bluuebunny/crossref_metadata_2025 huggingface dataset:
Immortal time bias for life-long conditions in retrospective observational studies using electronic health records
Authors: Tyrer Freya , Bhaskaran Krishnan , Rutherford Mark J.
Published: March 2022

Background

Immortal time bias is common in observational studies but is typically described for pharmacoepidemiology studies where there is a delay between cohort entry and treatment initiation.

Methods

This study used the Clinical Practice Research Datalink (CPRD) and linked national mortality data in England from 2000 to 2019 to investigate immortal time bias for a specific life-long condition, intellectual disability. Life expectancy (Chiang’s abridged life table approach) was compared for 33,867 exposed and 980,586 unexposed individuals aged 10+ years using five methods: (1) treating immortal time as observation time; (2) excluding time before date of first exposure diagnosis; (3) matching cohort entry to first exposure diagnosis; (4) excluding time before proxy date of inputting first exposure diagnosis (by the physician); and (5) treating exposure as a time-dependent measure.

Results

When not considered in the design or analysis (Method 1), immortal time bias led to disproportionately high life expectancy for the exposed population during the first calendar period (additional years expected to live: 2000–2004: 65.6 [95% CI: 63.6,67.6]) compared to the later calendar periods (2005–2009: 59.9 [58.8,60.9]; 2010–2014: 58.0 [57.1,58.9]; 2015–2019: 58.2 [56.8,59.7]). Date of entry of diagnosis (Method 4) was unreliable in this CPRD cohort. The final methods (Method 2, 3 and 5) appeared to solve the main theoretical problem but residual bias may have remained.

Conclusions

We conclude that immortal time bias is a significant issue for studies of life-long conditions that use electronic health record data and requires careful consideration of how clinical diagnoses are entered onto electronic health record systems.
A comparative analysis on characteristics and mortalities of four key transmission populations on antiretroviral therapy: a retrospective cohort study in Northwest China
Authors: Feng Shuo , Zhu Zirong , Yang Pengju , Jin Juan , Tuo Huihui , Wang Ning , Bai Ruimin , Sun Yan , Song Liumei , Zhang Xiu , Wang Shengbang , Duan Qiqi , Huang Yingjian , Zheng Yan , Xu Songhua
Published: March 2022

Background

This study explored disparities in characteristics and mortalities among four major transmission groups on antiretroviral therapy in northwest China as well as the survival impact of each transmission route.

Methods

We first examined disparities in demographics and clinical characteristics of the four transmission populations. Kaplan Meier analysis was subsequently conducted to compare survival rates among all groups. At last, Cox proportional hazards regression model was employed to analyze the survival impact of a transmission route among seven main categories of survival factors associated with all-cause mortalities.

Results

Survival analysis showed significant differences in all-cause, AIDS- and non-AIDS-related deaths among four HIV populations (all P < 0.05). Using homosexuals as the reference, Cox proportional hazards model further revealed that the risk of all-cause death for blood and plasma donors was significantly higher than that of the reference (aHR: 5.21, 95%CI: 1.54–17.67); the risk of non-AIDS-related death for heterosexuals (aHR: 2.07, 95%CI: 1.01–4.20) and that for blood and plasma donors (aHR: 19.81, 95%CI: 5.62–69.89) were both significantly higher than that of the reference.

Conclusions

Significant disparities were found in characteristics and mortalities among the four transmission groups where mortality disparities were mainly due to non-AIDS-related death. Suggestions are provided for each group to improve their survivorship.
NAP1L1 promotes tumor proliferation through HDGF/C-JUN signaling in ovarian cancer
Authors: Xiaohua Zhu  , Xie YingYing , Huang Wenyan , Chen Zigui , Guo SuiQun
Published: March 2022

Background

Nucleosome assembly protein 1-like 1 (NAP1L1) is highly expressed in various types of cancer and plays an important role in carcinogenesis, but its specific role in tumor development and progression remains largely unknown. In this study, we suggest the potential of NAP1L1 as a prognostic biomarker and therapeutic target for the treatment of ovarian cancer (OC).

Methods

In our study, a tissue microarray (TMA) slide containing specimens from 149 patients with OC and 11 normal ovarian tissues underwent immunohistochemistry (IHC) to analyze the correlation between NAP1L1 expression and clinicopathological features. Loss-of- function experiments were performed by transfecting siRNA and following lentiviral gene transduction into SKOV3 and OVCAR3 cells. Cell proliferation and the cell cycle were assessed by the Cell Counting Kit-8, EDU assay, flow cytometry, colony formation assay, and Western blot analysis. In addition, co-immunoprecipitation (Co-IP) and immunofluorescence assays were performed to confirm the relationship between NAP1L1 and its potential targets in SKOV3/OVCAR3 cells.

Results

High expression of NAP1L1 was closely related to poor clinical outcomes in OC patients. After knocking down NAP1L1 by siRNA or shRNA, both SKOV3 and OVCAR3 cells showed inhibition of cell proliferation, blocking of the G1/S phase, and increased apoptosis in vitro. Mechanism analysis indicated that NAP1L1 interacted with hepatoma-derived growth factor (HDGF) and they were co-localized in the cytoplasm. Furthermore, HDGF can interact with jun proto-oncogene (C-JUN), an oncogenic transformation factor that induces the expression of cyclin D1 (CCND1). Overexpressed HDGF in NAP1L1 knockdown OC cells not only increased the expression of C-JUN and CCND1, but it also reversed the suppressive effects of si-NAP1L1 on cell proliferation.

