bluuebunny/crossref_metadata_2025 huggingface dataset:
A study of screw placement to obtain the optimal pull-out resistance of lumbar pedicle screws—analysis of Hounsfield units measurements based on computed tomography
Authors: Li Dachuan , Sun Chi , Jiang Jianyuan , Lu Feizhou , Xia Xinlei , Wang Hongli , Zou Fei , Ma Xiaosheng
Published: February 2022

Objective

The screw path of lumbar pedicle screws in the vertebral body has certain variability. It is not clear whether the screw paths in different directions can obtain the same pull-out resistance. This study intends to use CT (Computed Tomography) to measure the Hounsfield unit (HU value) around the screw paths in different parts of the lumbar vertebral body to obtain the bone mineral density value of the corresponding parts which will provide some reference for the direction of lumbar pedicle screw placement.

Methods

This retrospective study included 200 patients with lumbar degenerative diseases selected randomly from the case base and the patient’s basic information was recorded. L1-L5 vertebral body was divided equally into the upper, middle and lower 1/3, which was consistent with the three sagittal entry directions of the pedicle screw head tilt, parallel endplate and caudal tilt, and the HU values were measured by CT cross-sectional scanning to indirectly reflect the local bone density values. The paired t-test (randomized block experiment) was used to compare the HU values of the upper, middle and lower 1 / 3 parts, with P < 0.05 being considered statistically significant.

Results

Comparison of HU values in different parts of each vertebral body revealed that HU values in the middle 1/3 of the L1,L2 (163.88 ± 58.44 and 152.94 ± 59.45) and in the lower 1/3 of the L4 (149.86 ± 60.18) were higher than in the other two parts of the vertebral body of the same segment(P < 0.0001,P = 0.0069 and P = 0.0024, respectively); According to the results of each stratification, patients with younger age and better bone condition had higher HU values in the middle 1/3 of L1 and L2, and higher HU values in the lower 1/3 of L3, L4 and L5; With the increase of age, the decrease of bone condition and the difference of HU value in each vertebral body gradually decreased.

Conclusion

Although further follow-up studies are needed, based on the analysis of the statistical results, we speculate that from the perspective of obtaining the best pull-out resistance of the lumbar pedicle screws, the placement direction of L1 and L2 in the sagittal position may be as parallel to the endplate as possible; L3, L4, and L5 may be as appropriate as possible to the tail tilt theoretically.
Collaborative case-based learning with programmatic team-based assessment: a novel methodology for developing advanced skills in early-years medical students
Authors: James Mariel , Baptista Ana Madeira Teixeira , Barnabas Deepak , Sadza Agata , Smith Susan , Usmani Omar , John Chris
Published: February 2022

Background

Imperial College London launched a new, spiral undergraduate medical curriculum in September 2019. Clinical & Scientific Integrative cases (CSI) is an innovative, flagship module, which uses pioneering methodology to provide early-years learning that [1] is patient-centred, [2] integrates clinical and scientific curriculum content, [3] develops advanced team-work skills and [4] provides engaging, student-driven learning. These aims are designed to produce medical graduates equipped to excel in a modern healthcare environment.

Methods

CSI has adopted a novel educational approach which utilises contemporary digital resources to deliver a collaborative case-based learning (CBL) component, paired with a team-based learning (TBL) component that incorporates both learning and programmatic assessment. This paper serves to explore how first-year students experienced CSI in relation to its key aims, drawing upon quantitative and qualitative data from feedback surveys from CSI’s inaugural year. It provides a description and analysis of the module’s design, delivery, successes and challenges.

Results

Our findings indicate that CSI has been extremely well-received and that the majority of students agree that it met its aims. Survey outputs indicate success in integrating multiple elements of the curriculum, developing an early holistic approach towards patients, expediting the development of important team-working skills, and delivering authentic and challenging clinical problems, which our students found highly relevant. Challenges have included supporting students to adapt to a student-driven, deep learning approach.

Conclusions

First-year students appear to have adopted a patient-centred outlook, the ability to integrate knowledge from across the curriculum, an appreciation for other team members and the self-efficacy to collaboratively tackle challenging, authentic clinical problems. Ultimately, CSI’s innovative design is attractive and pertinent to the needs of modern medical students and ultimately, future doctors.
Lifetime risk of cardiovascular-renal disease in type 2 diabetes: a population-based study in 473,399 individuals
Authors: Zhang Ruiqi , Mamza Jil Billy , Morris Tamsin , Godfrey George , Asselbergs Folkert W. , Denaxas Spiros , Hemingway Harry , Banerjee Amitava
Published: February 2022

Background

Cardiovascular and renal diseases (CVRD) are major causes of mortality in individuals with type 2 diabetes (T2D). Studies of lifetime risk have neither considered all CVRD together nor the relative contribution of major risk factors to combined disease burden.

Methods

In a population-based cohort study using national electronic health records, we studied 473,399 individuals with T2D in England 2007–2018. Lifetime risk of individual and combined major adverse renal cardiovascular events, MARCE (including CV death and CVRD: heart failure; chronic kidney disease; myocardial infarction; stroke or peripheral artery disease), were estimated, accounting for baseline CVRD status and competing risk of death. We calculated population attributable risk for individual CVRD components. Ideal cardiovascular health was defined by blood pressure, cholesterol, glucose, smoking, physical activity, diet, and body mass index (i.e. modifiable risk factors).

