bluuebunny/crossref_metadata_2025 huggingface dataset:
Artemether-lumefantrine efficacy among adults on antiretroviral therapy in Malawi
Authors: Nyangulu Wongani , Mungwira Randy G. , Divala Titus H. , Nampota-Nkomba Nginache , Nyirenda Osward M. , Buchwald Andrea G. , Miller Jernelle , Earland Dominique E. , Adams Matthew , Plowe Christopher V. , Taylor Terrie E. , Mallewa Jane E. , van Oosterhout Joep J. , Parikh Sunil , Laurens Matthew B. , Laufer Miriam K. ,   the TSCQ Study Team
Published: January 2023

Background

When people with human immunodeficiency virus (HIV) infection (PWH) develop malaria, they are at risk of poor anti-malarial treatment efficacy resulting from impairment in the immune response and/or drug-drug interactions that alter anti-malarial metabolism. The therapeutic efficacy of artemether-lumefantrine was evaluated in a cohort of PWH on antiretroviral therapy (ART) and included measurement of day 7 lumefantrine levels in a subset to evaluate for associations between lumefantrine exposure and treatment response.

Methods

Adults living with HIV (≥ 18 years), on ART for ≥ 6 months with undetectable HIV RNA viral load and CD4 count ≥ 250/mm3 were randomized to daily trimethoprim-sulfamethoxazole (TS), weekly chloroquine (CQ) or no prophylaxis. After diagnosis of uncomplicated Plasmodium falciparum malaria, a therapeutic efficacy monitoring was conducted with PCR-correction according to WHO guidelines. The plasma lumefantrine levels on day 7 in 100 episodes of uncomplicated malaria was measured. A frailty proportional hazards model with random effects models to account for clustering examined the relationship between participant characteristics and malaria treatment failure within 28 days. Pearson’s Chi—squared test was used to compare lumefantrine concentrations among patients with treatment failure and adequate clinical and parasitological response (ACPR).

Results

411 malaria episodes were observed among 186 participants over 5 years. The unadjusted ACPR rate was 81% (95% CI 77–86). However, after PCR correction to exclude new infections, ACPR rate was 94% (95% CI 92–97). Increasing age and living in Ndirande were associated with decreased hazard of treatment failure. In this population of adults with HIV on ART, 54% (51/94) had levels below a previously defined optimal day 7 lumefantrine level of 200 ng/ml. This occurred more commonly among participants who were receiving an efavirenz-based ART compared to other ART regimens (OR 5.09 [95% CI 1.52–7.9]). Participants who experienced treatment failure had lower day 7 median lumefantrine levels (91 ng/ml [95% CI 48–231]) than participants who experienced ACPR (190 ng/ml [95% CI 101–378], p-value < 0.008).

Conclusion

Recurrent malaria infections are frequent in this population of PWH on ART. The PCR-adjusted efficacy of AL meets the WHO criteria for acceptable treatment efficacy. Nevertheless, lumefantrine levels tend to be low in this population, particularly in those on efavirenz-based regimens, with lower concentrations associated with more frequent malaria infections following treatment. These results highlight the importance of understanding drug-drug interactions when diseases commonly co-occur.
An ethical analysis of policy dialogues
Authors: Mitchell Polly , Reinap Marge , Moat Kaelan , Kuchenmüller Tanja
Published: January 2023

Background

A policy dialogue is a tool which promotes evidence-informed policy-making. It involves deliberation about a high-priority issue, informed by a synthesis of the best-available evidence, where potential policy interventions are discussed by stakeholders. We offer an ethical analysis of policy dialogues – an argument about how policy dialogues ought to be conceived and executed – to guide those organizing and participating in policy dialogues. Our analysis focuses on the deliberative dialogues themselves, rather than ethical issues in the broader policy context within which they are situated.

Methods

We conduct a philosophical conceptual analysis of policy dialogues, informed by a formal and an interpretative literature review.

Results

We identify the objectives of policy dialogues, and consider the procedural and substantive values that should govern them. As knowledge translation tools, the chief objective of policy dialogues is to ensure that prospective evidence-informed health policies are appropriate for and likely to support evidence-informed decision-making in a particular context. We identify five core characteristics which serve this objective: policy dialogues are (i) focused on a high-priority issue, (ii) evidence-informed, (iii) deliberative, (iv) participatory and (v) action-oriented. In contrast to dominant ethical frameworks for policy-making, we argue that transparency and accountability are not central procedural values for policy dialogues, as they are liable to inhibit the open deliberation that is necessary for successful policy dialogues. Instead, policy dialogues are legitimate insofar as they pursue the objectives and embody the core characteristics identified above. Finally, we argue that good policy dialogues need to actively consider a range of substantive values other than health benefit and equity.

Conclusions

Policy dialogues should recognize the limits of effectiveness as a guiding value for policy-making, and operate with an expansive conception of successful outcomes. We offer a set of questions to support those organizing and participating in policy dialogues.
Using social networks to scale up and sustain community-based programmes to improve physical activity and diet in low-income and middle-income countries: a scoping review
Authors: Abrahams Nina , Khodabakhsh Sahar , Toumpakari Zoi , Marais Frederick , Lambert Estelle V. , Foster Charlie
Published: January 2023

Background

Community-based programmes [CBPs], targeting increased physical activity and/or healthier eating, have been used in the prevention and management of non-communicable diseases. However, CBPs are only useful, insofar as they can be scaled up and sustained in some meaningful way. Social networks—defined as “social structures that exists between actors, individuals or organizations”—may serve as an important tool to identify underlying mechanisms that contribute to this process. This scoping review aimed to map and collate literature on the role of social network research in scaling-up and sustaining physical activity and/or diet CBPs in low-and middle-income countries [LMICs].