Conclusions

Our data demonstrated that NAP1L1 could act as a prognostic biomarker in OC and can interact with HDGF to mediate the proliferation of OC, and this process of triggered proliferation may contribute to the activation of HDGF/C-JUN signaling in OC cells.
Iconic Therapy for the reduction of borderline personality disorder symptoms among suicidal youth: a preliminary study
Authors: Hurtado-Santiago Silvia , Guzmán-Parra José , Mayoral Fermín , Bersabé Rosa M.
Published: March 2022

Background

Iconic therapy (IT) is a new therapy that uses images to teach skills with the aim of improving the symptoms of borderline personality disorder. Preliminary results are promising, and there is indication that IT may be effective. The purpose of this preliminary study was to test the effectiveness of IT compared to a psychological supportive intervention (SI).

Methods

The study was carried out at the University Regional Hospital of Malaga. Young patients (N = 40; 15–30 years) with suicidal or parasuicidal behavior and borderline personality traits were randomized into IT (N = 20) or SI (N = 20). The main outcome variable was a change in the symptoms of borderline personality disorder (BSL-23) at the end of treatment. The secondary outcome variables were suicidal ideation and behavior, self-harm, the need for medication, the number of visits to mental health professionals, maladaptive behavior, satisfaction with therapy and perceived improvement, both at the end of the intensive treatment and at the 12-month follow-up.

Results

As expected, the two therapies produced a reduction in BPD symptoms at 10 weeks post-treatment and at the 12-month follow-up. Contrary to expectation, there were no statistically significant differences in the effectiveness of the two therapies (p > 0.05). However, at the 12-month follow-up, the effect sizes for the difference between the effectiveness of the two therapy groups on BSL-23 scores (d = 0.33) and on maladjustment to daily life (d = 0.39) was found to exceed the commonly used convention for a small effect (d = 0.20). Besides, participants in the IT group showed greater satisfaction with therapy than those who received SI. The mean difference between groups was statistically significant after the 10-week treatment period (p < .01), with a large effect size (d = 1.11). Nevertheless, this difference was not maintained at the 12-month follow-up (p > .05), although the effect size for this analysis (d = 0.34) was found to exceed a small effect.

Conclusions

This preliminary study did not find a statistically significant difference in the effectiveness of the two therapies, probably due to the small sample of participants, but there are some indicators (effect sizes) suggesting that perhaps IT may be superior for reducing BPD symptoms and maladjustment in daily life. Future studies with larger samples and comparisons with established treatments for borderline personality disorder are necessary to confirm that IT effects are significant and persistent in the long term.

Trial registration

ClinicalTrials.gov identifier: NCT03011190. First posted 05/01/2017. Last update posted 15/05/2018.
Multimodal prediction of pain and functional outcomes 6 months following total knee replacement: a prospective cohort study
Authors: Edwards Robert R. , Campbell Claudia , Schreiber Kristin L. , Meints Samantha , Lazaridou Asimina , Martel Marc O. , Cornelius Marise , Xu Xinling , Jamison Robert N. , Katz Jeffrey N. , Carriere Junie , Khanuja Harpal P. , Sterling Robert S. , Smith Michael T. , Haythornthwaite Jennifer A.
Published: March 2022

Background

Knee osteoarthritis (OA) is among the most common and disabling persistent pain conditions, with increasing prevalence and impact around the globe. In the U.S., the rising prevalence of knee OA has been paralleled by an increase in annual rates of total knee arthroplasty (TKA), a surgical treatment option for late-stage knee OA. While TKA outcomes are generally good, post-operative trajectories of pain and functional status vary substantially; a significant minority of patients report ongoing pain and impaired function following TKA. A number of studies have identified sets of biopsychosocial risk factors for poor post-TKA outcomes (e.g., comorbidities, negative affect, sensory sensitivity), but few prospective studies have systematically evaluated the unique and combined influence of a broad array of factors.

Methods

This multi-site longitudinal cohort study investigated predictors of 6-month pain and functional outcomes following TKA. A wide spectrum of relevant biopsychosocial predictors was assessed preoperatively by medical history, patient-reported questionnaire, functional testing, and quantitative sensory testing in 248 patients undergoing TKA, and subsequently examined for their predictive capacity.

Results

The majority of patients had mild or no pain at 6 months, and minimal pain-related impairment, but approximately 30% reported pain intensity ratings of 3/10 or higher. Reporting greater pain severity and dysfunction at 6 months post-TKA was predicted by higher preoperative levels of negative affect, prior pain history, opioid use, and disrupted sleep. Interestingly, lower levels of resilience-related “positive” psychosocial characteristics (i.e., lower agreeableness, lower social support) were among the strongest, most consistent predictors of poor outcomes in multivariable linear regression models. Maladaptive profiles of pain modulation (e.g., elevated temporal summation of pain), while not robust unique predictors, interacted with psychosocial risk factors such that the TKA patients with the most pain and dysfunction exhibited lower resilience and enhanced temporal summation of pain.

