bluuebunny/crossref_metadata_2025 huggingface dataset:
Lentivirus-mediated downregulation of α-synuclein reduces neuroinflammation and promotes functional recovery in rats with spinal cord injury
Authors: Zeng Hong , Liu Nan , Yang Yan-yan , Xing Hua-yi , Liu Xiao-xie , Li Fang , La Gao-yan , Huang Meng-jie , Zhou Mou-wang
Published: December 2019

Background

The prognosis of spinal cord injury (SCI) is closely related to secondary injury, which is dominated by neuroinflammation. There is evidence that α-synuclein aggregates after SCI and that inhibition of α-synuclein aggregation can improve the survival of neurons after SCI, but the mechanism is still unclear. This study was designed to investigate the effects of α-synuclein on neuroinflammation after SCI and to determine the underlying mechanisms.

Method

A T3 spinal cord contusion model was established in adult male Sprague-Dawley rats. An SNCA-shRNA-carrying lentivirus (LV-SNCA-shRNA) was injected into the injury site to block the expression of α-synuclein (forming the SCI+KD group), and the SCI and sham groups were injected with an empty vector. Basso-Beattie-Bresnahan (BBB) behavioural scores and footprint analysis were used to detect motor function. Inflammatory infiltration and myelin loss were measured in the spinal cord tissues of each group by haematoxylin-eosin (HE) and Luxol Fast Blue (LFB) staining, respectively. Immunohistochemistry, Western blot analysis, and RT-qPCR were used to analyse protein expression and transcription levels in the tissues. Immunofluorescence was used to determine the morphology and function of glial cells and the expression of matrix metalloproteinase-9 in the central canal of the spinal cord. Finally, peripheral serum cytokine levels were determined by enzyme-linked immunosorbent assay.

Results

Compared with the SCI group, the SCI+KD group exhibited reduced inflammatory infiltration, preserved myelin, and functional recovery. Specifically, the early arrest of α-synuclein inhibited the pro-inflammatory factors IL-1β, TNF-α, and IL-2 and increased the expression of the anti-inflammatory factors IL-10, TGF-β, and IL-4. The neuroinflammatory response was regulated by reduced proliferation of Iba1+ microglia/macrophages and promotion of the shift of M1-polarized Iba1+/iNOS+ microglia/macrophages to M2-polarized Iba1+/Arg1+ microglia/macrophages after injury. In addition, compared with the SCI group, the SCI+KD group also exhibited a smaller microglia/astrocyte (Iba1/GFAP) immunostaining area in the central canal, lower MMP-9 expression, and improved cerebrospinal barrier function.

Conclusion

Lentivirus-mediated downregulation of α-synuclein reduces neuroinflammation, improves blood-cerebrospinal barrier function, promotes functional recovery, reduces microglial activation, and promotes the polarization of M1 microglia/macrophages to an M2 phenotype to confer a neuroprotective immune microenvironment in rats with SCI.
Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events
Authors: Weekman Erica M. , Sudduth Tiffany L. , Price Brittani R. , Woolums Abigail E. , Hawthorne Danielle , Seaks Charles E. , Wilcock Donna M.
Published: December 2019

Background

Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind only Alzheimer’s disease (AD); however, VCID is commonly found as a co-morbidity with sporadic AD. We have previously established a mouse model of VCID by inducing hyperhomocysteinemia in both wild-type and amyloid depositing mice. While we have shown the time course of neuropathological events in the wild-type mice with hyperhomocysteinemia, the effect of amyloid deposition on this time course remains unknown; therefore, in this study, we determined the time course of neuropathological changes in our mouse model of hyperhomocysteinemia-induced VCID in amyloid depositing mice.

Methods

APP/PS1 mice were placed on either a diet deficient in folate and vitamins B6 and B12 and enriched in methionine to induce hyperhomocysteinemia or a control diet for 2, 6, 10, 14, or 18 weeks. Immunohistochemistry and gene expression analysis were used to determine neuroinflammatory changes. Microhemorrhages and amyloid deposition were analyzed using histology and, finally, behavior was assessed using the 2-day radial arm water maze.

Results

Neuroinflammation, specifically a pro-inflammatory phenotype, was the first pathological change to occur. Specifically, we see a significant increase in gene expression of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and interleukin 12a by 6 weeks. This was followed by cognitive deficits starting at 10 weeks. Finally, there is a significant increase in the number of microhemorrhages at 14 weeks on diet as well as redistribution of amyloid from the parenchyma to the vasculature.

