bluuebunny/crossref_metadata_2025 huggingface dataset:
A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease
Authors: Mader Gregory , Mladsi Deirdre , Sanon Myrlene , Purser Molly , Barnett Christine L. , Oberdhan Dorothee , Watnick Terry , Seliger Stephen
Published: October 2022

Background

Tolvaptan was approved in the United States in 2018 for patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression as assessed in a 3-year phase 3 clinical trial (TEMPO 3:4). An extension study (TEMPO 4:4) showed continued delay in progression at 2 years, and a trial in patients with later-stage disease (REPRISE) provided confirmatory evidence of efficacy. Given the relatively shorter-term duration of the clinical trials, estimating the longer-term benefit associated with tolvaptan via extrapolation of the treatment effect is an important undertaking.

Methods

A model was developed to simulate a cohort of patients with ADPKD at risk of rapid progression and predict their long-term outcomes using an algorithm organized around the Mayo Risk Classification system, which has five subclasses (1A through 1E) based on estimated kidney growth rates. The model base-case population represents 1280 patients enrolled in TEMPO 3:4 beginning in chronic kidney disease (CKD) stages G1, G2, and G3 across Mayo subclasses 1C, 1D, and 1E. The algorithm was used to predict longer-term natural history health outcomes. The estimated treatment effect of tolvaptan from TEMPO 3:4 was applied to the natural history to predict the longer-term treatment benefit of tolvaptan. For the cohort, analyzed once reflecting natural history and once assuming treatment with tolvaptan, the model estimated lifetime progression through CKD stages, end-stage renal disease (ESRD), and death.

Results

When treated with tolvaptan, the model cohort was predicted to experience a 3.1-year delay of ESRD (95% confidence interval: 1.8 to 4.4), approximately a 23% improvement over the estimated 13.7 years for patients not receiving tolvaptan. Patients beginning tolvaptan treatment in CKD stages G1, G2, and G3 were predicted to experience estimated delays of ESRD, compared with patients not receiving tolvaptan, of 3.8 years (21% improvement), 3.0 years (24% improvement), and 2.1 years (28% improvement), respectively.

Conclusions

The model estimated that patients treated with tolvaptan versus no treatment spent more time in earlier CKD stages and had later onset of ESRD. Findings highlight the potential long-term value of early intervention with tolvaptan in patients at risk of rapid ADPKD progression.
Timing and severity of COVID-19 during pregnancy and risk of preterm birth in the International Registry of Coronavirus Exposure in Pregnancy
Authors: Smith Louisa H. , Dollinger Camille Y. , VanderWeele Tyler J. , Wyszynski Diego F. , Hernández-Díaz Sonia
Published: October 2022

Background

Studies of preterm delivery after COVID-19 are often subject to selection bias and do not distinguish between early vs. late infection in pregnancy, nor between spontaneous vs. medically indicated preterm delivery. This study aimed to estimate the risk of preterm birth (overall, spontaneous, and indicated) after COVID-19 during pregnancy, while considering different levels of disease severity and timing.

Methods

Pregnant and recently pregnant people who were tested for or clinically diagnosed with COVID-19 during pregnancy enrolled in an international internet-based cohort study between June 2020 and July 2021. We used several analytic approaches to minimize confounding and immortal time bias, including multivariable regression, time-to-delivery models, and a case-time-control design.

Results

Among 14,264 eligible participants from 70 countries who did not report a pregnancy loss before 20 gestational weeks, 5893 had completed their pregnancies and reported delivery information; others were censored at time of their last follow-up. Participants with symptomatic COVID-19 before 20 weeks’ gestation had no increased risk of preterm delivery compared to those testing negative, with adjusted risks of 10.0% (95% CI 7.8, 12.0) vs. 9.8% (9.1, 10.5). Mild COVID-19 later in pregnancy was not clearly associated with preterm delivery. In contrast, severe COVID-19 after 20 weeks’ gestation led to an increase in preterm delivery compared to milder disease. For example, the risk ratio for preterm delivery comparing severe to mild/moderate COVID-19 at 35 weeks was 2.8 (2.0, 4.0); corresponding risk ratios for indicated and spontaneous preterm delivery were 3.7 (2.0, 7.0) and 2.3 (1.2, 3.9), respectively.

Conclusions

Severe COVID-19 late in pregnancy sharply increased the risk of preterm delivery compared to no COVID-19. This elevated risk was primarily due to an increase in medically indicated preterm deliveries, included preterm cesarean sections, although an increase in spontaneous preterm delivery was also observed. In contrast, mild or moderate COVID-19 conferred minimal risk, as did severe disease early in pregnancy.
Do coagulation or fibrinolysis reflect the disease condition in patients with soft tissue sarcoma?
Authors: Asanuma Kunihiro , Nakamura Tomoki , Okamoto Takayuki , Hagi Tomohito , Kita Kouji , Nakamura Koichi , Matsuyama Yumi , Yoshida Keisuke , Asanuma Yumiko , Sudo Akihiro
Published: October 2022

Background

Coagulation and fibrinolysis are distinct processes that are highly correlated. Cells control coagulation and fibrinolysis by expression of tissue factor and urokinase-type plasminogen activator receptor on their surface. Tumor cells express these proteins, adjust their microenvironment and induce tumor exacerbation. We hypothesized that the expression of plasma markers for coagulation and fibrinolysis in patients with soft tissue sarcomas (STSs) was dependent on the level of tumor malignancy. To elucidate which markers are predictive of recurrence, metastasis and prognosis, coagulation or fibrinolysis, we analyzed the correlation between plasma levels of thrombin-antithrombin III complex (TAT), soluble fibrin (SF), plasmin-α2 plasmin inhibitor complex (PIC), D-dimer (DD) and clinical parameters in patients with STSs.