Conclusions

This study underscores the importance of considering psychosocial (particularly positively-oriented resilience variables) and sensory profiles, as well as their interaction, in understanding post-surgical pain trajectories.
Full-endoscopic foraminoplasty for highly down-migrated lumbar disc herniation
Authors: Cai Hanhua , Liu Chunhua , Lin Haibin , Wu Zhiqiang , Chen Xuanhuang , Zhang Huaizhi
Published: March 2022

Background and study aims

Multiple surgical approaches have been studied and accepted for the removal of highly downward migrated lumbar disc herniation (LDH). Here, we investigated the efficacy and safety of full-endoscopic foraminoplasty for highly downward migrated LDH.

Patients and methods

Thirty-seven patients with highly down-migrated LDH treated by the full-endoscopic foraminoplasty between January 2018 and January 2020 were retrospectively investigated. Clinical parameters were evaluated preoperatively and 1, 6, and 12 months postoperatively, using pre- and post-operative Oswestry Disability Index (ODI) scores for functional improvement, visual analog scale (VAS) for leg and back pain, and modified MacNab criteria for patients satisfactory.

Results

Thirty-seven patients with highly downward migrated LDH were successfully removed via the transforaminal full-endoscopic discectomy. The average VAS back and leg pain scores were significantly reduced from 7.41 ± 1.17 and 8.68 ± 1.06 before operation to 3.14 ± 0.89 and 2.70 ± 0.46 at postoperative 1 month, and 1.76 ± 0.59 and 0.92 ± 0.28 at postoperative 12 months, respectively (P < 0.05). The average ODI scores were reduced from 92.86 ± 6.41 to 15.30 ± 4.43 at postoperative 1 month, and 9.81 ± 3.24 at postoperative 12 months (P < 0.05). Based on the modifed MacNab criteria, 36 out of 37 patients (97.30%) were rated as excellent or good outcomes.

Conclusion

The full-endoscopic foraminoplasty can be used successfully for surgical removal of high grade down-migrated LDH, and it could serve as an efficient alternative technique for patients with highly downward migrated LDH.
Evaluations of exercise intolerance with cardiopulmonary exercise tests in an 18-year-old adolescent with pituitary stalk interruption syndrome: a case report
Authors: Sung Wei Hung , Chang Shin Tsu , Teng Li Yun , Lin Ko Long
Published: March 2022

Background

Pituitary stalk interruption syndrome (PSIS) is a rare disease associated with different level of anterior pituitary hormone deficiency resulting with a variety of clinical manifestations which could limit exercise capacity. Cardiopulmonary exercise test (CPET) is valuable in differential diagnosis of exercise intolerance and exercise prescription.

Case presentation

An 18-year-old male adolescent was diagnosed with PSIS at 4 years old, had undergone growth hormone supplement until puberty, and was referred to rehabilitation department due to exercise intolerance. We arranged pulmonary function test (PFT) and CPET to clarify the cause of limited capacity. The test result provided evidence of moderate functional impairment (54% of predicted maximal oxygen uptake) mainly affected by physical unfitness without significant cardiovascular or pulmonary limitations.

Conclusion

CPET serves as a valuable tool for diagnostic purpose. Aerobic and resistance exercise training for the patient should be conducted promptly for better prognosis but under safe circumstances, with criteria which could be provided by CPET results.
Translating the Pelvic Organ Prolapse Score into Samoan using a modified back translation methodology
Authors: Dembinsky Melanie , Boodoosingh Ramona , Fulu-Aiolupotea Saunima’a Ma , Lima Uila Laifa , Ekeroma Alec , Bugge Carol , Hagen Suzanne
Published: March 2022

Background

Although Samoan women have a high prevalence of obesity and multiple parity which are risk factors of pelvic organ prolapse, there is no prevalence data on this condition.

Aims

Translate the Pelvic Organ Prolapse-Symptoms Score (POP-SS) from English into Samoan,

Materials and methods

Standardised methods for translating questionnaires, individual face to face audio-recorded interviews in which women completed the POP-SS using a Think Aloud method, analysis using a Framework approach.

Results

The POP-SS was successfully translated in to Samoan, an additional information leaflet was developed to support women’s understanding of what prolapse is, 14 Samoan women were recruited of which 13 were interviewed and completed the POP-SS, results of POP-SS (scores), results of think aloud, results in terms of research experience.

Conclusions

A Samoan version of the POP-SS is now available for further evaluation of its psychometric properties prior to wider use. The team continue to collaborate on their work on establishing the prevalence of prolapse whilst building local research capacity.
Early assessment of acute ischemic stroke in rabbits based on multi-parameter near-field coupling sensing
Authors: Li Gen , Yin Shengtong , Jian Man , Chen Jingbo , Zeng Lingxi , Bai Zelin , Zhuang Wei , Xu Bingxin , He Shengjie , Sun Jian , Chen Yujie
Published: March 2022

Background

Early diagnosis and continuous monitoring are the key to emergency treatment and intensive care of patients with acute ischemic stroke (AIS). Nevertheless, there has not been a fully accepted method targeting continuous assessment of AIS in clinical.