Results

In individuals with T2D, lifetime risk of MARCE was 80% in those free from CVRD and was 97%, 93%, 98%, 89% and 91% in individuals with heart failure, chronic kidney disease, myocardial infarction, stroke and peripheral arterial disease, respectively at baseline. Among CVRD-free individuals, lifetime risk of chronic kidney disease was highest (54%), followed by CV death (41%), heart failure (29%), stroke (20%), myocardial infarction (19%) and peripheral arterial disease (9%). In those with HF only, 75% of MARCE after index T2D can be attributed to HF after adjusting for age, gender, and comorbidities. Compared with those with > 1, < 3 and ≥3 modifiable health risk behaviours, achieving ideal cardiovascular health could reduce MARCE by approximately 41.5%, 23.6% and 17.2%, respectively, in the T2D population.

Conclusions

Four out of five individuals with T2D free from CVRD, and nearly all those with history of CVRD, will develop MARCE over their lifetime. Early preventive measures in T2D patients are clinical, public health and policy priorities.
Comparison between pressure support ventilation and T-piece in spontaneous breathing trials
Authors: Na Soo Jin , Ko Ryoung-Eun , Nam Jimyoung , Ko Myeong Gyun , Jeon Kyeongman
Published: February 2022

Background

Recent guidelines recommended conducting spontaneous breathing trial (SBT) with modest inspiratory pressure augmentation rather than T-piece or continuous positive airway pressure. However, it was based on few studies focused on the outcomes of extubation rather than the weaning process, despite the existence of various weaning situations in clinical practice. This study was designed to investigate the effects of SBT with pressure support ventilation (PSV) or T-piece on weaning outcomes.

Methods

All consecutive patients admitted to two medical intensive care units (ICUs) and those requiring mechanical ventilation (MV) for more than 24 h from November 1, 2017 to September 30, 2020 were prospectively registered. T-piece trial was used until March 2019, and then, pressure support of 8 cmH2O and 0 positive end-expiratory pressure were used for SBT since July 2019, after a 3-month transition period for the revised SBT protocol. The primary outcome of this study was successful weaning defined according to the WIND (Weaning according to a New Definition) definition and were compared between the T-piece group and PSV group. The association between the SBT method and weaning outcome was evaluated with logistic regression analysis.

Results

In this study, 787 eligible patients were divided into the T-piece (n = 473) and PSV (n = 314) groups after excluding patients for a 3-month transition period. Successful weaning was not different between the two groups (85.0% vs. 86.3%; p = 0.607). However, the PSV group had a higher proportion of short weaning (70.1% vs. 59.0%; p = 0.002) and lower proportion of difficult weaning (13.1% vs. 24.1%; p < 0.001) than the T-piece group. The proportion of prolonged weaning was similar between the two groups (16.9% vs. 16.9%; p = 0.990). After excluding patients who underwent tracheostomy before the SBTs, similar results were found. Reintubation rates at 48 h, 72 h, and 7 days following the planned extubation were not different between the PSV and T-piece groups. Moreover, no significant differences in intensive care unit and hospital mortality and length of stay were observed.

Conclusions

In critically ill medical patients, SBT using PSV was not associated with a higher rate of successful weaning compared with SBT using T-piece. However, PSV could shorten the weaning process without increasing the risk of reintubation.
Pneumothorax management: current state of practice in the UK
Authors: Hallifax Rob J. , Roberts Mark , Russell Nicky , Laskawiec-Szkonter Magda , Walker Steve P. , Maskell Nick A. , Rahman Najib M.
Published: February 2022

Background and objective

Spontaneous pneumothorax is a common pathology but optimal initial treatment regime is not well defined. Treatment options including conservative management, needle aspiration (NA) or insertion of a small-bore chest drain. Recent large randomised controlled trials may change the treatment paradigm: comparing conservative and ambulatory management to standard care, but current guidelines need to be updated. The aim of this study was to assess the current “state of play” in the management of pneumothorax in the UK.

Methods

Physicians and respiratory healthcare staff were invited to complete an online survey on the initial and subsequent management of pneumothorax.

Results

This study is the first survey of pneumothorax practice across the UK, which highlights variation in practice: 50% would manage a large primary pneumothorax with minimal symptoms conservatively, compared to only 3% if there were significant symptoms; 64% use suction if the pneumothorax had not resolved after > 2 days, 15% always clamp the chest drain prior to removal; whereas 30% never do. NICE guidance recommends the use of digital suction but this has not translated into widespread usage: only 23% use digital suction to check for resolution of air leak).

Conclusion

Whilst there has always been allowance for individual clinician preference in guidelines, there needs to be consensus on the optimum management strategy. The challenge the new guidelines face is to design a simple and pragmatic approach, using this new evidence base.
Targeting HNRNPU to overcome cisplatin resistance in bladder cancer
Authors: Shi Zhen-duo , Hao Lin , Han Xiao-xiao , Wu Zhuo-Xun , Pang Kun , Dong Yang , Qin Jia-xin , Wang Guang-yue , Zhang Xuan-ming , Xia Tian , Liang Qing , Zhao Yan , Li Rui , Zhang Shao-qi , Zhang Jun-hao , Chen Jian-gang , Wang Gong-cheng , Chen Zhe-Sheng , Han Cong-hui
Published: February 2022

Purpose

The overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic difference, and drug resistance. The genes that associated with cisplatin resistance remain unclear. Herein, we aimed to identify the cisplatin resistance associated genes in BUC.