Methods

TAT, SF, PIC or DD were measured in pre-treatment blood samples from 64 patients with primary STSs and analyzed with clinicopathological parameters, and 5-year recurrence free survival (RFS), 5-year metastasis free survival (MFS) and 5-year overall survival (OS) were evaluated.

Results

The metastasis group had significantly higher DD (p = 0.0394), PIC (p = 0.00532) and SF (p = 0.00249) concentrations than the group without metastasis. The group that died of disease showed significantly higher DD (p = 0.00105), PIC (p = 0.000542), SF (p = 0.000126) and TAT (p = 0.0373) than surviving patients. By dividing the patients into low and high groups, the group with high DD, PIC, SF and TAT showed significantly lower 5-year MFS and 5-year OS than the corresponding low group. Furthermore, in multivariate COX proportional hazard analysis of continuous variables for 5-year MFS, only PIC was found to be a significant factor (HR: 2.14).

Conclusion

Fibrinolysis was better than coagulation at reflecting the disease condition of patients with STS. Notably, PIC levels ≥ 1.1 can not only predict the risk of metastasis and poor prognosis, but also increasing PIC levels correspond to further increases in risks of metastasis and poor prognosis.
Loss to follow-up of HIV-exposed infants for confirmatory HIV test under Early Infant Diagnosis program in India: analysis of national-level data from reference laboratories
Authors: Gawde Nilesh , Kamble Suchit , Goel Noopur , Nikhare Kalyani , Bembalkar Shilpa , Thorwat Mohan , Jagtap Dhanashree , Kurle Swarali , Yadav Neeru , Verma Vinita , Kapoor Neha , Das Chinmoyee
Published: October 2022

Background

Early Infant Diagnosis was launched in India in 2010 and its effect on the diagnosis of HIV-exposed infants needs to be assessed. The present study was done to find out the median age at DBS sample collection for early infant diagnosis and its trend over years, the median age at diagnosis of HIV among the HIV-exposed infants with DNA PCR tests, and the proportion of infants who completed testing cascades after detection of HIV-1 in a sample.

Methods

DNA PCR data (from 2013 to 2017) maintained at all regional reference laboratories in India was collated with each infant identified by a unique code. Cohort analysis of the infant data was used to find the median age at sample collection and diagnosis. The outcomes of testing in each cascade and the overall outcomes of testing for infants were prepared.

Results

The median age at sample collection for the four years combined at all India level was 60 days (48–110 days). The median age at diagnosis of HIV was 285 days (174–418 days). HIV-1 was detected in samples of 1897 (6.3%) infants out of 30,216 infants who had a DNA PCR test, out of whom 1070 (56.4%) completed the testing cascade and the rest were lost to follow-up.

Conclusion

The data highlights delay in diagnosis; both due to delay in sample collection and turn-around-times. Loss to follow-up of HIV-exposed infants with virus detection is a significant concern to the Early Infant Diagnosis and tracking systems need to be strengthened.
Analysing the role of sleep quality, functional limitation and depressive symptoms in determining life satisfaction among the older Population in India: a moderated mediation approach
Authors: Banerjee Shreya , Boro Bandita
Published: October 2022

Background:

Life satisfaction (LS), a useful construct in the study of psycho-social well-being, is an important indicator of healthy aging. With a view to investigate whether the improved longevity in India is accompanied by commensurate levels of well-being and contentment among the older adults , this study aimed to examine (1) the association between LS and sleep quality among older Indian adults aged 60 years and above (2) the mediating role of depression that accounts for the association and (3) the moderating role of functional limitation in this mediation.

Methods:

Cross-sectional data from the Longitudinal Ageing Study in India (LASI), Wave-1 (2017-18) was used. Pearson’s correlation coefficients were calculated to investigate the pair-wise relationship between sleep quality, depressive symptoms, functional limitation, and LS. Structural Equation Model was employed to analyse the moderated-mediated association between sleep quality and the level of LS.

Results:

Sleep quality had a direct effect (β=-0.12) as well as an indirect effect (β=-0.024) via depressive symptoms on LS, accounting for 83.6 and 16.4 per cent of the total effects, respectively. Also, the interaction term between poor seep quality and functional limitation was positive (β = 0.03, p < 0.001) in determining depressive symptoms, suggesting that higher level of functional limitation aggravated the indirect effect of poor sleep quality on LS.

Conclusion:

The findings of the study suggested that ensuring both the physical as well as the mental well-being of the population during the life course may confer in later life the desired level of life satisfaction.
Role of community pharmacy professionals in child health service provision in Ethiopia: a cross-sectional survey in six cities of Amhara regional state
Authors: Ayele Asnakew Achaw , Cosh Suzanne , Islam Md Shahidul , East Leah
Published: October 2022

Background

Community pharmacy professionals have great potential to deliver various public health services aimed at improving service access, particularly in countries with a shortage of health professionals. However, little is known about their involvement in child health service provision in Ethiopia.