Methods

Arksey and O’Malley’s framework and its enhancement were followed. Inclusion criteria were peer-reviewed articles exploring the role of social networks in scaled-up and/or sustained physical activity and/or diet CBPs in adult populations, published in English since 2000, and based in a LMIC. Databases searched were PubMed, Cochrane, Scopus, Web of Science, CINAHL, SocIndex, International Bibliography of the Social Sciences, and Google Scholar. Books, conference abstracts, and programmes focused on children were excluded. Two reviewers independently selected and extracted eligible studies. Included publications were thematically analysed using the Framework Approach.

Results

Authors identified 12 articles for inclusion, covering 13 CBPs. Most were based in Latin America, with others in the Caribbean, the Pacific Islands, Iran, and India. All articles were published since 2009. Only three used social network analysis methods (with others using qualitative methods). Five main social network themes were identified: centralisation, cliques, leaders, quality over quantity, and shared goals. Contextual factors to be considered when scaling-up programmes in LMICs were also identified.

Conclusions

This review has shown that the evidence of the use of social network research in programme scale-up has not yet caught up to its theoretical possibilities. Programmes aiming to scale should consider conducting social network research with identified network themes in mind to help improve the evidence-base of what network mechanisms, in what contexts, might best support the strengthening of networks in physical activity and diet programmes. Importantly, the voice of individuals and communities in these networks should not be forgotten.
Does socioeconomic factors and healthcare coverage affect postpartum sterilization uptake in an urban, tertiary hospital?
Authors: Uaamnuichai Sutira , Phutrakool Phanupong , Thammasitchai Nareerat , Sathitloetsakun Sarochinee , Santibenchakul Somsook , Jaisamrarn Unnop
Published: January 2023

Background

Postpartum sterilization in Thailand has relatively few barriers compared to other countries. The procedure is covered by some healthcare plans, and paid out-of-pocket for others. We aim to determine if healthcare coverage and other socioeconomic factors affect the rate of postpartum sterilization in an urban, tertiary hospital.

Methods

We conducted a secondary analysis of data from a retrospective cohort of 4482 postpartum women who delivered at our hospital. Multivariable logistic regression was conducted to determine if sterilization reimbursement affects immediate postpartum sterilization rate.

Results

Overall immediate postpartum sterilization rate was 17.8%. Route of delivery and parity were similar in those who were reimbursed and those who were not. Women aged over 25 were more likely to have a healthcare plan that does not cover postpartum sterilization. Women whose healthcare plan reimbursed the procedure trended towards postpartum sterilization when compared to women who were not (aOR 1.05, 95% CI 0.86–1.28, p-value = 0.632). Women who delivered via cesarean section were more likely to undergo sterilization at the time of delivery (aOR = 5.87; 95% CI 4.77–7.24, p-value = < 0.001). Women aged 40–44 years were 2.70 times as likely to choose sterilization than those aged 20–24 years (aOR = 2.70; 95% CI 1.61–4.53, p-value < 0.001).

Conclusions

Healthcare coverage of the procedure was not associated with increased postpartum sterilization in our setting.
Comparative effects of kinect-based versus therapist-based constraint-induced movement therapy on motor control and daily motor function in children with unilateral cerebral palsy: a randomized control trial
Authors: Shih Tsai-Yu , Wang Tien-Ni , Shieh Jeng-Yi , Lin Szu-Yu , Ruan Shanq-Jang , Tang Hsien-Hui , Chen Hao-Ling
Published: January 2023

Background

Constraint-induced movement therapy (CIMT) is a prominent neurorehabilitation approach for improving affected upper extremity motor function in children with unilateral cerebral palsy (UCP). However, the restraint of the less-affected upper extremity and intensive training protocol during CIMT may decrease children’s motivation and increase the therapist’s workload and family’s burden. A kinect-based CIMT program, aiming to mitigate the concerns of CIMT, has been developed. The preliminary results demonstrated that this program was child-friendly and feasible for improving upper extremity motor function. However, whether the kinect-based CIMT can achieve better or at least comparable effects to that of traditional CIMT (i.e., therapist-based CIMT) should be further investigated. Therefore, this study aimed to compare the effects of kinect-based CIMT with that of therapist-based CIMT on upper extremity and trunk motor control and on daily motor function in children with UCP.

Methods

Twenty-nine children with UCP were recruited and randomly allocated to kinect-based CIMT (n = 14) or therapist-based CIMT (n = 15). The intervention dosage was 2.25 h a day, 2 days a week for 8 weeks. Outcome measures, namely upper extremity and trunk motor control and daily motor function, were evaluated before and after 36-h interventions. Upper extremity and trunk motor control were assessed with unimanual reach-to-grasp kinematics, and daily motor function was evaluated with the Revised Pediatric Motor Activity Log. Between-group comparisons of effectiveness on all outcome measures were analyzed by analysis of covariance (α = 0.05).

