernández-Rivas José Ángel , Montoro Juan , Rodriguez-Fernandez Alicia , Risco-Gálvez Irene , Rodríguez-Belenguer Pablo , Hernandez-Boluda Juan Carlos , García-Cadenas Irene , Ruiz-García Montserrat , Muñoz-Bellido Juan Luis , Solano Carlos , Cedillo Ángel , Sureda Anna , Navarro David ,   the Infectious Complications Subcommittee of the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group (GETH-TC)
Published: May 2022

Background

The clinical efficacy of SARS-CoV-2 vaccines according to antibody response in immunosuppressed patients such as hematological patients has not yet been established.

Patients and methods

A prospective multicenter registry-based cohort study conducted from December 2020 to December 2021 by the Spanish transplant and cell therapy group was used to analyze the relationship of antibody response at 3–6 weeks after full vaccination (2 doses) with breakthrough SARS-CoV-2 infection in 1394 patients with hematological disorders.

Results

At a median follow-up of 165 days after complete immunization, 37 out of 1394 (2.6%) developed breakthrough SARS-CoV-2 infection at median of 77 days (range 7–195) after full vaccination. The incidence rate was 6.39 per 100 persons-year. Most patients were asymptomatic (19/37, 51.4%), whereas only 19% developed pneumonia. The mortality rate was 8%. Lack of detectable antibodies at 3–6 weeks after full vaccination was the only variable associated with breakthrough infection in multivariate logistic regression analysis (Odds Ratio 2.35, 95% confidence interval 1.2–4.6, p = 0.012). Median antibody titers were lower in cases than in non-cases [1.83 binding antibody units (BAU)/mL (range 0–4854.93) vs 730.81 BAU/mL (range 0–56,800), respectively (p = 0.007)]. We identified 250 BAU/mL as a cutoff above which incidence and severity of the infection were significantly lower.

Conclusions

Our study highlights the benefit of developing an antibody response in these highly immunosuppressed patients. Level of antibody titers at 3 to 6 weeks after 2-dose vaccination links with protection against both breakthrough infection and severe disease for non-Omicron SARS-CoV-2 variants.
Kinesin family member 23, regulated by FOXM1, promotes triple negative breast cancer progression via activating Wnt/β-catenin pathway
Authors: Li Zhi , Yang Hai-Yan , Zhang Xiao-Lan , Zhang Xu , Huang Yu-Zhou , Dai Xin-Yuan , Shi Liang , Zhou Guo-Ren , Wei Ji-Fu , Ding Qiang
Published: May 2022

Background

Triple negative breast cancer (TNBC) is highly malignant and has a worse prognosis, compared with other subtypes of breast cancer due to the absence of therapeutic targets. KIF23 plays a crucial role in the tumorigenesis and cancer progression. However, the role of KIF23 in development of TNBC and the underlying mechanism remain unknown. The study aimed to elucidate the biological function and regulatory mechanism of KIF23 in TNBC.

Methods

Quantitative real-time PCR and Western blot were used to determine the KIF23 expression in breast cancer tissues and cell lines. Then, functional experiments in vitro and in vivo were performed to investigate the effects of KIF23 on tumor growth and metastasis in TNBC. Chromatin immunoprecipitation assay was conducted to illustrate the potential regulatory mechanisms of KIF23 in TNBC.

Results

We found that KIF23 was significantly up-regulated and associated with poor prognosis in TNBC. KIF23 could promote TNBC proliferation, migration and invasion in vitro and in vivo. KIF23 could activate Wnt/β-catenin pathway and promote EMT progression in TNBC. In addition, FOXM1, upregulated by WDR5 via H3K4me3 modification, directly bound to the promoter of KIF23 gene to promote its transcription and accelerated TNBC progression via Wnt/β-catenin pathway. Both of small inhibitor of FOXM1 and WDR5 could inhibit TNBC progression.