Objective

The purpose of this study was to evaluate the level of involvement of community pharmacy professionals in child health service provision within Ethiopia.

Methods

A multi-center cross-sectional survey was conducted among 238 community pharmacy professionals from March to July 2020 in Amhara regional state of Ethiopia. Independent samples t-test and one way Analysis of Variance (ANOVA) was used to test the mean difference.

Results

Most community pharmacy professionals were ‘involved’ in providing child health services related to‘advice about vitamins/supplements’(46.6%),‘advice about infant milk/formulas’(47.1%) and‘responding to minor symptoms’(50.8%) for children. The survey revealed that, community pharmacy professionals were less frequently involved in providing childhood‘vaccination’services. Further, level of involvement of community pharmacy professionals differed according to participants’ licensure level, setting type, responsibility in the facility and previous training experience in child health services.

Conclusion

Community pharmacy professionals have been delivering various levels of child health services, demonstrating ability and capacity in improving access to child health services in Ethiopia. However, there is a need for training and government support to optimize pharmacist engagement and contribution to service delivery.
Characteristics of events in which police responded to overdoses: an examination of incident reports in Rhode Island
Authors: Macmadu Alexandria , Yolken Annajane , Frueh Lisa , Toussaint Jai’el R. , Newman Roxxanne , Jacka Brendan P. , Collins Alexandra B. , Marshall Brandon D. L.
Published: October 2022

Background

Narrow or non-existent Good Samaritan Law protections and harsh drug selling statutes in the USA have been shown to deter bystanders from seeking medical assistance for overdoses. Additionally, little is known about the actions that police take when responding to overdose events. The objectives of this study were to assess the prevalence and correlates of naloxone administration by police, as well as to examine overdose events where arrests were made and those in which the person who overdosed was described as combative.

Methods

We analyzed incident reports of police responding to an overdose between September 1, 2019, and August 31, 2020 (i.e., 6 months prior to and during the COVID-19 pandemic), from a city in Rhode Island. We examined characteristics of incidents, as well as individual characteristics of the person who overdosed. Correlates of police naloxone administration were assessed using Wilcoxon rank sum tests and Fisher’s exact tests, and we examined incidents where arrests occurred and incidents in which the person who overdosed was described as combative descriptively.

Results

Among the 211 incidents in which police responded to an overdose during the study period, we found that police administered naloxone in approximately 10% of incidents. In most incidents, police were the last group of first responders to arrive on scene (59%), and most often, naloxone was administered by others (65%). Police were significantly more likely to administer naloxone when they were the first professionals to arrive, when naloxone had not been administered by others, and when the overdose occurred in public or in a vehicle. Arrests at overdose events were rarely reported (1%), and people who overdosed were rarely (1%) documented in incident reports as being ‘combative.’

Conclusions

Considering these findings, ideally, all jurisdictions should have sufficient first responder staffing and resources to ensure a rapid response to overdose events, with police rarely or never dispatched to respond to overdoses. However, until this ideal can be achieved, any available responders should be dispatched concurrently, with police instructed to resume patrol once other professional responders arrive on scene; additionally, warrant searches of persons on scene should be prohibited.
SARS-CoV-2 variants of concern and spike protein mutational dynamics in a Swedish cohort during 2021, studied by Nanopore sequencing
Authors: Mannsverk Steinar , Bergholm Julia , Palanisamy Navaneethan , Ellström Patrik , Kaden René , Lindh Johan , Lennerstrand Johan
Published: October 2022

Background

Since the beginning of the COVID-19 pandemic, new variants of significance to public health have emerged. Consequently, early detection of new mutations and variants through whole-genome sequencing remains crucial to assist health officials in employing appropriate public health measures.

Methods

We utilized the ARTIC Network SARS-CoV-2 tiled amplicon approach and Nanopore sequencing to sequence 4,674 COVID-19 positive patient samples from Uppsala County, Sweden, between week 15 and 52 in 2021. Using this data, we mapped the circulating variants of concern (VOC) in the county over time and analysed the Spike (S) protein mutational dynamics in the Delta variant throughout 2021.

Results

The distribution of the SARS-CoV-2 VOC matched the national VOC distribution in Sweden, in 2021. In the S protein of the Delta variant, we detected mutations attributable to variants under monitoring and variants of interest (e.g., E484Q, Q613H, Q677H, A222V and Y145H) and future VOC (e.g., T95I and Y144 deletion, which are signature mutations in the Omicron variant). We also frequently detected some less well-described S protein mutations in our Delta sequences, that might play a role in shaping future emerging variants. These include A262S, Q675K, I850L, Q1201H, V1228L and M1237I. Lastly, we observed that some of the Delta variant’s signature mutations were underrepresented in our study due to artifacts of the used bioinformatics tools, approach and sequencing method. We therefore discuss some pitfalls and considerations when sequencing SARS-CoV-2 genomes.