Experimental design

The cytotoxicity of cisplatin was evaluated in six bladder cancer cell lines to compare their responses to cisplatin. The T24 cancer cells exhibited the lowest sensitivity to cisplatin and was therefore selected to explore the mechanisms of drug resistance. We performed genome-wide CRISPR screening in T24 cancer cells in vitro, and identified that the gene heterogeneous nuclear ribonucleoprotein U (HNRNPU) was the top candidate gene related to cisplatin resistance. Epigenetic and transcriptional profiles of HNRNPU-depleted cells after cisplatin treatment were analyzed to investigate the relationship between HNRNPU and cisplatin resistance. In vivo experiments were also performed to demonstrate the function of HNRNPU depletion in cisplatin sensitivity.

Results

Significant correlation was found between HNRNPU expression level and sensitivity to cisplatin in bladder cancer cell lines. In the high HNRNPU expressing T24 cancer cells, knockout of HNRNPU inhibited cell proliferation, invasion, and migration. In addition, loss of HNRNPU promoted apoptosis and S-phase arrest in the T24 cells treated with cisplatin. Data from The Cancer Genome Atlas (TCGA) demonstrated that HNRNPU expression was significantly higher in tumor tissues than in normal tissues. High HNRNPU level was negatively correlated with patient survival. Transcriptomic profiling analysis showed that knockout of HNRNPU enhanced cisplatin sensitivity by regulating DNA damage repair genes. Furthermore, it was found that HNRNPU regulates chemosensitivity by affecting the expression of neurofibromin 1 (NF1).

Conclusions

Our study demonstrated that HNRNPU expression is associated with cisplatin sensitivity in bladder urothelial carcinoma cells. Inhibition of HNRNPU could be a potential therapy for cisplatin-resistant bladder cancer.
Causal systems mapping to promote healthy living for pandemic preparedness: a call to action for global public health
Authors: Pronk Nicolaas P. , Faghy Mark A.
Published: February 2022

COVID-19 has severely impacted population health and well-being globally. Acknowledging that COVID-19 will not be the world’s last pandemic, improving healthy living factors (i.e., physical activity, healthful nutrition, healthy weight), which are important in mitigating negative outcomes of future infectious disease pandemics, should be prioritized. Although well-documented, promoting healthy living factors remains challenged by a lack of scalability and sustainability due, in part, to a mismatch between intervention focus on individual behavior change as opposed to recognizing complex and multifactorial causes that prevent people from living healthy lifestyles and maintaining them long-term (such as political will, economic benefits, urban planning, etc.). To recognize this complexity in promoting healthy living, we propose the application of systems science methods for the creation of a comprehensive causal systems map of healthy living factors in the context of COVID-19 to inform future pandemic preparedness. Generating such a map would benefit researchers, practitioners, and policy makers in multi-sector collaborative efforts to improve public health preparedness in the context of future pandemics in a scalable, sustainable, and equitable manner. This effort should be facilitated by a trusted and widely respected governing body with global reach.
Neuroprotective effects of alisol A 24-acetate on cerebral ischaemia–reperfusion injury are mediated by regulating the PI3K/AKT pathway
Authors: Lu Taotao , Li Huihong , Zhou Yangjie , Wei Wei , Ding Linlin , Zhan Zengtu , Liu Weilin , Tao Jing , Xue Xiehua
Published: February 2022

Background

Neuroinflammation and apoptosis are involved in the pathogenesis of ischaemic stroke. Alisol A 24-acetate (24A) exerts a strong inhibitory effect on inflammation and cell apoptosis. The neuroprotective effect of 24A on global cerebral ischaemia/reperfusion (GCI/R) injury remains unclear.

Methods

GCI/R mice were used to investigate the neuroprotective effect of 24A. Modified neurological deficit scores, Morris water maze and object recognition tests were used to evaluate behaviours. Metabolism in brain regions was detected using magnetic resonance spectroscopy (MRS), and changes in microglia, astrocytes and neurons were detected. Inflammation and apoptosis were measured.

Results

The results showed that 24A suppressed neurological deficits scores and improved GCI/R induced cognitive dysfunction. It was also observed that 24A could alleviate neuroinflammation, which manifested as 24A inhibited microglia and astrocytes proliferation, downregulated the expression of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and inducible nitric oxide synthase (iNOS) in the GCI/R mice brain. The apoptosis of neurons reduced, and dendritic spines of hippocampal neurons increased in the presence of 24A. In addition, 24A could up-regulate the expression of phosphorylated phosphoinositide 3-kinases (p-PI3K) and phosphorylated protein kinase B (p-AKT) in GCI/R mice brain, and all the morphological, neurological, and biochemical changes of 24A treatment were abolished by the application of PI3K/AKT pathway inhibitor LY294002.

Conclusions

Taken together, our study indicated that 24A alleviated GCI/R injury by inhibiting neuroinflammation and apoptosis through the regulation of the PI3K/AKT pathway.
Gas6 induces inflammation and reduces plaque burden but worsens behavior in a sex-dependent manner in the APP/PS1 model of Alzheimer’s disease
Authors: Owlett Laura D. , Karaahmet Berke , Le Linh , Belcher Elizabeth K. , Dionisio-Santos Dawling , Olschowka John A. , Elliott Michael R. , O’Banion M. Kerry
Published: February 2022

Background

Alzheimer’s disease is the leading cause of dementia worldwide. TAM receptor tyrosine kinases (Tyro3, Axl, MerTK) are known for their role in engagement of phagocytosis and modulation of inflammation, and recent evidence suggests a complex relationship between Axl, Mer, and microglial phagocytosis of amyloid plaques in AD. Gas6, the primary CNS TAM ligand, reduces neuroinflammation and improves outcomes in murine models of CNS disease. Therefore, we hypothesized that AAV-mediated overexpression of Gas6 would alleviate plaque pathology, reduce neuroinflammation, and improve behavior in the APP/PS1 model of Alzheimer’s disease.