Methods

Near-field coupling (NFC) sensing can obtain the conductivity related to the volume of intracranial components with advantages of non-invasiveness, strong penetrability and real-time monitoring. In this work, we built a multi-parameter monitoring system that is able to measure changes of phase and amplitude in the process of electromagnetic wave (EW) reflection and transmission. For investigating its feasibility in AIS detection, 16 rabbits were chosen to establish AIS models by bilateral common carotid artery ligation and then were enrolled for monitoring experiments.

Results

During the 6 h after AIS, the reflection amplitude (RA) shows a decline trend with a range of 0.69 dB and reflection phase (RP) has an increased variation of 6.48° . Meanwhile, transmission amplitude (TA) and transmission phase (TP) decrease 2.14 dB and 24.29° , respectively. The statistical analysis illustrates that before ligation, 3 h after ligation and 6 h after ligation can be effectively distinguished by the four parameters individually. When all those parameters are regarded as recognition features in back propagation (BP) network, the classification accuracy of the three different periods reaches almost 100%.

Conclusion

These results prove the feasibility of multi-parameter NFC sensing to assess AIS, which is promised to become an outstanding point-of-care testing method in the future.
Orthogonal control of gene expression in plants using synthetic promoters and CRISPR-based transcription factors
Authors: Kar Shaunak , Bordiya Yogendra , Rodriguez Nestor , Kim Junghyun , Gardner Elizabeth C. , Gollihar Jimmy D. , Sung Sibum , Ellington Andrew D.
Published: March 2022

Background

The construction and application of synthetic genetic circuits is frequently improved if gene expression can be orthogonally controlled, relative to the host. In plants, orthogonality can be achieved via the use of CRISPR-based transcription factors that are programmed to act on natural or synthetic promoters. The construction of complex gene circuits can require multiple, orthogonal regulatory interactions, and this in turn requires that the full programmability of CRISPR elements be adapted to non-natural and non-standard promoters that have few constraints on their design. Therefore, we have developed synthetic promoter elements in which regions upstream of the minimal 35S CaMV promoter are designed from scratch to interact via programmed gRNAs with dCas9 fusions that allow activation of gene expression.

Results

A panel of three, mutually orthogonal promoters that can be acted on by artificial gRNAs bound by CRISPR regulators were designed. Guide RNA expression targeting these promoters was in turn controlled by either Pol III (U6) or ethylene-inducible Pol II promoters, implementing for the first time a fully artificial Orthogonal Control System (OCS). Following demonstration of the complete orthogonality of the designs, the OCS was tied to cellular metabolism by putting gRNA expression under the control of an endogenous plant signaling molecule, ethylene. The ability to form complex circuitry was demonstrated via the ethylene-driven, ratiometric expression of fluorescent proteins in single plants.

Conclusions

The design of synthetic promoters is highly generalizable to large tracts of sequence space, allowing Orthogonal Control Systems of increasing complexity to potentially be generated at will. The ability to tie in several different basal features of plant molecular biology (Pol II and Pol III promoters, ethylene regulation) to the OCS demonstrates multiple opportunities for engineering at the system level. Moreover, given the fungibility of the core 35S CaMV promoter elements, the derived synthetic promoters can potentially be utilized across a variety of plant species.
Overall treatment effects of aquatic physical therapy in knee osteoarthritis: a systematic review and meta-analysis
Authors: Ma Ji , Chen Xiaoyu , Xin Juan , Niu Xin , Liu Zhifang , Zhao Qian
Published: March 2022

Objective

To determine the benefits of aquatic physical therapy as a rehabilitation strategy for knee osteoarthritis patients.

Methods

Electronic databases systematically searched up to July 2021.

Results

580 RCTs were selected. A total of thirteen studies comprising 883 participants were included in the study. For pain, meta-analyses showed that aquatic physical therapy is associated with a significant change in Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain (SMD = − 1.09, 95%CI − 1.97, − 0.21, p = 0.02) and visual analog scale (VAS) (SMD = − 0.55, 95%CI − 0.98, − 0.12, p = 0.01). In addition, for physical function, meta-analyses showed that aquatic physical therapy effectively improved WOMAC physical function (SMD = − 0.57, 95%CI − 1.14, − 0.01, p = 0.05). However, our findings showed no significant improvements in symptoms of joints, quality of life (QOL), flexibility, and body composition with knee osteoarthritis. For muscle strength, we found that aquatic physical therapy can only improve knee extension muscle strength (MD = 2.11, 95%CI 0.02, 4.20, p = 0.05). Additionally, for walking ability, we observed that aquatic physical therapy effectively reduced Timed-Up-and-Go Test (TUGT) in a large degree (MD = − 0.89, 95%CI − 1.25, − 0.53, p < 0.05).

Conclusions

According to the findings reported in the studies analyzed in the review, aquatic physical therapy had a positive effect on the pain, physical function, knee extension muscle strength, and walking ability among people with knee osteoarthritis.
Cyclic mechanical strain with high-tensile triggers autophagy in growth plate chondrocytes
Authors: Zhang Jin-ming , Wang Zheng-gang , He Zhi-yi , Qin Liang , Wang Jiang , Zhu Wen-tao , Qi Jun
Published: March 2022

Background

Mechanical loading has been widely considered to be essential for growth plate to maintain metabolism and development. Cyclic mechanical strain has been demonstrated to induce autophagy, whereas the relationship between cyclic tensile strain (CTS) and autophagy in growth plate chondrocytes (GPCs) is not clear. The objective of this study was to investigate whether CTS can regulate autophagy in GPCs in vitro and explore the potential mechanisms of this regulation.