Conclusion

Our results suggest that genomic surveillance in a small, representative cohort can be used to make predictions about the circulating variants nationally. Moreover, we show that detection of transient mutations in currently circulating variants can give valuable clues to signature mutations of future VOC. Here we suggest six such mutations, that we detected frequently in the Delta variant during 2021. Lastly, we report multiple systematic errors that occurred when following the ARTIC Network SARS-CoV-2 tiled amplicon approach using the V3 primers and Nanopore sequencing, which led to the masking of some of the important signature mutations in the Delta sequences.
An area under the concentration–time curve threshold as a predictor of efficacy and nephrotoxicity for individualizing polymyxin B dosing in patients with carbapenem-resistant gram-negative bacteria
Authors: Yang Jing , Liu Shaohua , Lu Jingli , Sun Tongwen , Wang Peile , Zhang Xiaojian
Published: October 2022

Background

Evidence supports therapeutic drug monitoring of polymyxin B, but clinical data for establishing an area under the concentration–time curve across 24 h at steady state (AUCss,24 h) threshold are still limited. This study aimed to examine exposure–response/toxicity relationship for polymyxin B to establish an AUCss,24 h threshold in a real-world cohort of patients.

Methods

Using a validated Bayesian approach to estimate AUCss,24 h from two samples, AUCss,24 h threshold that impacted the risk of polymyxin B-related nephrotoxicity and clinical response were derived by classification and regression tree (CART) analysis and validated by Cox regression analysis and logical regression analysis.

Results

A total of 393 patients were included; acute kidney injury (AKI) was 29.0%, clinical response was 63.4%, and 30-day all-cause mortality was 35.4%. AUCss,24 h thresholds for AKI of > 99.4 mg h/L and clinical response of > 45.7 mg h/L were derived by CART analysis. Cox and logical regression analyses showed that AUCss,24 h of > 100 mg h/L was a significant predictor of AKI (HR 16.29, 95% CI 8.16–30.25, P < 0.001) and AUCss,24 h of ≥ 50 mg h/L (OR 4.39, 95% CI 2.56–7.47, P < 0.001) was independently associated with clinical response. However, these exposures were not associated with mortality. In addition, the correlation between trough concentration (1.2–2.8 mg/L) with outcomes was similar to AUCss,24 h.

Conclusions

For critically ill patients, AUCss,24 h threshold of 50–100 mg h/L was associated with decreased nephrotoxicity while assuring clinical efficacy. Therapeutic drug monitoring is recommended for individualizing polymyxin B dosing.
Elevated NRAS expression during DCIS is a potential driver for progression to basal-like properties and local invasiveness
Authors: Zheng Ze-Yi , Elsarraj Hanan , Lei Jonathan T. , Hong Yan , Anurag Meenakshi , Feng Long , Kennedy Hilda , Shen Yichao , Lo Flora , Zhao Zifan , Zhang Bing , Zhang Xiang H.-F. , Tawfik Ossama W. , Behbod Fariba , Chang Eric C.
Published: October 2022

Background

Ductal carcinoma in situ (DCIS) is the most common type of in situ premalignant breast cancers. What drives DCIS to invasive breast cancer is unclear. Basal-like invasive breast cancers are aggressive. We have previously shown that NRAS is highly expressed selectively in basal-like subtypes of invasive breast cancers and can promote their growth and progression. In this study, we investigated whether NRAS expression at the DCIS stage can control transition from luminal DCIS to basal-like invasive breast cancers.

Methods

Wilcoxon rank-sum test was performed to assess expression of NRAS in DCIS compared to invasive breast tumors in patients. NRAS mRNA levels were also determined by fluorescence in situ hybridization in patient tumor microarrays (TMAs) with concurrent normal, DCIS, and invasive breast cancer, and association of NRAS mRNA levels with DCIS and invasive breast cancer was assessed by paired Wilcoxon signed-rank test. Pearson’s correlation was calculated between NRAS mRNA levels and basal biomarkers in the TMAs, as well as in patient datasets. RNA-seq data were generated in cell lines, and unsupervised hierarchical clustering was performed after combining with RNA-seq data from a previously published patient cohort.

Results

Invasive breast cancers showed higher NRAS mRNA levels compared to DCIS samples. These NRAShigh lesions were also enriched with basal-like features, such as basal gene expression signatures, lower ER, and higher p53 protein and Ki67 levels. We have shown previously that NRAS drives aggressive features in DCIS-like and basal-like SUM102PT cells. Here, we found that NRAS-silencing induced a shift to a luminal gene expression pattern. Conversely, NRAS overexpression in the luminal DCIS SUM225 cells induced a basal-like gene expression pattern, as well as an epithelial-to-mesenchymal transition signature. Furthermore, these cells formed disorganized mammospheres containing cell masses with an apparent reduction in adhesion.