Conclusions

Our findings elucidate WDR5/FOXM1/KIF23/Wnt/β-catenin axis is associated with TNBC progression and may provide a novel and promising therapeutic target for TNBC treatment.
Survival of primary ankle replacements: data from global joint registries
Authors: Perry Thomas A. , Silman Alan , Culliford David , Gates Lucy , Arden Nigel , Bowen Catherine ,   the International Ankle Arthroplasty Registry Consortium
Published: May 2022

Background

Ankle arthroplasty, commonly known as ankle replacement, is a surgical procedure for treating end‐stage ankle osteoarthritis. Whilst evidence shows good clinical results after surgery, little is known of the long‐term survival of ankle replacements and the need for ankle revision. Using more recent implant data and long‐term data, there is now opportunity to examine at a population‐level the survival rate for ankle implants, to examine between‐country differences in ankle revision surgery, and to compare temporal trends in revision rates between countries.

Methods

Four national joint registries from Australia, New Zealand, Norway and Sweden provided the necessary data on revision outcome following primary ankle replacement, for various periods of observation – the earliest starting in 1993 up to the end of 2019. Data were either acquired from published, online annual reports or were provided from direct contact with the joint registries. The key information extracted were Kaplan‐Meier estimates to plot survival probability curves following primary ankle replacement.

Results

The survival rates varied between countries. At 2 years, across all registries, survival rates all exceeded 0.9 (range 0.91 to 0.97). The variation widened at 5 years (range 0.80 to 0.91), at 10 years (range 0.66 to 0.84) and further at 15‐years follow‐up (0.56 to 0.78). At each time point, implant survival was greater in Australia and New Zealand with lower rates in Sweden and Norway.

Conclusions

We observed variation in primary ankle replacement survival rates across these national registries, although even after 5 years, these population derived data show an 80% revision free survival. These data raise a number of hypotheses concerning the reasons for between‐country differences in revision‐free survival which will require access to primary data for analysis.
Helicopter inter-hospital transfer for patients undergoing extracorporeal membrane oxygenation: a retrospective 12-year analysis of a service system
Authors: Fuchs Alexander , Schmucki Renate , Meuli Lorenz , Wendel-Garcia Pedro David , Albrecht Roland , Greif Robert , Pietsch Urs
Published: May 2022

Background

Patients undergoing extracorporeal membrane oxygenation (ECMO) are critically ill and show high mortality. Inter-hospital transfer of these patients has to be safe, with high survival rates during transport without potentially serious and life-threatening adverse events. The Swiss Air-Rescue provides 24-h/7-days per week inter-hospital helicopter transfers that include on-site ECMO cannulation if needed. This retrospective observational study describes adverse events of patients on ECMO transported by helicopter, and their associated survival.

Methods

All patients on ECMO with inter-hospital transfer by helicopter from start of service in February 2009 until May 2021 were included. Patients not transported by helicopter or with missing medical records were excluded. Patient demographics (age, sex) and medical history (type of and reason for ECMO), mission details (flight distance, times, primary or secondary transport), adverse events during the inter-hospital transfer, and survival of transferred patients were recorded. The primary endpoint was patient survival during transfer. Secondary endpoints were adverse events during transfer and 28-day survival.

Results

We screened 214 ECMO-related missions and included 191 in this analysis. Median age was 54.6 [IQR 46.1–62.0] years, 70.7% were male, and most patients had veno-arterial ECMO (56.5%). The main reasons for ECMO were pulmonary (46.1%) or cardiac (44.0%) failure. Most were daytime (69.8%) and primary missions (n = 100), median total mission time was 182.0 [143.0–254.0] min, and median transfer distance was 52.7 [33.2–71.1] km. All patients survived the transfer. Forty-four adverse events were recorded during 37 missions (19.4%), where 31 (70.5%) were medical and none resulted in patient harm. Adverse events occurred more frequently during night-time missions (59.9%, p = 0.047). Data for 28-day survival were available for 157 patients, of which 86 (54.8%) were alive.