Results

The two groups demonstrated similar improvements in upper extremity motor control and daily motor function. In addition, the kinect-based CIMT group demonstrated greater improvements in trunk motor control than the therapist-based CIMT group did (F(1,28) > 4.862, p < 0.036).

Conclusion

Kinect-based CIMT has effects comparable to that of therapist-based CIMT on UE motor control and daily motor function. Moreover, kinect-based CIMT helps decrease trunk compensation during reaching in children with UCP. Therefore, kinect-based CIMT can be used as an alternative approach to therapist-based CIMT.

Trial registration: ClinicalTrials.gov Identifier: NCT02808195. Registered on 2016/06/21, https://clinicaltrials.gov/ct2/show/NCT02808195.
The Berlin Bimanual Test for Tetraplegia (BeBiTT): development, psychometric properties, and sensitivity to change in assistive hand exoskeleton application
Authors: Angerhöfer Cornelius , Vermehren Mareike , Colucci Annalisa , Nann Marius , Koßmehl Peter , Niedeggen Andreas , Kim Won-Seok , Chang Won Kee , Paik Nam-Jong , Hömberg Volker , Soekadar Surjo R.
Published: January 2023

Background

Assistive hand exoskeletons are promising tools to restore hand function after cervical spinal cord injury (SCI) but assessing their specific impact on bimanual hand and arm function is limited due to lack of reliable and valid clinical tests. Here, we introduce the Berlin Bimanual Test for Tetraplegia (BeBiTT) and demonstrate its psychometric properties and sensitivity to assistive hand exoskeleton-related improvements in bimanual task performance.

Methods

Fourteen study participants with subacute cervical SCI performed the BeBiTT unassisted (baseline). Thereafter, participants repeated the BeBiTT while wearing a brain/neural hand exoskeleton (B/NHE) (intervention). Online control of the B/NHE was established via a hybrid sensorimotor rhythm-based brain-computer interface (BCI) translating electroencephalographic (EEG) and electrooculographic (EOG) signals into open/close commands. For reliability assessment, BeBiTT scores were obtained by four independent observers. Besides internal consistency analysis, construct validity was assessed by correlating baseline BeBiTT scores with the Spinal Cord Independence Measure III (SCIM III) and Quadriplegia Index of Function (QIF). Sensitivity to differences in bimanual task performance was assessed with a bootstrapped pairedt-test.

Results

The BeBiTT showed excellent interrater reliability (intraclass correlation coefficients > 0.9) and internal consistency (α = 0.91). Validity of the BeBiTT was evidenced by strong correlations between BeBiTT scores and SCIM III as well as QIF. Wearing a B/NHE (intervention) improved the BeBiTT score significantly (p < 0.05) with high effect size (d = 1.063), documenting high sensitivity to intervention-related differences in bimanual task performance.

Conclusion

The BeBiTT is a reliable and valid test for evaluating bimanual task performance in persons with tetraplegia, suitable to assess the impact of assistive hand exoskeletons on bimanual function.
Speed-dependent biomechanical changes vary across individual gait metrics post-stroke relative to neurotypical adults
Authors: Kettlety Sarah A. , Finley James M. , Reisman Darcy S. , Schweighofer Nicolas , Leech Kristan A.
Published: January 2023

Background

Gait training at fast speeds is recommended to reduce walking activity limitations post-stroke. Fast walking may also reduce gait kinematic impairments post-stroke. However, it is unknown if differences in gait kinematics between people post-stroke and neurotypical adults decrease when walking at faster speeds.

Objective

To determine the effect of faster walking speeds on gait kinematics post-stroke relative to neurotypical adults walking at similar speeds.

Methods

We performed a secondary analysis with data from 28 people post-stroke and 50 neurotypical adults treadmill walking at multiple speeds. We evaluated the effects of speed and group on individual spatiotemporal and kinematic metrics and performed k-means clustering with all metrics at self-selected and fast speeds.

Results

People post-stroke decreased step length asymmetry and trailing limb angle impairment, reducing between-group differences at fast speeds. Speed-dependent changes in peak swing knee flexion, hip hiking, and temporal asymmetries exaggerated between-group differences. Our clustering analyses revealed two clusters. One represented neurotypical gait behavior, composed of neurotypical and post-stroke participants. The other characterized stroke gait behavior—comprised entirely of participants post-stroke with smaller lower extremity Fugl-Meyer scores than the post-stroke participants in the neurotypical gait behavior cluster. Cluster composition was largely consistent at both speeds, and the distance between clusters increased at fast speeds.

Conclusions

The biomechanical effect of fast walking post-stroke varied across individual gait metrics. For participants within the stroke gait behavior cluster, walking faster led to an overall gait pattern more different than neurotypical adults compared to the self-selected speed. This suggests that to potentiate the biomechanical benefits of walking at faster speeds and improve the overall gait pattern post-stroke, gait metrics with smaller speed-dependent changes may need to be specifically targeted within the context of fast walking.
Clear cell stromal tumor of the lung with multinucleated giant cells: a report of a case with YAP1-TFE3 fusion
Authors: Jakša Radek , Stružinská Ivana , Kendall Bártů Michaela , Trča Stanislav , Matěj Radoslav , Dundr Pavel
Published: January 2023

Background

Clear cell (hemangioblastoma-like) stromal tumor of the lung (CCSTL) is a rare pulmonary neoplasm. Recently, 9 cases of CCSTL harboring the YAP1-TFE3 gene fusion have been described, and it has been suggested that this aberration could be a characteristic feature of this tumor.