Methods

Adeno-associated viral vectors were used to overexpress Gas6 in the APP/PS1 model of Alzheimer’s disease. Nine-month-old male and female APP/PS1 and nontransgenic littermates received bilateral stereotactic hippocampal injections of AAV-Gas6 or AAV-control, which expresses a non-functional Gas6 protein. One month after injections, mice underwent a battery of behavioral tasks to assess cognitive function and brains were processed for immunohistochemical and transcriptional analyses.

Results

Gas6 overexpression reduced plaque burden in male APP/PS1 mice. However, contrary to our hypothesis, Gas6 increased pro-inflammatory microglial gene expression and worsened contextual fear conditioning compared to control-treated mice. Gas6 overexpression appeared to have no effect on phagocytic mechanisms in vitro or in vivo as measured by CD68 immunohistochemistry, microglial methoxy-04 uptake, and primary microglial uptake of fluorescent fibrillar amyloid beta.

Conclusion

Our data describes a triad of worsened behavior, reduced plaque number, and an increase in proinflammatory signaling in a sex-specific manner. While Gas6 has historically induced anti-inflammatory signatures in the peripheral nervous system, our data suggest an alternative, proinflammatory role in the context of Alzheimer’s disease pathology.
Neurocognitive impact of Zika virus infection in adult rhesus macaques
Authors: Hsu Denise C. , Chumpolkulwong Kesara , Corley Michael J. , Hunsawong Taweewun , Inthawong Dutsadee , Schuetz Alexandra , Imerbsin Rawiwan , Silsorn Decha , Nadee Panupat , Sopanaporn Jumpol , Phuang-Ngern Yuwadee , Klungthong Chonticha , Reed Matthew , Fernandez Stefan , Ndhlovu Lishomwa C. , Paul Robert , Lugo-Roman Luis , Michael Nelson L. , Modjarrad Kayvon , Vasan Sandhya
Published: February 2022

Background

Zika virus (ZIKV) is a mosquito-transmitted flavivirus that affects many regions of the world. Infection, in utero, causes microcephaly and later developmental and neurologic impairments. The impact of ZIKV infection on neurocognition in adults has not been well described. The objective of the study was to assess the neurocognitive impact of ZIKV infection in adult rhesus macaques.

Methods

Neurocognitive assessments were performed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) via a touch screen and modified Brinkman Board before and after subcutaneous ZIKV inoculation. Immune activation markers were measured in the blood and cerebral spinal fluid (CSF) by multiplex assay and flow cytometry.

Results

All animals (N = 8) had detectable ZIKV RNA in plasma at day 1 post-inoculation (PI) that peaked at day 2 PI (median 5.9, IQR 5.6–6.2 log10genome equivalents/mL). In all eight animals, ZIKV RNA became undetectable in plasma by day 14 PI, but persisted in lymphoid tissues. ZIKV RNA was not detected in the CSF supernatant at days 4, 8, 14 and 28 PI but was detected in the brain of 2 animals at days 8 and 28 PI. Elevations in markers of immune activation in the blood and CSF were accompanied by a reduction in accuracy and reaction speed on the CANTAB in the majority of animals.

Conclusions

The co-occurrence of systemic and CSF immune perturbations and neurocognitive impairment establishes this model as useful for studying the impact of neuroinflammation on neurobehavior in rhesus macaques, as it pertains to ZIKV infection and potentially other pathogens.
Intermediate-dose cytarabine is an effective therapy for adults with non-Langerhans cell histiocytosis
Authors: Liu Ting , Cai Hua-cong , Cai Hao , Chen Miao , Zhang Wei , Li Jian , Zhou Dao-bin , Cao Xin-xin
Published: February 2022

Background

Non-Langerhans cell histiocytosis, including Erdheim–Chester disease (ECD), Rosai–Dorfman disease (RDD), indeterminate cell histiocytosis (ICH), and unclassified histiocytosis, is a rare disorder lacking a standard treatment strategy. We report our experience using intermediate-dose cytarabine as the first or subsequent therapy in non-Langerhans cell histiocytosis.

Results

Nine ECD patients, 5 RDD patients, 1 ICH patient and 1 unclassified histiocytosis patient were enrolled. Intermediate-dose cytarabine therapy was administered as 0.5–1.0 g/m2 of intravenous cytarabine every 12 h for 3 days every 5 weeks. The median age at cytarabine initiation was 47.5 years (range 18–70 years). The median number of cycles of cytarabine administered was 5.5 (range 2–6). The overall response rate (ORR) was 87.5% in the overall cohort, including 12.5% with complete response and 75.0% with partial response. One patient experienced disease recurrence 19 months after cytarabine therapy. The median follow-up duration for the entire cohort was 15.5 months (range 6–68 months). The estimated 2-year progression-free survival and overall survival rates were 85.6% and 92.3%, respectively. The most common toxicity was haematological adverse events, including grade 4 neutropenia and grade 3–4 thrombocytopenia. No treatment-related deaths occurred.