Conclusions

These data suggest that elevated NRAS levels in DCIS are not only a marker but can also control the emergence of basal-like features leading to more aggressive tumor activity, thus supporting the therapeutic hypothesis that targeting NRAS and/or downstream pathways may block disease progression for a subset of DCIS patients with high NRAS.
StOP? II trial: cluster randomized clinical trial to test the implementation of a toolbox for structured communication in the operating room—study protocol
Authors: Keller Sandra , Tschan Franziska , Semmer Norbert K. , Trelle Sven , Manser Tanja , Beldi Guido
Published: October 2022

Background

Surgical care, which is performed by intensely interacting multidisciplinary teams of surgeons, anesthetists, and nurses, remains associated with significant morbidity and mortality. Intraoperative communication has been shown to be associated with surgical outcomes, but tools ensuring efficient intraoperative communication are lacking. In a previous study, we developed the StOP?-protocol that fosters structured intraoperative communication. Before the critical phases of the operation, the responsible surgeon initiates and leads one or several StOP?s. During a StOP?, the surgeon informs about the progress of the operation (status), next steps and proximal goals (objectives), and possible problems (problems) and encourages all team members to voice their observations and ask questions (?). In a before-after study performed mainly in visceral surgery, we found effects of the StOP?-protocol on mortality, length of hospital stay, and reoperation. We intend to assess the impact of the StOP?-protocol in a cluster randomized trial, in a wider variety of surgical specialties (i.e., general, visceral, thoracic, vascular surgery, surgical urology, and gynecology). The primary hypothesis is that the consistent use of the StOP?-protocol by the main surgeon reduces patient mortality within 30 days after the operation. The secondary hypothesis is that the consistent use of the StOP?-protocol by the main surgeon reduces unplanned reoperations, length of hospital stay, and unplanned hospital readmissions.

Methods

This study is designed as a multicenter, cluster-randomized parallel-group trial. Board-certified surgeons of participating clinical departments will be randomized 1:1 to the StOP? intervention group or to the standard of care (control) group. The intervention group will undergo a training to use the StOP?-protocol and receive regular feedback on their compliance with the protocol. The surgeons in the control group will communicate as usual during their operations. The unit of observation will be operations performed by cluster surgeons. Consecutive patients will be enrolled over 4 months per cluster. A total of 400 surgeons will be recruited, and we expect to collect patient outcome data for 14,000 surgical procedures.

Discussion

The StOP?-protocol was designed as a tool to structure communication during surgical procedures. Testing its effects on patient outcomes will contribute to implementing evidenced-based interventions to reduce surgical complications.

Trial registration

ClinicalTrials.gov NCT05356962. Registered on May 2, 2022
Traditional Chinese medicine based on Tongjiang methodology combined with proton pump inhibitor (PPI) step-down in treating non-erosive reflux disease: a study protocol for a multicentered, randomized controlled clinical trial
Authors: Li Xia , Wu Haomeng , Zhang Beihua , Chen Ting , Shi Xiaoshuang , Ma Jinxin , Zhang Jiaqi , Tang Xudong , Wang Fengyun
Published: October 2022

Background

Non-erosive reflux disease (NERD) is characterized by typical gastroesophageal reflux symptoms, such as heartburn and regurgitation but an absence of esophageal mucosal damage during upper gastrointestinal endoscopy. Although proton pump inhibitors (PPIs) are the first line therapy, almost 50% of patients with NERD fail to respond to this treatment. Traditional Chinese medicine (TCM) can better relieve the symptoms of NERD. Therefore, a randomized controlled trial (RCT) was designed to investigate the efficiency of TCM granules based on Tongjiang (TJ) methodology combined with PPI step-down therapy for NERD patients who did not respond to PPIs alone.

Method

This multicentered, double-blinded, RCT with two parallel groups will recruit 174 participants who will be randomized into the TCM granules combined with PPI step-down group (n = 87) and the TCM granules placebo combined with PPI step-down group (n = 87). Both groups of participants will receive 6 weeks of treatment and 4 weeks of follow-up, and all participants will be assessed for related symptoms, mental health status, and quality of life at each visit. The primary outcome measurements include visual analog scale (VAS) for heartburn and regurgitation and the major symptoms scale. The secondary outcome measurements include PPI withdrawal rate, symptom recurrence rate, minor symptoms scale, SF-36, PRO, SAS, SDS, GERD–HRQL, and TCM syndromes scales.

Discussion

Previous research has shown that TCM is capable to alleviate NERD symptoms. This trial will help to provide a better understanding of the synergistic efficiency of the combination of TCM and PPIs, to explore whether the dosage of PPIs can be reduced after the supplement of TCM granules and to provide a feasible plan to reduce dependencies or withdraw NERD patients from PPIs. The outcome of this trial is expected to reduce the symptom recurrence rates, lessen patients’ physical and psychological burdens, and achieve good social benefits.

Trial registration

Clinicaltrials.gov NCT04340297. Registered on April 9, 2020
FORWARDS-1: an adaptive, single-blind, placebo-controlled ascending dose study of acute baclofen on safety parameters in opioid dependence during methadone-maintenance treatment—a pharmacokinetic-pharmacodynamic study
Authors: Paterson L. M. , Barker D. , Cro S. , Mozgunov P. , Phillips R. , Smith C. , Nahar L. , Paterson S. , Lingford-Hughes A. R.
Published: October 2022

Background

Treatment of opiate addiction with opiate substitution treatment (e.g. methadone) is beneficial. However, some individuals desire or would benefit from abstinence but there are limited options to attenuate problems with opiate withdrawal. Preclinical and preliminary clinical evidence suggests that the GABA-B agonist, baclofen, has the desired properties to facilitate opiate detoxification and prevent relapse. This study aims to understand whether there are any safety issues in administering baclofen to opioid-dependent individuals receiving methadone.