Case presentation

We here report another case of CCSTL in a 57-year-old male, which presented as a solitary lung nodule 45 mm in the greatest dimension. Microscopically, the tumor consisted of epithelioid to spindled cells with mild-to-moderate nuclear atypia, finely granular or vesicular chromatin, and small nucleoli. Nuclear indentations were a common finding. There were up to 3 mitoses per 10 HPF. The cytoplasm was slightly eosinophilic or clear. Scattered non-tumor large multinucleated cells were present. Immunohistochemically, the tumor cells showed diffuse positivity for TFE3, CD10, vimentin, and IFITM1. Other markers examined were negative, and the expression of lineage-specific markers was not found. NGS analysis revealed a fusion transcript of the YAP1 and TFE3 genes, and a pathogenic variant of the MUTYH gene.

Conclusion

Our finding supports the recent data suggesting that CCSTL represents a distinct entity characterized by the recurrent YAP1-TFE3 fusion.
The optimal timing and intervention to reduce mortality for necrotizing pancreatitis: a systematic review and network meta-analysis
Authors: Yang Yang , Zhang Yu , Wen Shuaiyong , Cui Yunfeng
Published: January 2023

Background

A series of randomized controlled trials have investigated the efficacy and safety of different timings of interventions and methods of intervention. However, the optimal treatment strategy is not yet clear.

Methods

We searched PubMed, EMBASE, ClinicalTrials.gov and the Cochrane Library until November 30, 2022. A systematic review and Bayesian network meta-analysis were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Trials comparing different treatment strategies for necrotizing pancreatitis were included. This study was registered in the Prospective Register of Systematic Reviews (CRD42022364409) to ensure transparency.

Results

We analyzed a total of 10 studies involving 570 patients and 8 treatment strategies. Although no statistically significant differences were identified comparing odds ratios, trends were confirmed by the surface under the cumulative ranking (SUCRA) scores. The interventions with a low rate of mortality were delayed surgery (DS), delayed surgical step-up approach (DSU) and delayed endoscopic step-up approach (DEU), while the interventions with a low rate of major complications were DSU, DEU and DS. According to the clustered ranking plot, DSU performed the best overall in reducing mortality and major complications, while DD performed the worst. Analysis of the secondary endpoints confirmed the superiority of DEU and DSU in terms of individual components of major complications (organ failure, pancreatic fistula, bleeding, and visceral organ or enterocutaneous fistula), exocrine insufficiency, endocrine insufficiency and length of stay. Overall, DSU was superior to other interventions.

Conclusion

DSU was the optimal treatment strategy for necrotizing pancreatitis. Drainage alone should be avoided in clinical practice. Any interventions should be postponed for at least 4 weeks if possible. The step-up approach was preferred.
Study of single-level lumbar degenerative diseases treated by unilateral wiltse access with unilateral nail rod fixation assisted by a new automatic retraction device
Authors: Sun Yapeng , Zhang Wei , Zhang Fei , Li Jiaqi , Guo Lei
Published: January 2023

Objective

To evaluate the clinical efficacy of unilateral wiltse transforaminal lumbar interbody fusion (TLIF) combined with unilateral nail bar system fixation for single-level lumbar degenerative diseases with the assistance of a new automatic retraction device in a retrospective comparative study.

Methods

A total of 46 patients with single-level lumbar degenerative diseases from September 2019 to December 2021 were retrospectively analyzed. Bilateral nail bar fixation with bullet-type fusion cage (ctrl group, 24 patients) and unilateral nail bar fixation on the affected side with kidney-like fusion cage (study group, 22 patients) were performed in TLIF via wiltse intermuscular approach assisted by a new automatic retraction device. The differences in intraoperative blood loss, operative time, intraoperative fluoroscopy time, postoperative drainage, bed rest, VAS score, ODI score, JOA score, serological creatine kinase (CK), the proportion of multifidus atrophy, modified Pfirrmann classification and intervertebral space height of the upper intervertebral disc were compared between the two groups based on clinical and imaging data.

Results

Intraoperative bleeding, operative time, and postoperative drainage were significantly lower in study group than ctrl group, and there were no significant differences in bed rest time and intraoperative fluoroscopy time between them. In addition, there was no statistical difference in CK between the study group and the ctrl group at 24 and 48 h postoperatively. Moreover, no statistically significant difference was found in VAS score of low back pain, VAS score of lower limb pain, ODI index, modified Pfirrmann classification of the upper intervertebral disc and intervertebral space height of the upper intervertebral disc between two groups. The atrophy ratio of multifidus muscle was significantly lower in the study group.

Conclusion

The new automatic retraction device assisted unilateral TLIF surgery with wiltse approach combined with unilateral nail bar fixation is a simple, effective and easy to master surgical method for single-level lumbar degenerative diseases.
Anti-malaria drug artesunate prevents development of amyloid-β pathology in mice by upregulating PICALM at the blood-brain barrier
Authors: Kisler Kassandra , Sagare Abhay P. , Lazic Divna , Bazzi Sam , Lawson Erica , Hsu Ching-Ju , Wang Yaoming , Ramanathan Anita , Nelson Amy R. , Zhao Zhen , Zlokovic Berislav V.
Published: January 2023

Background

PICALM is one of the most significant susceptibility factors for Alzheimer’s disease (AD). In humans and mice, PICALM is highly expressed in brain endothelium. PICALM endothelial levels are reduced in AD brains. PICALM controls several steps in Aβ transcytosis across the blood-brain barrier (BBB). Its loss from brain endothelium in mice diminishes Aβ clearance at the BBB, which worsens Aβ pathology, but is reversible by endothelial PICALM re-expression. Thus, increasing PICALM at the BBB holds potential to slow down development of Aβ pathology.