Methods

The 2-week-old Sprague–Dawley rat GPCs were subjected to CTS of varying magnitude and duration at a frequency of 2.0 Hz. The mRNA levels of autophagy-related genes were measured by RT-qPCR. The autophagy in GPCs was verified by transmission electron microscopy (TME), immunofluorescence and Western blotting. The fluorescence-activated cell sorting (FACS) was employed to detect the percentage of apoptotic and necrotic cells.

Results

In GPCs, CTS significantly increased the mRNA and protein levels of autophagy-related genes, such asLC3,ULK1,ATG5andBECN1in a magnitude- and time-dependent manner. There was no significant difference in the proportion of apoptotic and necrotic cells between control group and CTS group. The autophagy inhibitors, 3-methyladenine (3MA) and chloroquine (CQ) reversed the CTS-induced autophagy via promoting the formation of autophagosomes. Cytochalasin D (cytoD), an inhibitor of G-actin polymerization into F-actin, could effectively block the CTS-induced autophagy in GPCs.

Conclusion

Cyclic mechanical strain with high-tensile triggers autophagy in GPCs, which can be suppressed by 3MA and CQ, and cytoskeletal F-actin microfilaments organization plays a key role in chondrocytes’ response to mechanical loading.
Can really plasma interleukin-6 predict postoperative delirium among patients undergoing open repair surgery of acute type A aortic dissection?
Authors: Yang Wen-He , Xue Fu-Shan , Li Cheng-Wen
Published: March 2022

The letter to the editor was written in response to “Plasma interleukin-6 is a potential predictive biomarker for postoperative delirium (POD) among acute type a aortic dissection patients treated with open surgical repair”, which is recently published by Lv et al. (J Cardiothorac Surg 16(1):146, 2021). In this article, Lv et al. conclude that plasma IL-6 is a potential biomarker for prediction of POD. However, we note several issues in this study that would have made interpretation of their results questionable. Our main concerns include the use of a short POD assessment time, no providing the data of analgesics and sedatives used in the ICU, application of incorrect statistical methods when assessing predictive ability of plasma IL-6 for the development of POD, and incorrect interpretation for the area under the receiver operating characteristic curve. We believe that addressing these issues will improve the transparency of this study and help the interpretation of findings.
Composition and short-term stability of gut microbiota in lean and spontaneously overweight healthy Labrador retriever dogs
Authors: Söder Josefin , Wernersson Sara , Höglund Katja , Hagman Ragnvi , Lindåse Sanna , Dicksved Johan
Published: March 2022

Background

The gut microbiota and its metabolic end-products act in close collaboration with the nutrient metabolism of the animal. A relationship between excess adiposity and alterations in gut microbiota composition has been identified in humans and rodents, but data are scarce for overweight dogs. This study compared composition and temporal variations of gut microbiota in healthy lean and spontaneously overweight dogs. The analysis was based on three individual fresh faeces samples from each dog during a 10-day period. Twenty-seven healthy and intact male Labrador retriever dogs were included, 12 of which were classified as lean (body condition score (BCS) 4–5 on a 9-point scale) and 15 as overweight (BCS 6–8). Gut microbiota was analysed by Illumina sequencing of the V3-V4 region of the 16S rRNA gene.

Results

Lean and overweight groups of dogs were not separated by principal coordinate analysis (PCoA), analysis of similarity (one-way ANOSIM, P = 0.99) or species indicator analysis (IndVal) using operational taxonomic units (OTU) data. Gut microbial taxa at phylum, family or genus level did not differ between lean and overweight dogs in mixed-model repeated measures analyses. Short-term stability, evaluated by similarity index, did not differ between lean and overweight dogs over the 10-day period. Pooled Firmicutes/Bacteroidetes (F/B) ratio was 3.1 ± 3.7 in overweight dogs and 2.1 ± 1.2 in lean dogs (P = 0.83). Individual dogs, irrespective of body condition (lean or overweight), displayed variation in mean alpha diversity (Chao-1 index range 122–245, Shannon index range 2.6–3.6) and mean similarity index (range 44–85%).

Conclusions

Healthy lean and spontaneously overweight Labrador retriever dogs had comparable gut microbiota composition and short-term stability over a 10-day sampling period. There were no alterations in microbial diversity or in relative abundance of specific taxa at phylum, family or genus level in overweight compared to lean dogs. Our findings suggest that there are few detectable differences in gut microbiota composition between healthy spontaneously overweight and lean dogs by the current method. Future application of metagenomic or metabolomic techniques could be used to investigate microbial genes or microbial end-products that may differ even when microbiota compositional analyses fail to detect a significant difference between lean and overweight dogs.
Identifying transferable lessons from cholera epidemic responses by Médecins Sans Frontières in Mozambique, Malawi and the Democratic Republic of Congo, 2015–2018: a scoping review
Authors: D’Mello-Guyett Lauren , Cumming Oliver , Rogers Elliot , D’hondt Rob , Mengitsu Estifanos , Mashako Maria , Van den Bergh Rafael , Welo Placide Okitayemba , Maes Peter , Checchi Francesco
Published: March 2022

Background

Cholera epidemics occur frequently in low-income countries affected by concurrent humanitarian crises. Evaluations of these epidemic response remains largely unpublished and there is a need to generate evidence on response efforts to inform future programmes. This review of MSF cholera epidemic responses aimed to describe the main characteristics of the cholera epidemics and related responses in these three countries, to identify challenges to different intervention strategies based on available data; and to make recommendations for epidemic prevention and control practice and policy.