Conclusions

The time course of these pathologies points to neuroinflammation as the initial, key player in homocysteine-induced VCID co-morbid with amyloid deposition and provides a possible therapeutic target and time points.
CoQ10 enhances PGC1α and increases expression of mitochondrial antioxidant proteins in chronically ischemic swine myocardium
Authors: Hocum Stone Laura , Chappuis Erin , Wright Christin , Kelly Rosemary F. , McFalls Edward O.
Published: December 2019

Background

Expression of mitochondrial proteins is reduced within hibernating myocardium (HM). It is unclear whether dietary supplementation with CoQ10 can increase expression of mitochondrial electron transport chain (ETC) and antioxidant proteins within this tissue. In a swine model of HM, we tested whether dietary administration of CoQ10 for four weeks enhances the expression of ETC and antioxidant proteins within the mitochondria via increased PGC1α signaling.

Methods

12 swine were instrumented with a fixed constrictor around the LAD artery to induce gradual stenosis. At three months, transthoracic ECHO was performed to confirm the presence of a wall motion abnormality in the anterior wall. Animals were then randomly assigned to receive daily dietary supplements of either CoQ10 (10 mg/kg/day) or placebo for four weeks. At this time, animals underwent a final ECHO and terminal procedure. Expression of nuclear-bound PGC1α (Western blots) and mitochondrial proteins (Tandem Mass Tag) were determined.

Results

Mitochondrial and nuclear membranes were isolated from the LAD region. Nuclear-bound PGC1α levels were > 200-fold higher with administration of four weeks of CoQ10 treatment (p = 0.016). Expression of ETC proteins was increased in those animals that received CoQ10. Compared with mitochondria in the LAD region from placebo-treated pigs, CoQ10-treated pigs had higher levels of Complex I (p = 0.03), Complex IV (p = 0.04) and Complex V (p = 0.028) peptides.

Conclusions

Four weeks of dietary CoQ10 in HM pigs enhances active, nuclear-bound PGC1α and increases the expression of ETC proteins within mitochondria of HM tissue.
Novel rotatable tabletop for total-body irradiation using a linac-based VMAT technique
Authors: Losert Christoph , Shpani Roel , Kießling Robert , Freislederer Philipp , Li Minglun , Walter Franziska , Niyazi Maximilian , Reiner Michael , Belka Claus , Corradini Stefanie
Published: December 2019

Background

Volumetric Modulated Arc Therapy (VMAT) techniques have recently been implemented in clinical practice for total-body irradiation (TBI). To date, most techniques still use special couches, translational tables, or other self-made immobilization devices for dose delivery. Aim of the present study was to report the first results of a newly developed rotatable tabletop designed for VMAT-TBI.

Methods

The VMAT-TBI technique theoretically allows the use of any standard positioning device at the linear accelerator. Nevertheless, the main problem is that patients taller than 120 cm cannot be treated in one position due to the limited cranial-caudal couch shift capacities of the linac. Therefore, patients are usually turned from a head-first supine position (HFS) to a feet-first supine position (FFS) to overcome this limitation. The newly developed rotatable tabletop consists completely of carbon fiber, including the ball bearing within the base plate of the rotation unit. The patient can be turned 180° from a HFS to a FFS position within a few seconds, without the need of repositioning.

Results

The first 20 patients had a median age of 47 years, and received TBI before bone marrow transplantation for acute myeloid leukemia. Most patients (13/20) received a TBI dose of 4 Gy in 2 fractions, twice daily. The mean number of applied monitor units (MU) was 6476 MU using a multi-arcs and multi-isocenter VMAT-TBI technique.

The tabletop has been successfully used in daily clinical practice and helped to keep the treatment times at an acceptable level. During the first treatment fraction, the mean overall treatment time (OTT) was 57 min. Since no additional image guidance was used in fraction 2 of the same day, the OTT was reduced to mean 38 min.

Conclusions

The easy and reproducible rotation of the patient on the treatment couch using the rotatable tabletop, is time-efficient and overcomes the need of repositioning the patient after turning from a HFS to a FFS position during VMAT TBI. Furthermore, it prevents couch-gantry collisions, incorrect isocenter shifts and beam mix-up due to predicted absolute table coordinates, which are recorded to the R + V system with the corresponding beams.
Frailty and functional decline after emergency abdominal surgery in the elderly: a prospective cohort study
Authors: Tan Hwee Leong , Chia Shermain Theng Xin , Nadkarni Nivedita Vikas , Ang Shin Yuh , Seow Dennis Chuen Chai , Wong Ting Hway
Published: December 2019

Background

Frailty has been associated with an increased risk of adverse postoperative outcomes in elderly patients. We examined the impact of preoperative frailty on loss of functional independence following emergency abdominal surgery in the elderly.

Methods

This prospective cohort study was performed at a tertiary hospital, enrolling patients 65 years of age and above who underwent emergency abdominal surgery from June 2016 to February 2018. Premorbid variables, perioperative characteristics and outcomes were collected. Two frailty measures were compared in this study—the Modified Fried’s Frailty Criteria (mFFC) and Modified Frailty Index-11 (mFI-11). Patients were followed-up for 1 year.