Methods

To identify a drug that could increase PICALM expression, we screened a library of 2007 FDA-approved drugs in HEK293t cells expressing luciferase driven by a human PICALM promoter, followed by a secondary mRNA screen in human Eahy926 endothelial cell line. In vivo studies with the lead hit were carried out in Picalm-deficient (Picalm+/−) mice, Picalm+/−; 5XFAD mice and Picalmlox/lox; Cdh5-Cre; 5XFAD mice with endothelial-specific Picalm knockout. We studied PICALM expression at the BBB, Aβ pathology and clearance from brain to blood, cerebral blood flow (CBF) responses, BBB integrity and behavior.

Results

Our screen identified anti-malaria drug artesunate as the lead hit. Artesunate elevated PICALM mRNA and protein levels in Eahy926 endothelial cells and in vivo in brain capillaries of Picalm+/− mice by 2–3-fold. Artesunate treatment (32 mg/kg/day for 2 months) of 3-month old Picalm+/−; 5XFAD mice compared to vehicle increased brain capillary PICALM levels by 2-fold, and reduced Aβ42 and Aβ40 levels and Aβ and thioflavin S-load in the cortex and hippocampus, and vascular Aβ load by 34–51%. Artesunate also increased circulating Aβ42 and Aβ40 levels by 2-fold confirming accelerated Aβ clearance from brain to blood. Consistent with reduced Aβ pathology, treatment of Picalm+/−; 5XFAD mice with artesunate improved CBF responses, BBB integrity and behavior on novel object location and recognition, burrowing and nesting. Endothelial-specific knockout of PICALM abolished all beneficial effects of artesunate in 5XFAD mice indicating that endothelial PICALM is required for its therapeutic effects.

Conclusions

Artesunate increases PICALM levels and Aβ clearance at the BBB which prevents development of Aβ pathology and functional deficits in mice and holds potential for translation to human AD.
Impact of continuous hypertonic (NaCl 20%) saline solution on renal outcomes after traumatic brain injury (TBI): a post hoc analysis of the COBI trial
Authors: Huet Olivier , Chapalain Xavier , Vermeersch Véronique , Moyer Jean-Denis , Lasocki Sigismond , Cohen Benjamin , Dahyot-Fizelier Claire , Chalard Kevin , Seguin P. , Hourmant Y. , Asehnoune Karim , Roquilly Antoine ,   for the Atlanrea Study Group and the Société Française d’Anesthésie Réanimation (SFAR) Research Network
Published: January 2023

Background

To evaluate if the increase in chloride intake during a continuous infusion of 20% hypertonic saline solution (HSS) is associated with an increase in the incidence of acute kidney injury (AKI) compared to standard of care in traumatic brain injury patients.

Methods

In this post hoc analysis of the COBI trial, 370 patients admitted for a moderate-to-severe TBI in the 9 participating ICUs were enrolled. The intervention consisted in a continuous infusion of HSS to maintain a blood sodium level between 150 and 155 mmol/L for at least 48 h. Patients enrolled in the control arm were treated as recommended by the latest Brain Trauma foundation guidelines. The primary outcome of this study was the occurrence of AKI within 28 days after enrollment. AKI was defined by stages 2 or 3 according to KDIGO criteria.

Results

After exclusion of missing data, 322 patients were included in this post hoc analysis. The patients randomized in the intervention arm received a significantly higher amount of chloride during the first 4 days (intervention group: 97.3 ± 31.6 g vs. control group: 61.3 ± 38.1 g;p < 0.001) and had higher blood chloride levels at day 4 (117.9 ± 10.7 mmol/L vs. 111.6 ± 9 mmol/L, respectively,p < 0.001). The incidence of AKI was not statistically different between the intervention and the control group (24.5% vs. 28.9%, respectively;p = 0.45).

Conclusions

Despite a significant increase in chloride intake, a continuous infusion of HSS was not associated with AKI in moderate-to-severe TBI patients. Our study does not confirm the potentially detrimental effect of chloride load on kidney function in ICU patients.

Trial registration: The COBI trial was registered on clinicaltrial.gov (Trial registration number: NCT03143751, date of registration: 8 May 2017).
Cannabis-opioid interaction in the treatment of fibromyalgia pain: an open-label, proof of concept study with randomization between treatment groups: cannabis, oxycodone or cannabis/oxycodone combination—the SPIRAL study
Authors: van Dam Cornelis Jan , van Velzen Monique , Kramers Cornelis , Schellekens Arnt , Olofsen Erik , Niesters Marieke , Dahan Albert
Published: January 2023

Background

Opioids continue to be widely prescribed for chronic noncancer pain, despite the awareness that opioids provide only short-time pain relief, lead to dose accumulation, have numerous adverse effects, and are difficult to wean. As an alternative, we previously showed advantages of using pharmaceutical-grade cannabis in a population of chronic pain patients with fibromyalgia. It remains unknown whether combining an opioid with pharmaceutical-grade cannabis has advantages, such as fewer side effects from lesser opioid consumption in chronic pain.