Conclusion

All patients under ECMO survived the helicopter transport. Adverse events were observed for about 20% of the flight missions, with a tendency during the night-time flights, none harmed the patients. Inter-hospital transfer for patients undergoing ECMO provided by 24-h/7-d per week helicopter emergency medical service teams can be considered as feasible and safe. The majority of the patients (54.8%) were still alive after 28 days.
Epidemiology and antimicrobial susceptibility of Staphylococcus aureus in children in a tertiary care pediatric hospital in Milan, Italy, 2017—2021
Authors: La Vecchia Adriano , Ippolito Giulio , Taccani Vittoria , Gatti Elisabetta , Bono Patrizia , Bettocchi Silvia , Pinzani Raffaella , Tagliabue Claudia , Bosis Samantha , Marchisio Paola , Agostoni Carlo
Published: May 2022

Background

Methicillin-resistant Staphylococcus aureus (MRSA) is highly prevalent worldwide and can cause severe diseases. MRSA is associated with other antibiotic resistance. COVID-19 pandemic increased antimicrobial resistance in adult patients. Only a few data report the antimicrobial susceptibility of S. aureus in the Italian pediatric population, before and during the COVID-19 pandemic.

Methods

We included all the S. aureus positive samples with an available antibiogram isolated from pediatric patients (< 18 years old) in a tertiary care hospital in Milan, Italy, from January 2017 to December 2021. We collected data on demographics, antimicrobial susceptibility, and clinical history. We compared methicillin-susceptible Staphylococcus aureus (MSSA) and MRSA strains. We calculated the frequency of isolation by year. The incidence of isolates during 2020 was compared with the average year isolation frequency using the univariate Poisson test. We compared the proportion of MRSA isolates during 2020 to the average proportion of other years with the Chi-squared test.

Results

Our dataset included a total of 255 S. aureus isolated from 226 patients, 120 (53%) males, and 106 (47%) females, with a median age of 3.4 years (IQR 0.8 – 10.5). The mean isolation frequency per year was 51. We observed a significant decrease of isolations during 2020 (p = 0.02), but after adjusting for the total number of hospitalization per year there was no evidence that the incidence changed. Seventy-six (30%) S. aureus were MRSA. Twenty (26%) MRSA vs 23 (13%) MSSA (p = 0.02) were hospital-acquired. MRSA strains showed higher resistance to cotrimoxazole, clindamycin, macrolides, levofloxacin, gentamicin, and tetracyclin than MSSA strains. None of MRSA were resistant to linezolid and vancomycin, one was resistant to daptomycin. The proportion of MRSA did not change during the COVID-19 pandemic. The overall clindamycin resistance was high (17%). Recent antibiotic therapy was related to MRSA infection.

Conclusion

The proportion of MRSA did not change during the COVID-19 pandemic and remained high. Clindamycin should not be used as an empirical MRSA treatment due to its high resistance.
Depressive risk among Italian socioeconomically disadvantaged children and adolescents during COVID-19 pandemic: a cross-sectional online survey
Authors: Serra Maria , Presicci Anna , Quaranta Luigi , Urbano Maria Rosaria Erminia , Marzulli Lucia , Matera Emilia , Margari Francesco , Margari Lucia
Published: May 2022

Background

Children and adolescents and low-income individuals are considered particularly vulnerable for mental health implications during the current COVID-19 pandemic. Depression is a frequent negative emotional response during an epidemic outbreak and is also prone importantly to environmental risk like stressors derived from income inequality. We aimed to assess depressive symptomatology in a sample of Italian low-income minors during the COVID-19 outbreak. We hypothesized that the stronger were the negative effects of the pandemic on socioeconomic conditions, the higher would have been the risk for showing depressive symptoms.

Methods

We performed a cross-sectional study during July 2020, at the end of the Italian first wave of COVID-19 pandemic. We recruited 109 Italian socioeconomically disadvantaged children and adolescents from 7 to 17 years. We used an online survey to collect socio-demographic and clinical data and information about pandemic-related stressors and to assess depressive symptoms with the Children’s Depression Inventory 2 (CDI 2), Parent Version (Emotional Problems subscale) and Self-Report Short Form. We performed logistic regression analysis to assess the association between depressive symptoms and potential risk factors for mental health.

Results

22% and 14% of participants showed depressive symptoms at the CDI 2 Parent Version and Self-Report, respectively. Participants coming from families experiencing a lack of basic supplies during the pandemic (34.9%) were more expected to show depressive symptoms at CDI 2 Parent Version. Participants with a pre-existing neuropsychiatric diagnosis (26.6%) were more likely to exhibit depressive symptoms measured by CDI 2 Parent Version.