Results

A total of 109 patients were prospectively recruited. At baseline, 101 (92.7%) were functionally independent, of whom seven (6.9%) had loss of independence at 1 year; 28 (25.7%) and 81 (74.3%) patients were frail and non-frail (by mFFC) respectively. On univariate analysis, age, Charlson Comorbidity Index and frailty (mFFC) (univariate OR 13.00, 95% CI 2.21–76.63, p < 0.01) were significantly associated with loss of functional independence at 1 year. However, frailty, as assessed by mFI-11, showed a weaker correlation than mFFC (univariate OR 4.42, 95% CI 0.84–23.12, p = 0.06). On multivariable analysis, only premorbid frailty (by mFFC) remained statistically significant (OR 15.63, 95% CI 2.12–111.11, p < 0.01).

Conclusions

The mFFC is useful for frailty screening amongst elderly patients undergoing emergency abdominal surgery and is a predictor for loss of functional independence at 1 year. Including the risk of loss of functional independence in perioperative discussions with patients and caregivers is important for patient-centric emergency surgical care. Early recognition of this at-risk group could help with discharge planning and priority for post-discharge support should be considered.
Prediction of time to prosthesis implantation as a function of joint anatomy in patients with developmental dysplasia of the hip
Authors: Müller Michael , Rakow Anasthasia , Wassilew Georgi I. , Winkler Tobias , Perka Carsten
Published: December 2019

Background

Developmental dysplasia of the hip (DDH) can lead to pain and premature secondary osteoarthritis at an early stage. Joint-preserving osteotomy is an established solution to this problem. In contrast, a conservative approach would result in pain persistence, ultimately raising the patients question for a possible date of expected prosthesis implantation.

The aim of the study was to identify the relationship between the dysplastic hip anatomy and the time of prosthesis implantation in order to enable prognostic predictions in younger patients with symptomatic DDH.

Materials and methods

Data from 129 hips who received THA due to secondary DDH osteoarthritis were evaluated. The preoperative hip anatomy was evaluated for AI and LCE angle. Multiple linear regression analyses were then used to correlate the influence of these parameters with the patient’s age at the time of surgery. In addition, a graphical relationship was derived by the method of power least squares curve fitting with second-degree polynomials.

Results

The mean age for THA was 54.3 ± 11 years. The time of surgery correlated significantly with LCE (0.37) and AI (− 0.3) (p < 0.001). The mean age of patients with LCE angle ≤ 10° was 41.9 ± 14.0 years, for LCE 11–20° 52.7 ± 9.5 years, and for LCE 21–30° 57.0 ± 10.3 years. The following formula could then be determined for the calculation of the potential patient age at the time of THA as a function of LCE angle: age pTHA = 40.2 + 0.8 × LCE angle − 0.01 × (LCE angle)2.

Conclusion

A significant correlation between the extent of dysplasia and the time of prosthesis implantation was identified. In particular, the LCE and the AI correlated strongly with the time of implantation. The more dysplastic the angles were, the sooner the THA was necessary. Using the calculations presented in this study, the probable age of prosthesis implantation can be prognosticated and included in a counseling session about treatment options for DDH.
Below-elbow or above-elbow cast for conservative treatment of extra-articular distal radius fractures with dorsal displacement: a prospective randomized trial
Authors: Caruso Gaetano , Tonon Francesco , Gildone Alessandro , Andreotti Mattia , Altavilla Roberto , Valentini Alessandra , Valpiani Giorgia , Massari Leo
Published: December 2019

Background

Distal radial fractures are common traumatic injuries, but their management remains controversial also in case of conservative treatment regarding the type of immobilisation. Hence, we conducted a two-arm, parallel-group, prospective randomised trial to compare the capacity of long casts (above-elbow) and short casts (below-elbow) to maintain the reduction of extra-articular distal radius fractures with dorsal displacement (AO/OTA classification: 2R3A2.2).

Methods

Seventy-four eligible patients with AO/OTA 2R3A2.2 fractures treated with closed reduction and cast immobilisation were randomised to the long cast group (n°= 37) or to the short cast group (n°= 37). Baseline radiological parameters, radial inclination (RI), radial height (RH), ulnar variance (UV) and palmar tilt (PT) were taken, and compared with clinical (DASH, Mayo Wrist and Mayo Elbow) and radiological scores taken at 7–10 days, 4 weeks and 12 weeks. Furthermore, to evaluate correlations between radiological parameters and functional outcomes, patients were divided into two groups according to whether or not their radiological parameters at Follow-ups 2 and 3 were acceptable, i.e. within the range 11–12 mm for RH, 16°–28° for RI, − 4–+ 2 mm for UV and 0°–22° for PT.