Methods

Case studies from the Democratic Republic of Congo, Malawi and Mozambique were purposively selected by MSF for this review due to the documented burden of cholera in each country, frequency of cholera outbreaks, and risk of humanitarian crises. Data were extracted on the characteristics of the epidemics; time between alert and response; and, the delivery of health and water, sanitation and hygiene interventions. A Theory of Change for cholera response programmes was built to assess factors that affected implementation of the responses.

Results and conclusions

20 epidemic response reports were identified, 15 in DRC, one in Malawi and four in Mozambique. All contexts experienced concurrent humanitarian crises, either armed conflict or natural disasters. Across the settings, median time between the date of alert and date of the start of the response by MSF was 23 days (IQR 14–41). Almost all responses targeted interventions community-wide, and all responses implemented in-patient treatment of suspected cholera cases in either established health care facilities (HCFs) or temporary cholera treatment units (CTUs). In three responses, interventions were delivered as case-area targeted interventions (CATI) and four responses targeted households of admitted suspected cholera cases. CATI or delivery of interventions to households of admitted suspected cases occurred from 2017 onwards only. Overall, 74 factors affecting implementation were identified including delayed supplies of materials, insufficient quantities of materials and limited or lack of coordination with local government or other agencies. Based on this review, the following recommendations are made to improve cholera prevention and control efforts: explore improved models for epidemic preparedness, including rapid mobilisation of supplies and deployment of trained staff; invest in and strengthen partnerships with national and local government and other agencies; and to standardise reporting templates that allow for rigorous and structured evaluations within and across countries to provide consistent and accessible data.
Rewiring mitochondrial metabolism to counteract exhaustion of CAR-T cells
Authors: Huang Yue , Si Xiaohui , Shao Mi , Teng Xinyi , Xiao Gang , Huang He
Published: March 2022

Short persistence and early exhaustion of T cells are major limits to the efficacy and broad application of immunotherapy. Exhausted T and chimeric antigen receptor (CAR)-T cells upregulate expression of genes associated with terminated T cell differentiation, aerobic glycolysis and apoptosis. Among cell exhaustion characteristics, impaired mitochondrial function and dynamics are considered hallmarks. Here, we review the mitochondrial characteristics of exhausted T cells and particularly discuss different aspects of mitochondrial metabolism and plasticity. Furthermore, we propose a novel strategy of rewiring mitochondrial metabolism to emancipate T cells from exhaustion and of targeting mitochondrial plasticity to boost CAR-T cell therapy efficacy.
hOA-DN30: a highly effective humanized single-arm MET antibody inducing remission of ‘MET-addicted’ cancers
Authors: Martinelli Ilaria , Modica Chiara , Chiriaco Cristina , Basilico Cristina , Hughes James M. , Corso Simona , Giordano Silvia , Comoglio Paolo M. , Vigna Elisa
Published: March 2022

Background

The tyrosine kinase receptor encoded by the MET oncogene is a major player in cancer. When MET is responsible for the onset and progression of the transformed phenotype (MET-addicted cancers), an efficient block of its oncogenic activation results in potent tumor growth inhibition.

Methods

Here we describe a molecular engineered MET antibody (hOA-DN30) and validate its pharmacological activity in MET-addicted cancer models in vitro and in vivo. Pharmacokinetics and safety profile in non-human primates have also been assessed.

Results

hOA-DN30 efficiently impaired MET activation and the intracellular signalling cascade by dose and time dependent removal of the receptor from the cell surface (shedding). In vitro, the antibody suppressed cell growth by blocking cell proliferation and by concomitantly inducing cell death in multiple MET-addicted human tumor cell lines. In mice xenografts, hOA-DN30 induced an impressive reduction of tumor masses, with a wide therapeutic window. Moreover, the antibody showed high therapeutic efficacy against patient-derived xenografts generated from MET-addicted gastric tumors, leading to complete tumor regression and long-lasting effects after treatment discontinuation. Finally, hOA-DN30 showed a highly favorable pharmacokinetic profile and substantial tolerability in Cynomolgus monkeys.

Conclusions

hOA-DN30 unique ability to simultaneously erase cell surface MET and release the ‘decoy’ receptor extracellular region results in a paramount MET blocking action. Its remarkable efficacy in a large number of pre-clinical models, as well as its pharmacological features and safety profile in non-human primates, strongly envisage a successful clinical application of this novel single-arm MET therapeutic antibody for the therapy of MET-addicted cancers.
Retention in RCTs of physical rehabilitation for adults with frailty: a systematic review and meta-analysis
Authors: O’Grady Heather K. , Farley Christopher , Takaoka Alyson , Mayens Elisa , Bosch Jackie , Turkstra Lyn , Kho Michelle E.
Published: March 2022

Background

Physical rehabilitation (PR) interventions can improve physical function for adults with frailty; however, participant retention rates in randomized controlled trials (RCTs) are unknown.