Conclusions

Intermediate-dose cytarabine is an efficient treatment option for non-Langerhans cell histiocytosis patients, especially for those with CNS involvement.
A serological survey of Toxoplasma gondii in Polish pigs from organic farms, other housing systems and in pigs of different age groups
Authors: Puchalska Martyna , Wiśniewski Jan , Klich Daniel , Gołąb Elżbieta , Jańczak Dawid , Sokołowska Justyna , Urbańska Kaja , Anusz Krzysztof
Published: February 2022

Background

The consumption of raw or undercooked meat, especially pork, and offal containing infective tissue cysts is suspected to be a significant route of infection withToxoplasma gondii. Although the use of “animal-friendly pig production systems” ensuring direct contact with the natural environment offers ethical benefits, it limits the ability to ensure animal health; it may also increase the probability of infections by pathogens such asT. gondii, and thus their entry into the food chain. This study determines the seroprevalence ofT. gondiiin pigs from different housing systems and farms with different hygiene standards in Poland, as well as among pigs of different age groups from farms with high hygiene standards. In total 760 pig serum samples were examined for the presence of specific antibodies using the PrioCHECK®Toxoplasma Ab porcine commercial ELISA test (Prionics, Switzerland).

Results

Test results with PP ≥ 20% were regarded as positive, as indicated by the manufacturer. Antibodies toT. gondiiwere found in 193 of 760 (25.4%) tested sera. Regarding different housing systems, antibodies were found in 117 pigs: of these, 52.6% (61/116) were from organic farms, 40.9% (47/115) from farms with low hygiene standards, 5.4% (9/167) from farms with high hygiene standards and 0% (0/40) from a farm with a high level of biosecurity. Regarding age groups, antibodies were found in 76 animals on farms with high hygiene standards: 11.1% (7/63) were pigs younger than 3 months, 0% (0/60) aged 3–4 months, 12.3% (7/57) aged 5–6 months (final fattening stage) and 43.7% (62/142) were sows aged 9 months and older.

Conclusions

Antibodies toT. gondiiwere most often found in pigs from organic and low-hygiene farms, as well as in pigs aged 9 months and older. Meat derived from seropositive animals can pose a potential source of infection for humans. As maternal antibodies toT. gondiican be present in the blood of piglets aged up to 3–4 months, serological examination is unjustified in piglets up to this age.
Identifying best practice for the supervision of mental health and psychosocial support in humanitarian emergencies: a Delphi study
Authors: Travers Áine , Abujaber Nadeen , McBride Kelly A , Tingsted Blum Pia , Wiedemann Nana , Vallières Frédérique
Published: February 2022

Background

Supportive supervision has been shown to improve worker resilience and wellbeing, which are particularly important in the context of humanitarian emergency settings. Despite its noted importance however, supervision remains an under-prioritised area in mental health and psychosocial support (MHPSS).

Method

The present study used a Delphi consensus-building methodology to examine levels of agreement among a diverse sample of MHPSS stakeholders (n = 48) on key ideas and concepts relating to supervision in humanitarian settings.

Results

The majority of statements presented showed a high degree of consensus, with some receiving almost universal agreement, such as the importance of using active listening skills in the supervisory context and the need for supervisors to have access to their own supervisory support. However, disagreement on several points remained. For example, participants disagreed about whether the qualities required to be an effective supervisor can be taught, or whether they are more innate and should be screened for when recruiting supervisors. Gender differences in responses were also analysed, with potential associations between gender and level of agreement emerging in relation to statements about power dynamics, remote supervision, and intervention quality enhancement.

Conclusions

The findings of the present study are discussed in terms of their implications for a forthcoming set of guidelines for supervision of MHPSS in humanitarian settings: The Integrated Model for Supervision (IMS).
Phase I pharmacokinetic study of single agent trametinib in patients with advanced cancer and hepatic dysfunction
Authors: Voon Pei Jye , Chen Eric X. , Chen Helen X. , Lockhart Albert C. , Sahebjam Solmaz , Kelly Karen , Vaishampayan Ulka N. , Subbiah Vivek , Razak Albiruni R. , Renouf Daniel J. , Hotte Sebastien J. , Singh Arti , Bedard Philippe L. , Hansen Aaron R. , Ivy S. Percy , Wang Lisa , Stayner Lee-Anne , Siu Lillian L. , Spreafico Anna
Published: February 2022

Background

Trametinib is an oral MEK 1/2 inhibitor, with a single agent recommended phase 2 dose (RP2D) of 2 mg daily (QD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib in patients with advanced solid tumors who had various degrees of hepatic dysfunction (HD).

Methods

Advanced cancer patients were stratified into 4 HD groups based on Organ Dysfunction Working Group hepatic function stratification criteria: normal (Norm), mild (Mild), moderate (Mod), severe (Sev). Dose escalation was based on “3 + 3” design within each HD group. PK samples were collected at cycle 1 days 15-16.