Results

Patient demographic and baseline radiological parameters were similar between groups. At follow-up, there were no statistically significant differences between the two types of cast in terms of RI, RH, UV or PT, or Mayo wrist or DASH scores. Short cast group patients displayed better Mayo elbow score at follow-up 2 (4 weeks), but this difference was no longer statistically significant at follow-up 3 (12 weeks). No statistically significant differences in clinical outcomes were found between patients who presented acceptable radiographic parameters at follow-up and those who did not.

Conclusion

As there were no significant differences between short casts and long casts in terms of fracture reduction maintenance or clinical outcomes, short casts are an effective method of post-reduction immobilisation in AO/OTA 2R3A2.2 fracture of the radius. Radiological parameters outside the range conventionally considered acceptable do not preclude a satisfactory clinical outcome.

Trial registration

ClinicalTrials.gov PRS, NCT04062110. Registred 20 August 2019.
The factors driving self-efficacy in intractable chronic pain patients: a retrospective study
Authors: Tsuji Hironori , Tetsunaga Tomoko , Tetsunaga Tomonori , Nishida Keiichiro , Misawa Haruo , Ozaki Toshifumi
Published: December 2019

Background

The fear-avoidance model is a theoretical paradigm for explaining acute and chronic pain. In this model, pain catastrophizing plays an important role. On the other hand, self-efficacy influences whether patients view their pain optimistically, ultimately preventing the conversion of pain into intractable pain. The aim of the present study was to evaluate the factors that influence self-efficacy in patients with chronic pain.

Methods

Study participants included 147 outpatients (35 men, 112 women) with intractable chronic pain who visited our hospital between September 2014 and July 2015. Their mean age was 71.0 (range 32–92) years. Pain sites were as follows: low back, 97 patients; knee, 71 patients; shoulder, 34 patients; and hip, 15 patients. All patients were assessed using the following measures: Numeric Rating Scale (NRS), Pain Catastrophizing Scale (PCS), Hospital Anxiety and Depression Scale (HADS), Pain Disability Assessment Scale (PDAS), and Pain Self-Efficacy Questionnaire (PSEQ). All participants were further divided into two groups based on median PSEQ scores (group L: PSEQ of 35 points or less, n = 74; group H: PSEQ greater than 35 points, n = 73). The factors that influenced self-efficacy in these patients were analyzed using univariate and multiple linear regression analyses.

Results

Significant differences were observed in gender; pain duration; and NRS, PDAS, HADS, and PCS scores between group L and group H. Multiple linear regression analysis revealed that self-efficacy was correlated with PDAS score, HADS depression score, and pain duration.

Conclusions

Patients with longer pain duration indicated greater self-efficacy and patients with higher pain disability and depression exhibited lower self-efficacy.
Comparison of the operative time for open door laminoplasty using titanium plate spacers or hydroxyapatite block spacers: a retrospective study
Authors: Inui Takahiro , Inokuchi Koichi , Watanabe Yoshinobu , Matsui Kentaro , Nakayama Yuhei , Ishii Keisuke , Suzuki Takashi , Kurozumi Taketo , Kawano Hirotaka
Published: December 2019

Background

Titanium plate (TP) and hydroxyapatite (HA) spacers are widely used during open-door laminoplasty, performed with the patient in a prone position. Reducing operative time is an important consideration, particularly to reduce the risk of postoperative complications in older patients. The purpose of this retrospective cohort study was to compare the operative time for open-door laminoplasty using TP or HA spacers.

Methods

Consecutive patients with a spinal cord injury, without bone injury, and ≥ 50 years of age were included. Multivariate regression analysis was used to compare the operative time between patients in the TP and HA group, adjusting for known factors that can influence surgical and postoperative outcomes. Propensity score matching was used to confirm the robustness of the primary outcome. The cumulative incidence of postoperative complications over 1-year after surgery was also compared.

Results

Of the 164 patients forming our study group, TP spacers were used in 62 and HA in 102. Operative time was significantly shorter for the TP (128 min) than HA (158 min) group (p < 0.001). Both multivariate and propensity score matching analyses confirmed a significant reduction in operative time for the TP, compared to HA, group (regression coefficient, − 30 min and − 38 min, p < 0.001 and p < 0.001, respectively). There was no significant difference in the cumulative incidence of postoperative complications.

Conclusions

The use of TP spacers reduced the operative time for cervical open-door laminoplasty by about 30 min, compared to the use of HA spacers, with no difference in the rate of postoperative complications.
Preoperative platelet count, preoperative hemoglobin concentration and deep hypothermic circulatory arrest duration are risk factors for acute kidney injury after pulmonary endarterectomy: a retrospective cohort study
Authors: Zhang Congya , Wang Guyan , Zhou Hui , Lei Guiyu , Yang Lijing , Fang Zhongrong , Shi Sheng , Li Jun , Han Zhiyan , Song Yunhu , Liu Sheng
Published: December 2019

Background

Acute kidney injury (AKI) is a major postoperative morbidity of patients undergoing cardiac surgery and has a negative effect on prognosis. The kidney outcomes after pulmonary endarterectomy (PEA) have not yet been reported; However, several perioperative characteristics of PEA may induce postoperative AKI. The objective of our study was to identify the incidence and risk factors for postoperative AKI and its association with short-term outcomes.