Objective is to summarize participant retention rates in RCTs of PR for adults with frailty.

Design is a systematic review and meta-analysis (DOI:10.17605/OSF.IO/G6XR2).

Participants are adults ≥ 18 years with frailty.

Setting consists of inpatient, outpatient and community-based interventions.

Intervention includes any PR intervention.

Methods

We searched 7 electronic databases from inception to April 15, 2020 for published RCTs. Our primary outcome was participant retention rate to primary outcome measurement. Secondary outcomes included retention by study group, participant retention to intervention completion, reported reasons for attrition and reported strategies for maximizing retention. We completed screening, data extraction and risk of bias (ROB) assessments independently and in duplicate. We conducted a meta-analysis, calculating retention rates and 95% confidence intervals (CIs) using fixed or random-effects models, as appropriate.

Results

We included 21 RCTs, enrolling 1685 adults with frailty (median age 82.5 years (79.0, 82.2), 59.8% female (57.5, 69.8)). Twenty RCTs reported retention data, of which 90.0% (n = 18) had high ROB. The pooled participant retention rate to primary outcome measurement was 85.0% [95%CI (80.0, 90.0), I2 = 83.9%, p < 0.05]. There were no differences by group for retention to the primary outcome [intervention 87.0% (83.0, 91.0), p < 0.05, comparator 85.0% (79.0, 90.0), p < 0.05] or in retention to intervention completion [83.0% (95.0% CI (78.0–87.0), p < 0.05]. Of the 18 studies reporting 24 reasons for attrition, 51.3% were categorized as potentially modifiable by the research team (e.g. low motivation). Only 20.0% (n = 4) of studies reported strategies for maximizing retention.

Conclusions

In this review of 21 RCTs of PR, we identified acceptable rates of retention for adults with frailty. High retention in PR interventions appears to be feasible in this population; however, our results are limited by a high ROB and heterogeneity.
Electrical dry needling versus conventional physiotherapy in the treatment of active and latent myofascial trigger points in patients with nonspecific chronic low back pain
Authors: Lara-Palomo Inmaculada Carmen , Gil-Martínez Esther , Antequera-Soler Eduardo , Castro-Sánchez Adelaida María , Fernández-Sánchez Manuel , García-López Héctor
Published: March 2022

Background

Chronic low back pain is considered to be one of the main causes of absenteeism from work and primary and specialized consultations. The symptoms of nonspecific chronic low back pain may be accompanied by the activation of myofascial trigger points in the muscles, together with local and/or referred pain. Electrical dry needling is increasingly used in the treatment of lumbar myofascial pain. Conventional physiotherapy, however, is a popular approach to chronic pathologies, and there is evidence of different modalities of physiotherapy being used in the treatment of chronic low back pain. The aim of this study has been to determine the effectiveness of electrical dry needling versus conventional physiotherapy when applied to active and latent myofascial trigger points in patients with nonspecific chronic low back pain.

Methods

This is a controlled, randomized, two-arm, double-blind study. A total of 92 patients with chronic low back pain (time to onset ≥ 3 months, Roland Morris Disability Questionnaire score ≥ 4) will be recruited from the University of Almería. Participants will be divided into two study groups (n = 40) to receive treatment of low back pain with electrical dry needling and conventional physiotherapy (ischaemic compression, analytic stretching and postural education training dossier). A total of 6 sessions will be administered once a week for 6 weeks. Pain intensity, disability, fear of movement, quality of life, quality of sleep, anxiety and depression, pressure pain threshold, abdominal strength and lumbar mobility will be recorded at 6 weeks (post-immediate) and 2 months after the end of treatment.

Discussion

We believe that an approach including electrical dry needling to chronic low back pain dysfunction will be more effective in these patients. The results of this study will inform clinicians on which type of treatment is more beneficial for patients with chronic low back pain.

Trial registration

ClinicalTrials.gov NCT04804228. Registered on 14 January 2021
Clinical- and cost-effectiveness of a technology-supported and solution-focused intervention (DIALOG+) in treatment of patients with chronic depression—study protocol for a multi-site, cluster randomised controlled trial [TACK]
Authors: McNamee Philip , Matanov Aleksandra , Jerome Lauren , Kerry Sally , Walker Neil , Feng Yan , Molodynski Andrew , Scott Shonagh , Guruvaiah Latha , Collinson Sue , McCabe Rose , Geddes John , Priebe Stefan , Bird Victoria
Published: March 2022

Background

Many with an acute depressive disorder go on to develop chronic depression, despite ongoing care. There are few specifically designed interventions to treat chronic depression. DIALOG+, a technology-assisted intervention based on the principles of solution-focused therapy, may be beneficial. It has been shown to be effective as a treatment for patients with psychotic disorders, especially in regards to increasing quality of life. DIALOG+ was designed to be flexibly applied and not diagnosis-specific, aiming to structure communication and generate a personally-tailored care plan. This cluster randomised controlled trial (RCT) is part of a programme of research to adapt and test DIALOG+ for patients with chronic depression.