Conclusions

The results of our study showed that a group of Italian socioeconomically disadvantaged children and adolescents were more vulnerable to depressive symptoms if they suffered from a paucity of essential supplies during the pandemic or had pre-existing neurodevelopmental disorders. The promotion of educational and child-care programs and activities could be crucial in sustaining the prevention of mental distress in those frail subjects who particularly need support outside the family. Further studies are needed to detect effective preventive and therapeutic strategies to adopt promptly in the case of another pandemic wave.
Lung response to prone positioning in mechanically-ventilated patients with COVID-19
Authors: Protti Alessandro , Santini Alessandro , Pennati Francesca , Chiurazzi Chiara , Ferrari Michele , Iapichino Giacomo E. , Carenzo Luca , Dalla Corte Francesca , Lanza Ezio , Martinetti Nicolò , Aliverti Andrea , Cecconi Maurizio
Published: May 2022

Background

Prone positioning improves survival in moderate-to-severe acute respiratory distress syndrome (ARDS) unrelated to the novel coronavirus disease (COVID-19). This benefit is probably mediated by a decrease in alveolar collapse and hyperinflation and a more homogeneous distribution of lung aeration, with fewer harms from mechanical ventilation. In this preliminary physiological study we aimed to verify whether prone positioning causes analogue changes in lung aeration in COVID-19. A positive result would support prone positioning even in this other population.

Methods

Fifteen mechanically-ventilated patients with COVID-19 underwent a lung computed tomography in the supine and prone position with a constant positive end-expiratory pressure (PEEP) within three days of endotracheal intubation. Using quantitative analysis, we measured the volume of the non-aerated, poorly-aerated, well-aerated, and over-aerated compartments and the gas-to-tissue ratio of the ten vertical levels of the lung. In addition, we expressed the heterogeneity of lung aeration with the standardized median absolute deviation of the ten vertical gas-to-tissue ratios, with lower values indicating less heterogeneity.

Results

By the time of the study, PEEP was 12 (10–14) cmH2O and the PaO2:FiO2107 (84–173) mmHg in the supine position. With prone positioning, the volume of the non-aerated compartment decreased by 82 (26–147) ml, of the poorly-aerated compartment increased by 82 (53–174) ml, of the normally-aerated compartment did not significantly change, and of the over-aerated compartment decreased by 28 (11–186) ml. In eight (53%) patients, the volume of the over-aerated compartment decreased more than the volume of the non-aerated compartment. The gas-to-tissue ratio of the ten vertical levels of the lung decreased by 0.34 (0.25–0.49) ml/g per level in the supine position and by 0.03 (− 0.11 to 0.14) ml/g in the prone position (p < 0.001). The standardized median absolute deviation of the gas-to-tissue ratios of those ten levels decreased in all patients, from 0.55 (0.50–0.71) to 0.20 (0.14–0.27) (p < 0.001).

Conclusions

In fifteen patients with COVID-19, prone positioning decreased alveolar collapse, hyperinflation, and homogenized lung aeration. A similar response has been observed in other ARDS, where prone positioning improves outcome. Therefore, our data provide a pathophysiological rationale to support prone positioning even in COVID-19.
Operational complexity versus design efficiency: challenges of implementing a phase IIa multiple parallel cohort targeted treatment platform trial in advanced breast cancer
Authors: Snowdon Claire , Kernaghan Sarah , Moretti Laura , Turner Nicholas C. , Ring Alistair , Wilkinson Katie , Martin Sue , Foster Stephanie , Kilburn Lucy S. , Bliss Judith M.
Published: May 2022

Background

Platform trial designs are used increasingly in cancer clinical research and are considered an efficient model for evaluating multiple compounds within a single disease or disease subtype. However, these trial designs can be challenging to operationalise.