Methods

Trial design: a single-center, randomized, three-arm, open-label, exploratory trial.

Trial population: 60 patients with fibromyalgia according to the 2010 definition of the American College of Rheumatologists.

Intervention: Patients will be randomized to receive up to 4 daily 5 mg oral oxycodone sustained release (SR) tablet, up to 5 times 150 mg inhaled cannabis (Bediol®, containing 6.3% Δ9-tetrahydrocannabinol and 8% cannabidiol), or the combination of both treatments. Treatment is aimed at self-titration with the daily maximum doses given. Treatment will continue for 6 weeks, after which there is a 6-week follow-up period.

Main trial endpoint: The number of side effects observed during the course of treatment using a composite adverse effect score that includes the following 10 symptoms: dizziness (when getting up), sleepiness, insomnia, headache, nausea, vomiting, constipation, drug high, hallucinations, and paranoia.

Secondary and tertiary endpoints include pain relief and number of oxycodone doses and cannabis inhalations.

Discussion

The trial is designed to determine whether self-titration of oxycodone and cannabis will reduce side effects in chronic pain patients with fibromyalgia.

Trial registration {2a and 2b}

EU trial register 2019–001861-33, URLhttps://www.clinicaltrialsregister.eu, on July 17, 2019; World Health Organization International Clinical Trials Research Platform NL7902, URLhttps://trialsearch.who.int, on July 26, 2019.
Clinical features and biomarkers of semantic variant primary progressive aphasia with MAPT mutation
Authors: Xu Jing , Xia Yanmin , Meng Meng , Liu Fang , Che Ping , Zhang Yanxin , Wang Ying , Cai Li , Qin Wen , Zhang Nan
Published: January 2023

Background

Semantic variant primary progressive aphasia (svPPA) is generally sporadic, with very few reports of tau pathology caused by MAPT mutations.

Methods

A 64-year-old man was diagnosed with svPPA with MAPT P301L mutation. Clinical information, cognitive and language functions, multimodal magnetic resonance imaging (MRI), blood biomarkers, fluorodeoxyglucose (FDG) imaging and tau positron emission tomography (PET) were obtained.

Results

Semantic memory impairment was the earliest and most prominent symptom in this family. Tau accumulation and hypometabolism were observed prior to brain atrophy in mutation carriers. Plasma NfL and GFAP concentrations were elevated in the two svPPA patients. Some relative decreases and some relative increases in regional cerebral blood flow (CBF) as measured by arterial spin labelling (ASL) were observed in mutation carriers compared to noncarriers.

Conclusions

This study describes a large svPPA-affected family with the MAPT P301L mutation and provides an ideal model for inferring underlying pathology and pathophysiological processes in svPPA caused by tauopathies.
A comparison of international modelling methods to evaluate health economics of colorectal cancer screening: a systematic review protocol
Authors: Adair Olivia , McFerran Ethna , Owen Tracy , McKee Christine , Lamrock Felicity , Lawler Mark
Published: January 2023

Background

Colorectal cancer (CRC) is becoming an increasing health problem worldwide. However, with the help of screening, early diagnosis can reduce incidence and mortality rates. To elevate the economic burden that CRC can cause, cost-effectiveness analysis (CEA) can assist healthcare systems to make screening programmes more cost-effective and prolong survival for early-stage CRC patients. This review aims to identify different CEA modelling methods used internationally to evaluate health economics of CRC screening.

Methods

This review will systematically search electronic databases which include MEDLINE, EMBASE, Web of Science and Scopus. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidance recommendations will design the review, and the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement will be used to extract relevant data from studies retrieved. Two reviewers will screen through the evidence using the PICOS (Participant, Intervention, Comparators, Outcomes, Study Design) framework, with a third reviewer to settle any disagreements. Once data extraction and quality assessment are complete, the results will be presented qualitatively and tabulated using the CHEERS checklist.

Discussion

The results obtained from the systematic review will highlight how different CRC screening programmes around the world utilise and incorporate health economic modelling methods to be more cost-effective. This information can help modellers develop CEA models which can be adapted to suit the specific screening programmes that they are evaluating.

Systematic review registration

PROSPERO CRD42022296113
Effects of low-level laser therapy on orthodontic miniscrew stability: a systematic review
Authors: Zheng De-Hua , Hou Feng-Chun , Zang Yan-Jun , Li Bing
Published: January 2023

Background

Miniscrews as auxiliary anchorage devices in orthodontic treatment have definite advantages and efficacy. The aim of the present study was to investigate the scientific evidence including randomized controlled trials (RCTs) or controlled clinical trials (CCTs) to support the application of low-level laser therapy to improve miniscrews stability in orthodontic treatment.

Methods

An extensive literature research was conducted with the Cochrane Library, PubMed, EMBASE, Web of Science and ScienceDirect without language limitations. All searches were inclusive until June 2020. The Cochrane Risk of Bias Tool was used to assess the risk of bias (RoB) in the included RCTs.

Results

Through the electronic searches, 428 titles and abstracts were identified. From these, 4 articles were retrieved for review, and 3 of these met the inclusion criteria. Two RCTs reported increased miniscrews stability with low-intensity laser therapy, but the other one reported no difference. Except one study assessed as “high risk of bias” the other two were rated as “low risk of bias”.