Methods

This was a single-center, retrospective, observational, cohort study. Assessments of AKI diagnosis was executed based on the Kidney Disease Improving Global Outcomes (KDIGO) criteria.

Results

A total of 123 consecutive patients who underwent PEA between 2014 and 2018 were included.

The incidence of postoperative AKI was 45% in the study population. Stage 3 AKI was associated with worse short-term outcomes and 90-day mortality (p < 0.001, p = 0.002, respectively). The independent predictors of postoperative AKI were the preoperative platelet count (OR 0.992; 95%CI 0.984–0.999; P = 0.022), preoperative hemoglobin concentration (OR 0.969; 95%CI 0.946–0.993; P = 0.01) and deep hypothermic circulatory arrest (DHCA) time (OR 1.197; 95%CI 1.052–1.362; P = 0.006) in the multivariate analysis.

Conclusion

The incidence of postoperative AKI was relatively high after PEA compared with other types of cardiothoracic surgeries. The preoperative platelet count, preoperative hemoglobin concentration and DHCA duration were modifiable predictors of AKI, and patients may benefit from some low-risk, low-cost perioperative measures.
Novel phenotypes and genotypes in Antley-Bixler syndrome caused by cytochrome P450 oxidoreductase deficiency: based on the first cohort of Chinese children
Authors: Fan Lijun , Ren Xiaoya , Song Yanning , Su Chang , Fu Junfen , Gong Chunxiu
Published: December 2019

Background

Antley-Bixler syndrome (ABS) caused by P450 oxidoreductase deficiency (PORD) is a congenital adrenal hyperplasia with skeletal malformations and disordered sex development in both sexes. There have been no reports of ABS caused by PORD in Chinese children.

Methods

We described the clinical and genetic characteristics of eight Chinese children with ABS caused by PORD and compared them with those of subjects in previous studies.

Results

Eight patients, aged 6 months–17.8 years, showed strikingly similar craniofacial malformations. We first described four unreported features: lower eyelid fat pads (4/8), prominent lower eyelid-zygoma transverse line (4/8), underdeveloped or absent antihelix (5/8) and single earlobe crease (5/8). Five 46, XY patients presented various degrees of undervirilization, while three 46, XX cases showed masculinization. Basal endocrine measurements revealed the following consistent results: normal cortisol; elevated adrenocorticotropic hormone, progesterone, pregnenolone, 17-hydroxypropgesterone, and corticosterone; and decreased or normal testosterone/oestradiol. We identified three previously reported variants and four novel variants (c.51719_51710delGGCCCCTGTGinsC, p.D210G, p.Y248X and p.R554X) of POR. The most prevalent variant was p.R457H (8/16). The hydrocortisone dosages of patients differed because of variable degrees of adrenal insufficiency.

Conclusions

We described novel phenotypes and genotypes of ABS caused by PORD. The variant p.R457H was the most prevalent in this cohort. All subjects had combined characteristics of 17-hydroxylase and 21-hydroxylase deficiency. Steroid replacement therapy for patients with PORD requires individually tailored dosing.
TNF-α mediated upregulation of NaV1.7 currents in rat dorsal root ganglion neurons is independent of CRMP2 SUMOylation
Authors: de Macedo Flávio Henrique Pequeno , Aires Rosária Dias , Fonseca Esdras Guedes , Ferreira Renata Cristina Mendes , Machado Daniel Portela Dias , Chen Lina , Zhang Fang-Xiong , Souza Ivana A. , Lemos Virgínia Soares , Romero Thiago Roberto Lima , Moutal Aubin , Khanna Rajesh , Zamponi Gerald W. , Cruz Jader S.
Published: December 2019