The use of platform trials in oncology clinical research has increased considerably in recent years as advances in molecular biology enable molecularly defined stratification of patient populations and targeted therapy evaluation. Whereas multiple separate trials may be deemed infeasible, platform designs allow efficient, parallel evaluation of multiple targeted therapies in relatively small biologically defined patient sub-populations with the promise of increased molecular screening efficiency and reduced time for drug evaluation. Whilst the theoretical efficiencies are widely reported, the operational challenges associated with these designs (complexity, cost, regulatory, resource) are not always well understood.

Main

In this commentary, we describe our practical experience of the implementation and delivery of the UK plasmaMATCH trial, a platform trial in advanced breast cancer, comprising an integrated screening component and multiple parallel downstream mutation-directed therapeutic cohorts. plasmaMATCH reported its primary results within 3 years of opening to recruitment. We reflect on the operational challenges encountered and share lessons learnt to inform the successful conduct of future trials. Key to the success of the plasmaMATCH trial was well co-ordinated stakeholder engagement by an experienced clinical trials unit with expert methodology and trial management expertise, a federated model of clinical leadership, a well-written protocol integrating screening and treatment components and including justification for the chosen structure and intentions for future adaptions, and an integrated funding model with streamlined contractual arrangements across multiple partners. Findings based on our practical experience include the importance of early engagement with the regulators and consideration of a flexible resource infrastructure to allow adequate resource allocation to support concurrent trial activities as adaptions are implemented in parallel to the continued management of patient safety and data quality of the ongoing trial cohorts.

Conclusion

Platform trial designs allow the efficient reporting of multiple treatment cohorts. Operational challenges can be overcome through multidisciplinary engagement, streamlined contracting processes, rationalised protocol and database design and appropriate resourcing.
Comparison of the effects of neostigmine and sugammadex on postoperative residual curarization and postoperative pulmonary complications by means of diaphragm and lung ultrasonography: a study protocol for prospective double-blind randomized controlled trial
Authors: Zhang Yu-guan , Chen Ying , Zhang Yue-Lun , Yi Jie
Published: May 2022

Background

Postoperative residual curarization (PORC) may be a potential risk factor of postoperative pulmonary complications (PPCs), and both of them will lead to adverse consequences on surgical patient recovery. The train-of-four ratio (TOFr) which is detected by acceleromyography of the adductor pollicis is thought as the gold standard for the measurement of PORC. However, diaphragm function recovery may differ from that of the peripheral muscles. Recent studies suggested that diaphragm ultrasonography may be useful to reveal the diaphragm function recovery, and similarly, lung ultrasound was reported for the assessment of PPCs in recent years as well. Sugammadex reversal of neuromuscular blockade is rapid and complete, and there appear to be fewer postoperative complications than with neostigmine. This study aims to compare the effects of neostigmine and sugammadex, on PORC and PPCs employing diaphragm and lung ultrasonography, respectively.

Methods/design

In this prospective, double-blind, randomized controlled trial, patients of the American Society of Anesthesiologists Physical Status I–III, aged over 60, will be enrolled. They will be scheduled to undergo arthroplasty under general anesthesia. All patients will be allocated randomly into two groups, group NEO (neostigmine) and group SUG (sugammadex), using these two drugs for reversing rocuronium. The primary outcome of the study is the incidence of PPCs in the NEO and SUG groups. The secondary outcomes are the evaluation of diaphragm ultrasonography and lung ultrasound, performed by an independent sonographer before anesthesia, and at 10 min and 30 min after extubation in the post-anesthesia care unit, respectively.

Discussion

Elimination of PORC is a priority at the emergence of anesthesia, and it may be associated with reducing postoperative complications like PPCs. Sugammadex was reported to be superior to reverse neuromuscular blockade than neostigmine. Theoretically, complete recovery of neuromuscular function should be indicated by TOFr > 0.9. However, the diaphragm function recovery may not be the same matter, which probably harms pulmonary function. The hypothesis will be proposed that sugammadex is more beneficial than neostigmine to reduce the incidence of PPCs and strongly favorable for the recovery of diaphragm function in our study setting.