Methods

Patients will be eligible for the trial, if they have exhibited symptoms of depression or non-psychotic low mood for at least 2 years, have regular contact with a clinician and have a low subjective quality of life and moderate depressive symptoms. Clinicians, who routinely see eligible patients, will be recruited from a number of sites across NHS England. Clusters will have between 1 and 6 patients per clinician and will be randomised in a 1:1 ratio to either the intervention (DIALOG+) or active control group (treatment as usual + DIALOG scale). Clinicians in the intervention group are trained and asked to deliver the intervention regularly for 12 months. Active control participants receive treatment as usual and are asked to rate their satisfaction with areas of life and treatment on the DIALOG scale at the end of the clinical session. Approximately 112 clinician clusters will be recruited to reach a total patient sample size of 376. Clinical and social outcomes including costs are assessed at baseline and 3, 6 and 12 months post randomisation. The primary outcome will be subjective quality of life at 12 months.

Discussion

This definitive multi-site, cluster RCT aims to evaluate the clinical- and cost-effectiveness of DIALOG+ for people with chronic depression. If shown to be effective for this patient population it could be used to improve outcomes of mental health care on a larger scale, ensuring that patients with complex and co-morbid diagnoses can benefit.

Trial registration

ISRCTN11301686. Registered on 13 Jun 2019.
Nyssorhynchus darlingi genome-wide studies related to microgeographic dispersion and blood-seeking behavior
Authors: Alvarez Marcus Vinicius Niz , Alonso Diego Peres , Kadri Samir Moura , Rufalco-Moutinho Paulo , Bernardes Isabella Ariadne Ferrari , de Mello Ana Carolina Florindo , Souto Ana Carolina , Carrasco-Escobar Gabriel , Moreno Marta , Gamboa Dionicia , Vinetz Joseph M. , Conn Jan E. , Ribolla Paulo E. M.
Published: March 2022

Background

In Brazil, malaria is concentrated in the Amazon Basin, where more than 99% of the annual cases are reported. The main goal of this study was to investigate the population structure and genetic association of the biting behavior of Nyssorhynchus (also known as Anopheles) darlingi, the major malaria vector in the Amazon region of Brazil, using low-coverage genomic sequencing data.

Methods

Samples were collected in the municipality of Mâncio Lima, Acre state, Brazil between 2016 and 2017. Different approaches using genotype imputation and no gene imputation for data treatment and low-coverage sequencing genotyping were performed. After the samples were genotyped, population stratification analysis was performed.

Results

Weak but statistically significant stratification signatures were identified between subpopulations separated by distances of approximately 2–3 km. Genome-wide association studies (GWAS) were performed to compare indoor/outdoor biting behavior and blood-seeking at dusk/dawn. A statistically significant association was observed between biting behavior and single nucleotide polymorphism (SNP) markers adjacent to the gene associated with cytochrome P450 (CYP) 4H14, which is associated with insecticide resistance. A statistically significant association between blood-seeking periodicity and SNP markers adjacent to genes associated with the circadian cycle was also observed.

Conclusion

The data presented here suggest that low-coverage whole-genome sequencing with adequate processing is a powerful tool to genetically characterize vector populations at a microgeographic scale in malaria transmission areas, as well as for use in GWAS. Female mosquitoes entering houses to take a blood meal may be related to a specific CYP4H14 allele, and female timing of blood-seeking is related to circadian rhythm genes.

Graphical Abstract
Use of novel lab assays to examine the effect of pyrethroid-treated bed nets on blood-feeding success and longevity of highly insecticide-resistant Anopheles gambiae s.l. mosquitoes
Authors: Barreaux Priscille , Koella Jacob C. , N’Guessan Raphael , Thomas Matthew B.
Published: March 2022

Background

There is a pressing need to improve understanding of how insecticide resistance affects the functional performance of insecticide-treated nets (ITNs). Standard WHO insecticide resistance monitoring assays are designed for resistance surveillance and do not necessarily provide insight into how different frequencies, mechanisms or intensities of resistance affect the ability of ITNs to reduce malaria transmission.

Methods

The current study presents some novel laboratory-based assays that attempt to better simulate realistic exposure of mosquitoes to ITNs and to quantify impact of exposure not only on instantaneous mortality, but also on blood-feeding and longevity, two traits that are central to transmission. The assays evaluated the performance of a standard ITN (Permanet® 2.0; Vestergaard Frandsen), a ‘next generation’ combination ITN with a resistance-breaking synergist (Permanet® 3.0) and an untreated net (UTN), against field-derived Anopheles gambiae sensu lato mosquitoes from Côte d’Ivoire exhibiting a 1500-fold increase in pyrethroid resistance relative to a standard susceptible strain.

Results

The study revealed that the standard ITN induced negligible instantaneous mortality against the resistant mosquitoes, whereas the resistance-breaking net caused high mortality and a reduction in blood-feeding. However, both ITNs still impacted long-term survival relative to the UTN. The impact on longevity depended on feeding status, with blood-fed mosquitoes living longer than unfed mosquitoes following ITN exposure. Exposure to both ITNs also reduced the blood-feeding success, the time spent on the net and blood-feeding duration, relative to the untreated net.

Conclusion

Although a standard ITN did not have as substantial instantaneous impact as the resistance-breaking net, it still had significant impacts on traits important for transmission. These results highlight the benefit of improved bioefficacy assays that allow for realistic exposure and consider sub- or pre-lethal effects to help assess the functional significance of insecticide resistance.

Graphical Abstract