Clinical and preclinical studies have shown that patients with Diabetic Neuropathy Pain (DNP) present with increased tumor necrosis factor alpha (TNF-α) serum concentration, whereas studies with diabetic animals have shown that TNF-α induces an increase in NaV1.7 sodium channel expression. This is expected to result in sensitization of nociceptor neuron terminals, and therefore the development of DNP. For further study of this mechanism, dissociated dorsal root ganglion (DRG) neurons were exposed to TNF-α for 6 h, at a concentration equivalent to that measured in STZ-induced diabetic rats that developed hyperalgesia. Tetrodotoxin sensitive (TTXs), resistant (TTXr) and total sodium current was studied in these DRG neurons. Total sodium current was also studied in DRG neurons expressing the collapsin response mediator protein 2 (CRMP2) SUMO-incompetent mutant protein (CRMP2-K374A), which causes a significant reduction in NaV1.7 membrane cell expression levels. Our results show that TNF-α exposure increased the density of the total, TTXs and TTXr sodium current in DRG neurons. Furthermore, TNF-α shifted the steady state activation and inactivation curves of the total and TTXs sodium current. DRG neurons expressing the CRMP2-K374A mutant also exhibited total sodium current increases after exposure to TNF-α, indicating that these effects were independent of SUMOylation of CRMP2. In conclusion, TNF-α sensitizes DRG neurons via augmentation of whole cell sodium current. This may underlie the pronociceptive effects of TNF-α and suggests a molecular mechanism responsible for pain hypersensitivity in diabetic neuropathy patients.
Emerging organoid models: leaping forward in cancer research
Authors: Fan Han , Demirci Utkan , Chen Pu
Published: December 2019

Cancer heterogeneity is regarded as the main reason for the failure of conventional cancer therapy. The ability to reconstruct intra- and interpatient heterogeneity in cancer models is crucial for understanding cancer biology as well as for developing personalized anti-cancer therapy. Cancer organoids represent an emerging approach for creating patient-derived in vitro cancer models that closely recapitulate the pathophysiological features of natural tumorigenesis and metastasis. Meanwhile, cancer organoids have recently been utilized in the discovery of personalized anti-cancer therapy and prognostic biomarkers. Further, the synergistic combination of cancer organoids with organ-on-a-chip and 3D bioprinting presents a new avenue in the development of more sophisticated and optimized model systems to recapitulate complex cancer-stroma or multiorgan metastasis. Here, we summarize the recent advances in cancer organoids from a perspective of the in vitro emulation of natural cancer evolution and the applications in personalized cancer theranostics. We also discuss the challenges and trends in reconstructing more comprehensive cancer models for basic and clinical cancer research.
Long-term overall survival and prognostic score predicting survival: the IMPACT study in precision medicine
Authors: Tsimberidou Apostolia-Maria , Hong David S. , Wheler Jennifer J. , Falchook Gerald S. , Janku Filip , Naing Aung , Fu Siqing , Piha-Paul Sarina , Cartwright Carrie , Broaddus Russell R. , Nogueras Gonzalez Graciela M. , Hwu Patrick , Kurzrock Razelle
Published: December 2019

Background

In 2007, we initiated IMPACT, a precision medicine program for patients referred for participation in early-phase clinical trials. We assessed the correlation of factors, including genomically matched therapy, with overall survival (OS).

Patients and methods

We performed molecular profiling (Clinical Laboratory Improvement Amendments) (genes ≤ 182) for patients with lethal/refractory advanced cancers referred to the Phase 1 Clinical Trials Program. Matched therapy, if available, was selected on the basis of genomics. Clinical trials varied over time and included investigational drugs against various targets (single agents or combinations). Patients were followed up for up to 10 years.

Results

Of 3487 patients who underwent tumor molecular profiling, 1307 (37.5%) had ≥ 1 alteration and received therapy (matched, 711; unmatched, 596; median age, 57 years; 39% men). Most common tumors were gastrointestinal, gynecologic, breast, melanoma, and lung. Objective response rates were: matched 16.4%, unmatched 5.4% (p < .0001); objective response plus stable disease ≥ 6 months rates were: matched 35.3% and unmatched 20.3%, (p < .001). Respective median progression-free survival: 4.0 and 2.8 months (p < .0001); OS, 9.3 and 7.3 months; 3-year, 15% versus 7%; 10-year, 6% vs. 1% (p < .0001). Independent factors associated with shorter OS (multivariate analysis) were performance status > 1 (p < .001), liver metastases (p < .001), lactate dehydrogenase levels > upper limit of normal (p < .001), PI3K/AKT/mTOR pathway alterations (p < .001), and non-matched therapy (p < .001). The five independent factors predicting shorter OS were used to design a prognostic score.

Conclusions

Matched targeted therapy was an independent factor predicting longer OS. A score to predict an individual patient’s risk of death is proposed.

Trial registration

ClinicalTrials.gov, NCT00851032, date of registration February 25, 2009.
Impact of a goal-directed factor-based coagulation management on thromboembolic events following major trauma
Authors: Stein Anais L. , Rössler Julian , Braun Julia , Sprengel Kai , Beeler Patrick E. , Spahn Donat R. , Kaserer Alexander , Stein Philipp
Published: December 2019

Background

A factor-based coagulation management following major trauma is recommended as standard of care by the European Trauma Treatment Guidelines. However, concerns about the thromboembolic risk of this approach are still prevalent. Our study therefore aims to assess if such a haemostatic management is associated with an increased risk for thromboembolic events.