Conclusion

There is insufficient evidence to support or refute the effectiveness of LLLT for improvement of miniscrew stability. Further studies with a better study design, reliable evaluation method, comprehensive evaluation intervals and appropriate loading protocol are required to provide more reliable evidence for the clinical application of LLLT.
Current advances and challenges in CAR T-Cell therapy for solid tumors: tumor-associated antigens and the tumor microenvironment
Authors: Yan Ting , Zhu Lingfeng , Chen Jin
Published: January 2023

The past decade has witnessed ongoing progress in immune therapy to ameliorate human health. As an emerging technique, chimeric antigen receptor (CAR) T-cell therapy has the advantages of specific killing of cancer cells, a high remission rate of cancer-induced symptoms, rapid tumor eradication, and long-lasting tumor immunity, opening a new window for tumor treatment. However, challenges remain in CAR T-cell therapy for solid tumors due to target diversity, tumor heterogeneity, and the complex microenvironment. In this review, we have outlined the development of the CAR T-cell technique, summarized the current advances in tumor-associated antigens (TAAs), and highlighted the importance of tumor-specific antigens (TSAs) or neoantigens for solid tumors. We also addressed the challenge of the TAA binding domain in CARs to overcome off-tumor toxicity. Moreover, we illustrated the dominant tumor microenvironment (TME)-induced challenges and new strategies based on TME-associated antigens (TMAs) for solid tumor CAR T-cell therapy.
Depletion of polyfunctional CD26highCD8+ T cells repertoire in chronic lymphocytic leukemia
Authors: Bozorgmehr Najmeh , Hnatiuk Mark , Peters Anthea C. , Elahi Shokrollah
Published: January 2023

Background

CD8+ T cells play an essential role against tumors but the role of human CD8+CD26+ T cell subset against tumors, in particular, haematological cancers such as chronic lymphocytic leukemia (CLL) remains unknown. Although CD4+CD26highT cells are considered for adoptive cancer immunotherapy, the role of CD8+CD26+T cells is ill-defined. Therefore, further studies are required to better determine the role of CD8+CD26+T cells in solid tumors and haematological cancers.

Methods

We studied 55 CLL and 44 age-sex-matched healthy controls (HCs). The expression of CD26 on different T cell subsets (e.g. naïve, memory, effector, and etc.) was analyzed. Also, functional properties of CD8+CD26+and CD8+CD26−T cells were evaluated. Finally, the plasma cytokine/chemokine and Galectin-9 (Gal-9) levels were examined.

Results

CD26 expression identifies three CD8+T cell subsets with distinct immunological properties. While CD26negCD8+T cells are mainly transitional, effector memory and effectors, CD26lowCD8+T cells are mainly naïve, stem cell, and central memory but CD26high T cells are differentiated to transitional and effector memory. CD26+CD8+T cells are significantly reduced in CLL patients versus HCs. CD26high cells are enriched with Mucosal Associated Invariant T (MAIT) cells co-expressing CD161TVα7.2 and IL-18Rα. Also, CD26highcells have a rich chemokine receptor profile (e.g. CCR5 and CCR6), profound cytokine (TNF-α, IFN-γ, and IL-2), and cytolytic molecules (Granzyme B, K, and perforin) expression upon stimulation. CD26highand CD26lowT cells exhibit significantly lower frequencies of CD160, 2B4, TIGIT, ICOS, CD39, and PD-1 but higher levels of CD27, CD28, and CD73 versus CD26negcells. To understand the mechanism linked to CD26highdepletion, we found that malignant B cells by shedding Galectin-9 (Gal-9) contribute to the elevation of plasma Gal-9 in CLL patients. In turn, Gal-9 and the inflammatory milieu (IL-18, IL-12, and IL-15) in CLL patients contribute to increased apoptosis of CD26highT cells.

Conclusions

Our results demonstrate that CD26+ T cells possess a natural polyfunctionality to traffic and exhibit effector functions and resist exhaustion. Therefore, they can be proposed for adoptive cancer immunotherapy. Finally, neutralizing and/or inhibiting Gal-9 may preserve CD26highCD8+T cells in CLL.
Lack of a protective effect of the Tmem106b “protective SNP” in the Grn knockout mouse model for frontotemporal lobar degeneration
Authors: Cabron Anne-Sophie , Borgmeyer Uwe , Richter Julia , Peisker Helga , Gutbrod Katharina , Dörmann Peter , Capell Anja , Damme Markus
Published: January 2023