Methods

Opiate-dependent individuals (DSM-5 severe opioid use disorder) maintained on methadone will be recruited from addiction services in northwest London (NHS and third sector providers). Participants will be medically healthy with no severe chronic obstructive pulmonary disease or type 2 respiratory failure, no current dependence on other substances (excluding nicotine), no current severe DSM-5 psychiatric disorders, and no contraindications for baclofen or 4800 IU vitamin D (placebo). Eligible participants will be randomised in a 3:1 ratio to receive baclofen or placebo in an adaptive, single-blind, ascending dose design. A Bayesian dose-escalation model will inform the baclofen dose (10, 30, 60, or 90 mg) based on the incidence of ‘dose-limiting toxicity’ (DLT) events and participant-specific methadone dose. A range of respiratory, cardiovascular, and sedative measures including the National Early Warning Score (NEWS2) and Glasgow Coma Scale will determine DLT. On the experimental day, participants will consume their usual daily dose of methadone followed by an acute dose of baclofen or placebo (vitamin D3) ~ 1 h later. Measures including oxygen saturation, transcutaneous CO2, respiratory rate, QTc interval, subjective effects (sedation, drug liking, craving), plasma levels (baclofen, methadone), and adverse events will be obtained using validated questionnaires and examinations periodically for 5 h after dosing.

Discussion

Study outcomes will determine what dose of baclofen is safe to prescribe to those receiving methadone, to inform a subsequent proof-of-concept trial of the efficacy baclofen to facilitate opiate detoxification. To proceed, the minimum acceptable dose is 30 mg of baclofen in patients receiving ≤ 60 mg/day methadone based on the clinical experience of baclofen’s use in alcoholism and guidelines for the management of opiate dependence.

Trial registration

Clinicaltrials.gov NCT05161351. Registered on 16 December 2021.
Experiences of the Data Monitoring Committee for the RECOVERY trial, a large-scale adaptive platform randomised trial of treatments for patients hospitalised with COVID-19
Authors: Sandercock Peter A. G. , Darbyshire Janet , DeMets David , Fowler Robert , Lalloo David G. , Munavvar Mohammed , Staplin Natalie , Warris Adilia , Wittes Janet , Emberson Jonathan R.
Published: October 2022

Aim

To inform the oversight of future clinical trials during a pandemic, we summarise the experiences of the Data Monitoring Committee (DMC) for the Randomised Evaluation of COVID therapy trial (RECOVERY), a large-scale randomised adaptive platform clinical trial of treatments for hospitalised patients with COVID-19.

Methods and findings

During the first 24 months of the trial (March 2020 to February 2022), the DMC oversaw accumulating data for 14 treatments in adults (plus 10 in children) involving > 45,000 randomised patients. Five trial aspects key for the DMC in performing its role were: a large committee of members, including some with extensive DMC experience and others who had broad clinical expertise; clear strategic planning, communication, and responsiveness by the trial principal investigators; data collection and analysis systems able to cope with phases of very rapid recruitment and link to electronic health records; an ability to work constructively with regulators (and other DMCs) to address emerging concerns without the need to release unblinded mortality results; and the use of videoconferencing systems that enabled national and international members to meet at short notice and from home during the pandemic when physical meetings were impossible. Challenges included that the first four treatments introduced were effectively ‘competing’ for patients (increasing pressure to make rapid decisions on each one); balancing the global health imperative to report on findings with the need to maintain confidentiality until the results were sufficiently certain to appropriately inform treatment decisions; and reliably assessing safety, especially for newer agents introduced after the initial wave and in the small numbers of pregnant women and children included. We present a series of case vignettes to illustrate some of the issues and the DMC decision-making related to hydroxychloroquine, dexamethasone, casirivimab + imdevimab, and tocilizumab.

Conclusions

RECOVERY’s streamlined adaptive platform design, linked to hospital-level and population-level health data, enabled the rapid and reliable assessment of multiple treatments for hospitalised patients with COVID-19. The later introduction of factorial assessments increased the trial’s efficiency, without compromising the DMC’s ability to assess safety and efficacy. Requests for the release of unblinded primary outcome data to regulators at points when data were not mature required significant efforts in communication with the regulators by the DMC to avoid inappropriate early trial termination.
Males of Aedes aegypti show different clock gene expression profiles in the presence of conspecific females
Authors: Bezerra Jéssica Rodrigues Assunção , Bruno Rafaela Vieira , Araripe Luciana Ordunha
Published: October 2022

Background

The study of behavioral and physiological traits in mosquitoes has been mainly focused on females since males are not hematophagous and thus do not transfer the parasites that cause diseases in human populations. However, the performance of male mosquitoes is key for the expansion of populations and the perpetuation of mosquito species. Pre-copulatory communication between males and females is the initial and essential step for the success of copulation and studying the male facet of this interaction provides fertile ground for the improvement of vector control strategies. Like in most animals, reproduction, feeding, and oviposition are closely associated with locomotor activity in mosquitoes. Rhythmic cycles of locomotor activity have been previously described inAedes aegypti, and in females, they are known to be altered by blood-feeding and arbovirus infection. In previous work, we found that males in the presence of females significantly change their locomotor activity profiles, with a shift in the phase of the activity peak. Here, we investigated whether this shift is associated with changes in the expression level of three central circadian clock genes.