Methods

In this retrospective observational study carried out at the University Hospital Zurich we compared two three-year periods before (period 1: 2005–2007) and after (period 2: 2012–2014) implementation of a factor-based coagulation algorithm. We included all adult patients following major trauma primarily admitted to the University Hospital Zurich. Thromboembolic events were defined as a new in-hospital appearance of any peripheral thrombosis, arterial embolism, pulmonary embolism, stroke or myocardial infarction. A logistic regression was performed to investigate the association of thromboembolic events with possible confounders such as age, sex, specific Abbreviated Injury Scale (AIS) subgroups, allogeneic blood products, and the coagulation management.

Results

Out of 1138 patients, 772 met the inclusion criteria: 344 patients in period 1 and 428 patients in period 2. Thromboembolic events were present in 25 patients (7.3%) of period 1 and in 42 patients (9.8%) of period 2 (raw OR 1.39, 95% CI 0.83 to 2.33, p = 0.21). Only AIS extremities (adjusted OR 1.26, 95% CI 1.05 to 1.52, p = 0.015) and exposure to allogeneic blood products (adjusted OR 2.39, 95% CI 1.33 to 4.30, p = 0.004) were independently associated with thromboembolic events in the logistic regression, but the factor-based coagulation management was not (adjusted OR 1.60, 95% CI 0.90–2.86, p = 0.11).

Conclusion

There is no evidence that a goal-directed, factor-based coagulation management is associated with an increased risk for thromboembolic events following major trauma.
A randomised controlled trial of an exercise intervention promoting activity, independence and stability in older adults with mild cognitive impairment and early dementia (PrAISED) - A Protocol
Authors: Bajwa Rupinder K. , Goldberg Sarah E. , Van der Wardt Veronika , Burgon Clare , Di Lorito Claudio , Godfrey Maureen , Dunlop Marianne , Logan Pip , Masud Tahir , Gladman John , Smith Helen , Hood-Moore Vicky , Booth Vicky , Das Nair Roshan , Pollock Kristian , Vedhara Kavita , Edwards Rhiannon Tudor , Jones Carys , Hoare Zoe , Brand Andrew , Harwood Rowan H.
Published: December 2019

Background

People with dementia progressively lose cognitive and functional abilities. Interventions promoting exercise and activity may slow decline. We developed a novel intervention to promote activity and independence and prevent falls in people with mild cognitive impairment (MCI) or early dementia. We successfully undertook a feasibility randomised controlled trial (RCT) to refine the intervention and research delivery. We are now delivering a multi-centred RCT to evaluate its clinical and cost-effectiveness.

Methods

We will recruit 368 people with MCI or early dementia (Montreal Cognitive Assessment score 13–25) and a family member or carer from memory assessment clinics, other community health or social care venues or an online register (the National Institute for Health Research Join Dementia Research). Participants will be randomised to an individually tailored activity and exercise programme delivered using motivational theory to promote adherence and continued engagement, with up to 50 supervised sessions over one year, or a brief falls prevention assessment (control). The intervention will be delivered in participants’ homes by trained physiotherapists, occupational therapists and therapy assistants. We will measure disabilities in activities of daily living, physical activity, balance, cognition, mood, quality of life, falls, carer strain and healthcare and social care use. We will use a mixed methods approach to conduct a process evaluation to assess staff training and delivery of the intervention, and to identify individual- and context-level mechanisms affecting intervention engagement and activity maintenance. We will undertake a health economic evaluation to determine if the intervention is cost-effective.

Discussion

We describe the protocol for a multi-centre RCT that will evaluate the clinical and cost-effectiveness of a therapy programme designed to promote activity and independence amongst people living with dementia.

Trial registration

ISRCTN, ISRCTN15320670. Registered on 4 September 2018.
Testing effectiveness of the revised Cape Town modified early warning and SBAR systems: a pilot pragmatic parallel group randomised controlled trial
Authors: Kyriacos Una , Burger Debora , Jordan Sue
Published: December 2019

Background

Nurses’ recognition of clinical deterioration is crucial for patient survival. Evidence for the effectiveness of modified early warning scores (MEWS) is derived from large observation studies in developed countries.

Methods

We tested the effectiveness of the paper-based Cape Town (CT) MEWS vital signs observation chart and situation-background-assessment-recommendation (SBAR) communication guide. Outcomes were: proportion of appropriate responses to deterioration, differences in recording of clinical parameters and serious adverse events (SAEs) in intervention and control trial arms. Public teaching hospitals for adult patients in Cape Town were randomised to implementation of the CT MEWS/SBAR guide or usual care (observation chart without track-and-trigger information) for 31 days on general medical and surgical wards. Nurses in intervention wards received training, as they had no prior knowledge of early warning systems. Identification and reporting of patient deterioration in intervention and control wards were compared. In the intervention arm, 24 day-shift and 23 night-shift nurses received training. Clinical records were reviewed retrospectively at trial end. Only records of patients who had given signed consent were reviewed.