Genetic variants in TMEM106B are a common risk factor for frontotemporal lobar degeneration and the most important modifier of disease risk in patients with progranulin (GRN) mutations (FTLD-GRN). TMEM106B is encoding a lysosomal transmembrane protein of unknown molecular function. How it mediates its disease-modifying function remains enigmatic. Several TMEM106B single nucleotide polymorphisms (SNPs) are significantly associated with disease risk in FTLD-GRN carriers, of which all except one are within intronic sequences of TMEM106B. Of note, the non-coding SNPs are in high linkage disequilibrium with the coding SNP rs3173615 located in exon six of TMEM106B, resulting in a threonine to serine change at amino acid 185 in the minor allele, which is protective in FTLD-GRN carriers. To investigate the functional consequences of this variant in vivo, we generated and characterized a knockin mouse model harboring the Tmem106bT186S variant. We analyzed the effect of this protective variant on FTLD pathology by crossing Tmem106bT186S mice with Grn−/− knockout mice, a model for GRN-mediated FTLD. We did not observe the amelioration of any of the investigated Grn−/− knockout phenotypes, including transcriptomic changes, lipid alterations, or microgliosis in Tmem106bT186S/T186S × Grn−/− mice, indicating that the Tmem106bT186S variant is not protective in the Grn−/− knockout mouse model. These data suggest that effects of the associated SNPs not directly linked to the amino acid exchange in TMEM106B are critical for the modifying effect.
Comparison of the effect of Triticum Vulgare and Hyperici Oleum on healing in traumatic membrane perforation: an animal study
Authors: Bora Adem , Durmuş Kasım , İnan Zeynep D.Şahin , Demirkıran Berat Baturay , Altuntas Emine E.
Published: January 2023

Background

Traumatic tympanic membrane (TM) perforations usually heal spontaneously. The aim of this study was to investigate whether the topical application of Triticum Vulgare (TV) in experimentally induced traumatic TM perforations in the rats has a positive effect on wound healing process.

Methods

The rats were randomly assigned to four experimental groups. Drugs were introduced twice a day for 7 days. On the 7th day, specimens were sent for histological examination.

Results

Mean values found in group NC in terms of epithelial regeneration mean scores are as follows: fibroblast and collagen density, neovascularization, and density of inflammation cells were lower than all groups (p < 0.05).

It was found that reepithelization on the post-perforation 7th day was better in the HO group than the TV group. In terms of the subepithelial fibroblast cells, density of collagen fibers, formation of new veins, and inflammatory cell accumulation, it was observed that the group TV was better than the group HO.

Conclusion

This is the first study investigating the potential curative role of TV in an experimental rat model of tympanic membrane perforation. Considering these findings, it is concluded that TV can be more effective than HO on wound healing in TM perforation.
A longitudinal epigenome-wide association study of preeclamptic and normotensive pregnancy
Authors: Liu Shuwei , Fu Haoyi , Ray Mitali , Heinsberg Lacey W. , Conley Yvette P. , Anderson Cindy M. , Hubel Carl A. , Roberts James M. , Jeyabalan Arun , Weeks Daniel E. , Schmella Mandy J.
Published: January 2023

Background

While preeclampsia (PE) is a leading cause of pregnancy-related morbidity/mortality, its underlying mechanisms are not fully understood. DNA methylation (DNAm) is a dynamic regulator of gene expression that may offer insight into PE pathophysiology and/or serve as a biomarker (e.g., risk, subtype, a therapeutic response). This study’s purpose was to evaluate for differences in blood-based DNAm across all trimesters between individuals eventually diagnosed with PE (cases) and individuals who remained normotensive throughout pregnancy, did not develop proteinuria, and birthed a normally grown infant (controls).

Results

In the discovery phase, longitudinal, genome-wide DNAm data were generated across three trimesters of pregnancy in 56 participants (n=28 cases,n=28 controls) individually matched on self-identified race, pre-pregnancy body mass index, smoking, and gestational age at sample collection. An epigenome-wide association study (EWAS) was conducted, using surrogate variable analysis to account for unwanted sources of variation. No CpGs met the genome-wide significancepvalue threshold of 9×10-8, but 16 CpGs (trimester 1: 5; trimester 2: 1; trimester 3: 10) met the suggestive significance threshold of 1×10-5. DNAm data were also evaluated for differentially methylated regions (DMRs) by PE status. Three DMRs in each trimester were significant after Bonferonni-adjustment. Since only third-trimester samples were available from an independent replication sample (n=64 cases,n=50 controls), the top suggestive hits from trimester 3 (cg16155413 and cg21882990 associated withTRAF3IP2-AS1/TRAF3IP2genes, which also made up the top DMR) were carried forward for replication. During replication, DNAm data were also generated for validation purposes from discovery phase third trimester samples. While significant associations between DNAm and PE status were observed at both sites in the validation sample, no associations between DNAm and PE status were observed in the independent replication sample.

Conclusions

The discovery phase findings for cg16155413/cg21882990 (TRAF3IP2-AS1/TRAF3IP2) were validated with a new platform but were not replicated in an independent sample. Given the differences in participant characteristics between the discovery and replication samples, we cannot rule out important signals for these CpGs. Additional research is warranted for cg16155413/cg21882990, as well as top hits in trimesters 1–2 and significant DMRs that were not examined in the replication phase.
Partial agonists of dopamine receptors: clinical effects and dopamine receptor interactions in combining aripiprazole with a full antagonist in treating psychosis
Authors: Cookson John , Pimm Jonathan , Reynolds Gavin
Published: January 2023

Partial agonists of dopamine receptors are used in combination with full antagonists in treating psychosis, either to mitigate side-effects or in the hope of increasing effectiveness. We examine how combinations may affect the occupancy of D2/D3dopamine receptors and explore how these can explain the outcomes in the light of the dopamine hypothesis of psychosis. The combinations considered here are from published studies combining aripiprazole with amisulpride, with risperidone in people with hyperprolactinaemia and with olanzapine to mitigate weight gain. We discuss possible worsening of symptoms by the addition of a partial agonist or switching. We also examine the potentially adverse interaction with a full antagonist such as haloperidol given during a subsequent relapse to control severe agitation.