Trial registration

ClinicalTrials.gov NCT05040490. Registered on 3 September 2021
Engineering proton-coupled hexose uptake in Saccharomyces cerevisiae for improved ethanol yield
Authors: de Valk Sophie C. , Bouwmeester Susan E. , de Hulster Erik , Mans Robert
Published: May 2022

Background

In the yeast Saccharomyces cerevisiae, which is widely applied for industrial bioethanol production, uptake of hexoses is mediated by transporters with a facilitated diffusion mechanism. In anaerobic cultures, a higher ethanol yield can be achieved when transport of hexoses is proton-coupled, because of the lower net ATP yield of sugar dissimilation. In this study, the facilitated diffusion transport system for hexose sugars of S. cerevisiae was replaced by hexose–proton symport.

Results

Introduction of heterologous glucose– or fructose–proton symporters in an hxt0 yeast background strain (derived from CEN.PK2-1C) restored growth on the corresponding sugar under aerobic conditions. After applying an evolutionary engineering strategy to enable anaerobic growth, the hexose–proton symporter-expressing strains were grown in anaerobic, hexose-limited chemostats on synthetic defined medium, which showed that the biomass yield of the resulting strains was decreased by 44.0-47.6%, whereas the ethanol yield had increased by up to 17.2% (from 1.51 to 1.77 mol mol hexose−1) compared to an isogenic strain expressing the hexose uniporter HXT5. To apply this strategy to increase the ethanol yield on sucrose, we constructed a platform strain in which all genes encoding hexose transporters, disaccharide transporters and disaccharide hydrolases were deleted, after which a combination of a glucose–proton symporter, fructose–proton symporter and extracellular invertase (SUC2) were introduced. After evolution, the resulting strain exhibited a 16.6% increased anaerobic ethanol yield (from 1.51 to 1.76 mol mol hexose equivalent−1) and 46.6% decreased biomass yield on sucrose.

Conclusions

This study provides a proof-of-concept for the replacement of the endogenous hexose transporters of S. cerevisiae by hexose-proton symport, and the concomitant decrease in ATP yield, to greatly improve the anaerobic yield of ethanol on sugar. Moreover, the sugar-negative platform strain constructed in this study acts as a valuable starting point for future studies on sugar transport or development of cell factories requiring specific sugar transport mechanisms.
Comparative analysis on transcriptomics of ivermectin resistant and susceptible strains of Haemonchus contortus
Authors: Tuersong Waresi , Zhou Caixian , Wu Simin , Qin Peixi , Wang Chunqun , Di Wenda , Liu Lu , Liu Hui , Hu Min
Published: May 2022

Background

Ivermectin (IVM) is one of the most important and widely used anthelmintics in veterinary medicine. However, its efficacy is increasingly compromised by widespread resistance, and the exact mechanism of IVM resistance remains unclear for most parasitic nematodes, including Haemonchus contortus, a blood-sucking parasitic nematode of small ruminants.

Methods

In this study, an H. contortus IVM-resistant strain from Zhaosu, Xinjiang, China, was isolated and assessed by the control test, faecal egg count reduction test (FECRT) and the larval development assay (LDA). Subsequently, comparative analyses on the transcriptomics of IVM-susceptible and IVM-resistant adult worms of this parasite were carried out using RNA sequencing (RNA-seq) and bioinformatics.

Results

In total, 543 (416 known, 127 novel) and 359 (309 known, 50 novel) differentially expressed genes (DEGs) were identified in male and female adult worms of the resistant strain compared with those of the susceptible strain, respectively. In addition to several previously known candidate genes which were supposed to be associated with IVM resistance and whose functions were involved in receptor activity, transport, and detoxification, we found some new potential target genes, including those related to lipid metabolism, structural constituent of cuticle, and important pathways such as antigen processing and presentation, lysosome, autophagy, apoptosis, and NOD1-like receptor signalling pathways. Finally, the results of quantitative real-time polymerase chain reaction confirmed that the transcriptional profiles of selected DEGs (male: 8 genes, female: 10 genes) were consistent with those obtained by the RNA-seq.

Conclusions

Our results indicate that IVM has multiple effects, including both neuromuscular and non-neuromuscular targets, and provide valuable information for further studies on the IVM resistance mechanism in H. contortus.

Graphical Abstract