Results

Forty-six patients were enrolled with 44 evaluable for safety [Norm=17, Mild=7, Mod (1.5 mg)=4, Mod (2 mg)=5, Sev (1 mg)=9, Sev (1.5 mg)=2] and 22 for PK analysis. Treatment related adverse events were consistent with prior trametinib studies. No treatment related deaths occurred. Dose limiting toxicities (DLTs) were evaluable in 15 patients (Mild=6, Mod (1.5 mg)=3, Mod (2 mg)=2, Sev (1 mg)=3 and Sev (1.5 mg)=1). One DLT (grade 3 acneiform rash) was observed in a Sev patient (1.5 mg). Dose interruptions or reductions due to treatment related adverse events occurred in 15 patients (34%) [Norm=9, 53%; Mild=2, 29%; Mod (1.5 mg)=1, 33%; Mod (2 mg)=2, 33%; Sev (1 mg)=1, 11%; Sev (1.5 mg)=1; 50%]. There were no significant differences across HD groups for all PK parameters when trametinib was normalized to 2 mg. However, only limited PK data were available for the Mod (n = 3) and Sev (n = 3) groups compared to Norm (n = 10) and Mild (n = 6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p = 0.26).

Conclusions

RP2D for trametinib in Mild HD patients is 2 mg QD. There are insufficient number of evaluable patients due to difficulty of patient accrual to declare RP2D and MTD for Mod and Sev HD groups. DLTs were not observed in the highest dose cohorts that reached three evaluable patients – 1.5 mg QD in Mod group, and 1 mg QD in Sev group.

Trial registration

This study was registered in the ClinicalTrials.gov website (NCT 02070549) on February 25, 2014. .
Statistical analysis plan for the OPTIMUM study: optimising immunisation using mixed schedules, an adaptive randomised controlled trial of a mixed whole-cell/acellular pertussis vaccine schedule
Authors: Totterdell James A. , Chacon Gladymar Perez , Estcourt Marie J. , Jones Mark , Richmond Peter , Snelling Thomas L. , Marsh Julie A.
Published: February 2022

Objective

The purpose of this double-blind, randomised, controlled trial is to compare allergic outcomes in children following vaccination with acellular pertussis (aP) antigen (standard of care in Australia) given at 2 months of age versus whole cell pertussis (wP) in the infant vaccine schedule.

Participants

Up to 3000 Australian infants 6 to <12 weeks of age born ≥32 weeks gestation.

Interventions

The intervention is a wP containing vaccine as the first scheduled pertussis vaccine dose instead of an aP containing vaccine.

Outcomes

The primary outcome is a binary indicator of history of IgE-mediated food allergy at the age of 12 months confirmed, where necessary, with an oral food challenge before 18 months of age. Secondary outcomes include (1) history of parent-reported clinician-diagnosed new onset of atopic dermatitis by 6 or 12 months of age with a positive skin prick test to any allergen before 12 months of age, (2) geometric mean concentration in pertussis toxin-specific IgG before and 21 to 35 days after a booster dose of aP at 18 months of age, and (3) sensitisation to at least one allergen by 12 months of age.

Results

Operating characteristics of trial decision rules were evaluated by trial simulation. The selected rules for success and futility approximately maintain type I error of 0.05 and achieved power 0.85 for a reduction in the primary outcome from 10% in the control group to 7% in the intervention group.

Discussion

A detailed, prospective statistical analysis plan (SAP) is presented for this Bayesian adaptive design. The plan was written by the trial statistician and details the study design, pre-specified adaptive elements, decision thresholds, statistical methods, and the simulations used to evaluate the operating characteristics of the trial. Application of this SAP will minimise bias and supports transparent and reproducible research.

Trial registration

Australia & New Zealand Clinical Trials Registry,ACTRN12617000065392. Registered on 12 January 2017

Study protocol

10.1136/bmjopen-2020-042838
The Best Services Trial (BeST?): a cluster randomised controlled trial comparing the clinical and cost-effectiveness of New Orleans Intervention Model with services as usual (SAU) for infants and young children entering care
Authors: Crawford Karen , Fitzpatick Bridie , McMahon Lynn , Forde Matt , Miller Susanne , McConnachie Alex , Messow Martina , Henderson Marion , McIntosh Emma , Boyd Kathleen , Ougrin Dennis , Wilson Phil , Watson Nicholas , Minnis Helen
Published: February 2022

Background

Abused and neglected children are at increased risk of health problems throughout life, but negative effects may be ameliorated by nurturing family care. It is not known whether it is better to place these children permanently with substitute (foster or adoptive) families or to attempt to reform their birth families.

Previously, we conducted a feasibility randomised controlled trial (RCT) of the New Orleans Intervention Model (NIM) for children aged 0–60 months coming into foster care in Glasgow. NIM is delivered by a multidisciplinary health and social care team and offers families, whose child has been taken into foster care, a structured assessment of family relationships followed by a trial of treatment aiming to improve family functioning. A recommendation is then made for the child to return home or for adoption.

In the feasibility RCT, families were willing to be randomised to NIM or optimised social work services as usual and equipoise was maintained. Here we present the protocol of a substantive RCT of NIM including a new London site.

Methods

The study is a multi-site, pragmatic, single-blind, parallel group, cluster randomised controlled superiority trial with an allocation ratio of 1:1. We plan to recruit approximately 390 families across the sites, including those recruited in our feasibility RCT. They will be randomly allocated to NIM or optimised services as usual and followed up to 2.5 years post-randomisation. The principal outcome measure will be child mental health, and secondary outcomes will be child quality of life, the time taken for the child to be placed in permanent care (rehabilitation home or adoption) and the quality of the relationship with the primary caregiver.