Methods

Real-time PCR reactions were performed for the geneperiod,cycle, andcryptochrome 2in samples of heads, antennae, and abdominal tips of solitary males and males in the presence of females. Assays with antennae-ablated males were also performed, asking whether this is an essential organ mediating the communication and the variation in activity profiles.

Results

The geneperiodshowed a conserved expression pattern in all tissues and conditions, while the other two genes varied according to the male condition. A remarking pattern was observed incry2, where the difference between the amplitude of expression at the beginning of photophase and the expression peak in the scotophase was greater when males were in the presence of females. Antennae ablation in males did not have a significant effect on the expression profiles, suggesting that female recognition may involve other senses besides hearing and olfaction.

Conclusion

Our results suggest that the expression of genecryptochrome 2varies in association with the interaction between males and females.

Graphical abstract
Long-term maintenance of human endometrial epithelial stem cells and their therapeutic effects on intrauterine adhesion
Authors: He Wen , Zhu Xuejing , Xin Aijie , Zhang Hongdan , Sun Yiming , Xu Hua , Li He , Yang Tianying , Zhou Dan , Yan Hexin , Sun Xiaoxi
Published: October 2022

Background

The human endometrium is a highly regenerative tissue that is believed to have two main types of stem cells: endometrial mesenchymal/stromal stem cells (eMSCs) and endometrial epithelial stem cells (eESCs). So far, eMSCs have been extensively studied, whereas the studies of eESCs are constrained by the inability to culture and expand them in vitro. The aim of this study is to establish an efficient method for the production of eESCs from human endometrium for potential clinical application in intrauterine adhesion (IUA).

Results

Here we developed a culture condition with a combination of some small molecules for in vitro culturing and expansion of human SSEA-1+ cells. The SSEA-1+ cells exhibited stem/progenitor cell activity in vitro, including clonogenicity and differentiation capacity into endometrial epithelial cell-like cells. In addition, the SSEA-1+ cells, embedded in extracellular matrix, swiftly self-organized into organoid structures with long-term expansion capacity and histological phenotype of the human endometrial epithelium. Specifically, we found that the SSEA-1+ cells showed stronger therapeutic potential than eMSCs for IUA in vitro. In a rat model of IUA, in situ injection of the SSEA-1+ cells-laden chitosan could efficiently reduce fibrosis and facilitate endometrial regeneration.

Conclusions

Our work demonstrates an approach for isolation and expansion of human eESCs in vitro, and an appropriate marker, SSEA-1, to identify eESCs. Furthermore, the SSEA-1+ cells-laden chitosan might provide a novel cell-based approach for IUA treatment. These findings will advance the understanding of pathophysiology during endometrial restoration which may ultimately lead to more rational clinical practice.

Graphical Abstract
DLC1 deficiency at diagnosis predicts poor prognosis in acute myeloid leukemia
Authors: Li Xueqian , Qi Jiaqian , Song Xiaofei , Xu Xiaoyan , Pan Tingting , Wang Hong , Yang Jingyi , Han Yue
Published: October 2022

Acute myeloid leukemia (AML) is a complex, heterogeneous malignant hematologic disease. Although multiple prognostic-related genes gave been explored in previous studies, there are still many genes whose prognostic value remains unclear. In this study, a total of 1532 AML patients from three GEO databases were included, five genes with potential prognostic value (DLC1, NF1B, DENND5B, TANC2 and ELAVL4) were screened by weighted gene co-expression network analysis (WGCNA), least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE). Based on this, we conducted survival analysis of the above five genes through the TCGA database and found that low level of DLC1 was detrimental to the long-term prognosis of AML patients. We also performed external validation in 48 AML patients from our medical center to analyze the impact of DLC1 level on prognosis. In conclusion, DLC1 may be a potential marker affecting the prognosis of AML, and its deficiency is associated with poor prognosis.
Co-occurring psychotic and eating disorders in England: findings from the 2014 Adult Psychiatric Morbidity Survey
Authors: Rodgers Ellen , Marwaha Steven , Humpston Clara
Published: October 2022

Background

Psychotic disorders and eating disorders are complex mental illnesses associated with increased mortality and functional impairment. This study aimed to investigate the co-occurrence and relationships between eating disorders and psychotic disorders and assess the mediation effect of mood instability.

Methods

This study used data from the Adult Psychiatric Morbidity Survey (APMS) 2014, a general population-based survey in England. Participants (total N = 7546, female N = 4488, male N = 3058, mean age = 52.3 years) were categorised based on psychotic disorder status into the groups of probable psychosis, diagnosed psychosis, and healthy controls without psychosis. The dependent variable of this study was the presence or absence of an eating disorder, with mood instability as the mediator. Logistic regression and mediation analyses were conducted to assess the relationships between these variables.

Results

Both probable and diagnosed psychoses were significantly related to the presence of an eating disorder, and mood instability was found to be a mediating variable with moderate effect.