Discussion

The study is novel in that infant mental health professionals rarely have a role in judicial decisions about children’s care placements, and RCTs are rare in the judicial context. The trial will allow us to determine whether NIM is clinically and cost-effective in the UK and findings may have important implications for the use of mental health assessment and treatment as part of the decision-making about children in the care system.
Bifunctional optogenetic switch for improving shikimic acid production in E. coli
Authors: Komera Irene , Gao Cong , Guo Liang , Hu Guipeng , Chen Xiulai , Liu Liming
Published: February 2022

Background

Biomass formation and product synthesis decoupling have been proven to be promising to increase the titer of desired value add products. Optogenetics provides a potential strategy to develop light-induced circuits that conditionally control metabolic flux redistribution for enhanced microbial production. However, the limited number of light-sensitive proteins available to date hinders the progress of light-controlled tools.

Results

To address these issues, two optogenetic systems (TPRS and TPAS) were constructed by reprogramming the widely used repressor TetR and protease TEVp to expand the current optogenetic toolkit. By merging the two systems, a bifunctional optogenetic switch was constructed to enable orthogonally regulated gene transcription and protein accumulation. Application of this bifunctional switch to decouple biomass formation and shikimic acid biosynthesis allowed 35 g/L of shikimic acid production in a minimal medium from glucose, representing the highest titer reported to date by E. coli without the addition of any chemical inducers and expensive aromatic amino acids. This titer was further boosted to 76 g/L when using rich medium fermentation.

Conclusion

The cost effective and light-controlled switch reported here provides important insights into environmentally friendly tools for metabolic pathway regulation and should be applicable to the production of other value-add chemicals.
Effects of a taped filter mask on peak power, perceived breathlessness, heart rate, blood lactate and oxygen saturation during a graded exercise test in young healthy adults: a randomized controlled trial
Authors: Ng Hoi Lam , Trefz Johannes , Schönfelder Martin , Wackerhage Henning
Published: February 2022

Background

Face masks are an effective, non-pharmacological strategy to reduce the transmission of Severe Acute Respiratory Syndrome Coronavirus-2 and other pathogens. However, it is a challenge to keep masks sealed during exercise, as ventilation can increase from 5 to 10 L/min at rest to up to 200 L/min so that masks may be blown away from the face. To reduce leakage e.g. during exercise, a face mask was developed that is taped onto the face. The aim of this study was to investigate during a graded exercise test the effect of a taped filter mask on the perception of breathlessness, heart rate, blood lactate concentration, and oxygen saturation when compared to a surgical mask and no mask.

Methods

Eight healthy trained participants (4 females), aged 24.5 ± 3.3 years performed graded exercise test until volitional exhaustion under three conditions: (1) No mask/control, (2) surgical mask or (3) taped filter mask. During these tests, we measured perception of breathlessness, heart rate, blood lactate concentration and peripheral oxygen saturation and analysed the resultant data with one or two-way repeated measures ANOVAs. We also used a questionnaire to evaluate mask comfort and analysed the data with paired t-tests.

Results

When compared to wearing no mask, maximal workload was significantly reduced with a taped filter face mask by 12 ± 6% (p < 0.001) and with a surgical mask by 3 ± 6% (p > 0.05). Moreover, subjects perceive the sensation of "severe breathlessness" at a 12 ± 9% lower workload (p = 0.012) with a taped face mask, and 7 ± 13% lower workload with a surgical mask (p > 0.05) when compared to wearing no mask. Oxygen saturation at 65% of the maximal workload is 1.5% lower (p = 0.018) with a taped mask than no mask. Heart rate and blood lactate concentration are not significantly different in-between no mask, surgical mask and taped mask at any workload. When compared to wearing a surgical mask, wearing a taped filter face mask has a significantly better wearing comfort (p = 0.038), feels better on the skin (p = 0.004), there is a lower sensation of moisture (p = 0.026) and wearers perceive that less heat is generated (p = 0.021). We found no sex/gender differences for any of the measured parameters.

Conclusions

A taped mask is well tolerated during light and moderate exercise intensity but reduces maximal exercise capacity.
Spontaneous regression of breast lymphoproliferative disorders after withdrawal of methotrexate in rheumatoid arthritis patients with Epstein–Barr virus infection: a case report and review of the literature
Authors: Ogawa Ayumi , Nakagawa Tsuyoshi , Kumaki Yuichi , Hosoya Tokuko , Oda Goshi , Mori Mio , Fujioka Tomoyuki , Kubota Kazunori , Onishi Iichiro , Uetake Hiroyuki
Published: February 2022

Background

Lymphoproliferative disorder (LPD) has been shown to occur after treatment with methotrexate (MTX). Currently, MTX-LPD has become widely recognized, but its mechanism and prognostic factors remain unclear.

Case presentation

We report the first case of Epstein–Barr virus (EBV)-associated MTX-LPD of the breast. A 63-year-old Asian woman with long-term rheumatoid arthritis presented to our facility with intermittent fever. A physical examination revealed a 3-cm lump in her left breast. She had been taking MTX for the past 15 years. Laboratory studies revealed slightly elevated levels of EBV-viral capsid antigen antibody immunoglobulin G and EBV nuclear antibody. Contrast-enhanced computer tomography revealed a mass in the left breast, a subcutaneous nodule in the abdomen, a mass in the left lung, and a nodule in the left retroperitoneum. The definitive diagnosis was consistent with MTX-LPD merging into an EBV-positive, diffuse large B-cell lymphoma. Six months following the withdrawal of MTX, the breast mass had markedly shrunk and the patient remained in good health for 1 year with no evidence of relapse of LPD.

Conclusion

MTX-LPD rarely occurs in the breast, and it is difficult to diagnose because there have only been six reported cases of breast MTX-LPD reported in the literature. EBV-positive MTX-LPD tends to regress spontaneously after MTX withdrawal, and our case also had similar results. It is important to make an appropriate diagnosis of MTX-LPD of the breast based on imaging and pathology to determine the appropriate treatment protocol for this rare disorder.
Book review of The Contested Lands of Laikipia. Histories of Claims and Conflict in a Kenyan Landscape by Marie Ladekjær Gravesen
Authors: Hughes Lotte
Published: February 2022

Book details

Marie Ladekjær Gravesen

The Contested Lands of Laikipia. Histories of Claims and Conflict in a Kenyan Landscape

Brill: Leiden and Boston, 2021

ISSN 15668-1203. ISSN 978-90-04-43519-3 (paperback). ISBN 978-90-43520-9 (e-book). 263 pages
Remediation mechanism of “double-resistant” bacteria—Sedum alfredii Hance on Pb- and Cd-contaminated soil
Authors: Mo Tongdong , Jiang Daihua , Shi Dingding , Xu Shaohui , Huang Xuejiao , Huang Zhigang
Published: February 2022

Background

Concentrations of heavy metals continue to increase in soil environments as a result of both anthropogenic activities and natural processes. Cadmium (Cd) and lead (Pb) is one of the most toxic heavy metals and pose health risks to both humans and the ecosystem. Therefore, effectively solving the problem of heavy metal pollution is the concern of soil workers. Among the existing remediation techniques, only the combined use of microorganisms and plants for remediation of heavy metal-contaminated soil is the greenest and most developed one. Consequently, based on this background, this study investigates the remediation mechanism of Pb and Cd heavy metals using the combined action of bacteria and Sedum alfredii Hance.

Methods

In order to enrich the research theory of combined plant and microorganism remediation of heavy metal-contaminated soil, we constructed a heavy metal composite pollution remediation system by combining Pb and Cd-tolerant bacteria with the Pb and Cd hyperaccumulator plant—Sedum alfredii Hance to investigate its combined remediation effect on Pb and Cd composite contaminated soil.

Results

The results showed that resistant bacteria were able to promote enrichment of Pb and Cd in Sedum alfredii Hance and J2 (200 ml of bacterial solution) was significantly (P < 0.05) more effective than J1 (100 ml of bacterial solution). The resistant bacteria were able to alleviate the toxic effects of Pb and Cd heavy metals on Sedum alfredii Hance and promote growth while reducing rhizosphere soil pH. The resistant bacteria were able to significantly reduce the effective state of Pb and Cd in the rhizosphere soil (P < 0.05), with the greatest reduction in the effective state of Pb in treatment A (Cd7Pb100 mg/kg), where J2 was reduced by 9.98% compared to J0, and the greatest reduction in the effective state of Cd in treatment C (Cd28Pb400 mg/kg), where J2 was 43.53% lower than J0. In addition, the resistant bacteria were able to increase the exchangeable state Cd content by 0.97 to 9.85%. The resistant bacteria had a weakly promoting effect and a highly inhibitory effect on the absorption of Pb by Sedum alfredii Hance.

Conclusions

The resistant bacteria can change the rhizosphere environment and significantly improve the remediation effect of Sedum alfredii Hance on heavy metal cadmium. The role of “double-resistant” bacteria in promoting the accumulation of Cd was greater than that of Pb.
Soil and water conservation practice effects on soil physicochemical properties and crop yield in Ethiopia: review and synthesis
Authors: Jiru Endale Bekele , Wegari Habtamu Temesgen
Published: February 2022

Background

Land degradation is an urgent agenda that requires great effort and resources to ameliorate. It worsens soil components through disrupting ecological functions and threatens agriculture production. To overcome it, different soil and water conservation (SWC) practices have been undertaken in numerous parts of Ethiopia. This paper aims to review the effects of SWC practices on soil physicochemical properties and crop yield. Data were collected from secondary sources via a computer library using various databases based on developed criteria. The collected data were organized, categorized, and analyzed through descriptive statistics. The mean difference of selected soil physicochemical properties obtained from treated and untreated farmland was tested using paired t-test. Factors influencing crop yield on treated farmland were determined by a multiple linear regression model.

Results

SWC practices influenced the soil physicochemical properties and crop yield either positively or negatively. The mean values of available phosphorus (10.6 ppm, 8.7 ppm), total nitrogen (0.5%, 0.4%), soil pH (6.0%, 5.8%), soil organic matter (4.4%, 3.8%), and soil organic carbon (2.2%, 1.8%) were on treated and untreated farmland under physical SWC practices, respectively. Similarly, the mean values of these variables were higher on treated farmland than untreated farmland under both biological and integrated SWC practices. The mean value of bulk density was higher on untreated farmland than treated one and statistically significant under all SWC practices. Fanya juu and stone-faced soil bund constantly increased crop yield, whereas soil bund and stone bund did not.

Conclusion

Proper implementation of SWC technologies through integrating physical and biological measures will boost the effectiveness of the practice in restoring soil physicochemical properties and improving crop yield. Meanwhile, government due attention paid for land resources management in Ethiopia, whereby the annual SWC and tree planting campaign underwent for a couple of decades, entails further scientific support for its efficacy.