Conclusion

The present study demonstrates a significant relationship between eating disorders and psychotic disorders in the English general population, indicating higher levels of co-occurrence between these two groups of disorders than when compared with healthy controls. The findings also suggest the relationship between eating and psychotic disorders is mediated, to an extent, by the presence of mood instability traits. Future research could extend the present study’s findings through assessing whether specific eating disorders are more significantly related to psychotic disorders than others.
Exploring the role of language knowledge and background knowledge in reading comprehension of specific-purpose tests in higher education
Authors: Tarlani-Aliabadi Hasan , Tazik Khalil , Azizi Zeinab
Published: October 2022

Though the empirical findings of the past studies in the literature have offered strong support to the significant role of language knowledge and background knowledge in reading comprehension, this issue has not been explored with regard to specific purposes tests in the Iranian higher education context. Therefore, this study aimed at exploring the interaction effects between language knowledge and background knowledge among Iranian university students majoring in economics. For this purpose, a total of 90 students including male students (n = 35) and female students (n = 55) majoring in economics were selected through a convenience sampling method. Having been divided into three proficiency levels, they took three high-stakes reading tests constructed by the National Organization of Educational Testing in Iran for Economics candidates. Based on three criteria, including sentences with passive, Flesch Readability Index, and sentences with participles as attributes, the three texts were ranked in order of easy to difficult (text 1, text 2, and text 3). Afterward, 15 participants participated in semi-structured interviews to express their experiences with the reading tests. The results indicated that background knowledge had marked effects on the performances of the participants across the three reading texts. However, in the more specific reading text (text 3), neither general language knowledge nor general background knowledge were strong indicators. Additionally, the results of the semi-structured interviews with the participants revealed they lacked the required language and content knowledge to perform well on the reading text 3. In light of the findings, a range of implications is proposed for pertinent stakeholders.
Virtual reconstruction of the painting process and original colors of a color-changed Northern Wei Dynasty mural in Cave 254 of the Mogao Grottoes
Authors: Bolong Chai , Zongren Yu , Manli Sun , Zhongwei Shan , Jinli Zhao , Biwen Shui , Zhuo Wang , Yaopeng Yin , Bomin Su
Published: October 2022

The Northern Wei Dynasty (386–534 CE) murals of Cave 254 in the Mogao Grottoes, China, have been extensively affected by pigment color changes and fading. These issues severely hinder efforts to correctly understand the value and painting process of murals from this historic period. The virtual reconstruction of the faded murals reflects the analysis results of the pigments applied during the painting process and provides a new direction for conservation and art research. However, simple virtual reconstructions may not be accurate owing to deficiencies in our understanding of the color-changed pigments and fading of image lines. In this study, multi-band imaging (MSI) was performed to obtain infrared-reflected false color, ultraviolet-reflected false color, and ultraviolet luminescence images of the mural. A portable X-ray fluorescence spectrometer, portable digital microscope, scanning electron microscope, energy dispersive X-ray spectrometer, liquid chromatography–mass spectrometer, and confocal Raman microscope were used. Non-invasive and minimally invasive analyses of local portions of different color areas were performed to identify their pigments and map the strata, and a hue–saturation–brightness palette was constructed for these pigments. Finally, the pigment analysis results were combined with the multi-band image features to determine the pigment distribution of the mural, which was then used to virtually reconstruct the original color and appearance of the faded mural under ideal conditions. This study is the first to use a virtual reconstruction based on objective analyses to simulate the original color, painting processes, and pigment stratigraphy of a mural from the Northern Wei Dynasty. A preliminary discussion of the relationship between the painting processes of the mural and color changes in its pigments was also performed. The findings of this study will provide new perspectives on the study of Northern Wei Dynasty murals.
High-resolution metabolomics-based biomarker discovery using exhaled breath condensate from patients with lung cancer
Authors: Bang Geul , Park Ji Hyun , Park Changyoung , Kim Kwan-joong , Kim Jae Kwan , Lee Sung Yong , Kim Jin Young , Park Youngja Hwang
Published: October 2022

Early diagnosis and treatment are critical for improving the survival of patients with lung cancer, which is the leading cause of cancer-related deaths worldwide. In this study, we investigated whether the metabolomics analysis of exhaled breath condensate (EBC) from patients with lung cancer can provide biomarkers that can be used for noninvasive screening for lung cancer diagnosis. EBC samples obtained from patients with lung cancer (n = 20) and healthy individuals (n = 5) were subjected to high-resolution metabolomics (HRM) using liquid chromatography–mass spectrometry (LC–MS). Univariate analysis, with a false discovery rate (FDR), q = 0.05, and hierarchical clustering analysis were performed to discover significantly different metabolites between the healthy controls and patients with lung cancer. This was followed by the identification of the metabolites using the METLIN database. Pathway analysis based on the identified metabolites revealed that arachidonic acid (AA) metabolism was the most significantly affected pathway. Finally, 5-hydroxyicosatetraenoic acid (HETE) (m/z 343.2233, [M + Na]+), a metabolite involved in AA metabolism, was found to be significantly higher in patients with lung cancer than in healthy counterparts. Our finding suggested that the HRM of EBC samples is a useful approach for identifying biomarkers for noninvasive screening for lung cancer diagnosis.