Results

We recruited two of six CT general hospitals. We consented 363 patients and analysed 292 (80.4%) patient records (n = 150, 51.4% intervention, n = 142, 48.6% control arm). Assistance was summoned for fewer patients with abnormal vital signs in the intervention arm (2/45, 4.4% versus (vs) 11/81, 13.6%, OR 0.29 (0.06–1.39)), particularly low systolic blood pressure. There was a significant difference in recording between trial arms for parameters listed on the MEWS chart but omitted from the standard observations chart: oxygen saturation, level of consciousness, pallor/cyanosis, pain, sweating, wound oozing, pedal pulses, glucose concentration, haemoglobin concentration, and “looks unwell”. SBAR was used twice. There was no statistically significant difference in SAEs (5/150, 3.3% vs 3/143, 2.1% P = 0.72, OR 1.61 (0.38–6.86)).

Conclusions

The revised CT MEWS observations chart improved recording of certain parameters, but did not improve nurses’ ability to identify early signs of clinical deterioration and to summon assistance. Recruitment of only two hospitals and exclusion of patients too ill to consent limits generalisation of results. Further work is needed on educational preparation for the CT MEWS/SBAR and its impact on nurses’ reporting behaviour.

Trial registration

Pan African Clinical Trials Registry, PACTR201406000838118. Registered on 2 June 2014, www.pactr.org.
A counseling intervention to address HIV stigma at entry into antenatal care in Tanzania (Maisha): study protocol for a pilot randomized controlled trial
Authors: Watt Melissa H. , Knippler Elizabeth T. , Minja Linda , Kisigo Godfrey , Knettel Brandon A. , Ngocho James S. , Renju Jenny , Osaki Haika , Mwamba Rimel , Rogathi Jane J. , Mmbaga Blandina T.
Published: December 2019

Background

HIV-related stigma significantly impacts HIV care engagement, including in prevention of mother-to-child transmission of HIV (PMTCT) programs. Maisha is a stigma-based counseling intervention delivered during the first antenatal care (ANC) visit, complementing routine HIV counseling and testing. The goal of Maisha is to promote readiness to initiate and sustain treatment among those who are HIV-positive, and to reduce HIV stigmatizing attitudes among those who test negative.

Methods

A pilot randomized control trial will assess the feasibility and acceptability of delivering Maisha in a clinical setting, and the potential efficacy of the intervention on HIV care engagement outcomes (for HIV-positive participants) and HIV stigma constructs (for all participants). A total of 1000 women and approximately 700 male partners will be recruited from two study clinics in the Moshi municipality of Tanzania. Participants will be enrolled at their first ANC visit, prior to HIV testing. It is estimated that 50 women (5%) will be identified as HIV-positive. Following consent and a baseline survey, participants will be randomly assigned to either the control (standard of care) or the Maisha intervention. The Maisha intervention includes a video and counseling session prior to HIV testing, and two additional counseling sessions if the participant tests positive for HIV or has an established HIV diagnosis. A subset of approximately 500 enrolled participants (all HIV-positive participants, and a random selection of HIV-negative participants who have elevated stigma attitude scores) will complete a follow-up assessment at 3 months. Measures will include health outcomes (care engagement, antiretroviral adherence, depression) and HIV stigma outcomes. Quality assurance data will be collected and the feasibility and acceptability of the intervention will be described. Statistical analysis will examine potential differences between conditions in health outcomes and stigma measures, stratified by HIV status.

Discussion

ANC provides a unique and important entry point to address HIV stigma. Interventions are needed to improve retention in PMTCT care and to improve community attitudes toward people living with HIV. Results of the Maisha pilot trial will be used to generate parameter estimates and potential ranges of values to estimate power for a full cluster-randomized trial in PMTCT settings, with extended follow-up and enhanced adherence measurement using a biomarker.

Trial registration

ClinicalTrials.gov, NCT03600142. Registered on 25 July 2018.
Using an incentive spirometer reduces pulmonary complications in patients with traumatic rib fractures: a randomized controlled trial
Authors: Sum Shao-Kai , Peng Ya-Chuan , Yin Shun-Ying , Huang Pin-Fu , Wang Yao-Chang , Chen Tzu-Ping , Tung Heng-Hsin , Yeh Chi-Hsiao
Published: December 2019

Background

An incentive spirometer (IS) is a mechanical device that promotes lung expansion. It is commonly used to prevent postoperative lung atelectasis and decrease pulmonary complications after cardiac, lung, or abdominal surgery. This study explored its effect on lung function and pulmonary complication rates in patients with rib fractures.

Methods

Between June 2014 and May 2017, 50 adult patients with traumatic rib fractures were prospectively investigated. Patients who were unconscious, had a history of chronic obstructive pulmonary disease or asthma, or an Injury Severity Score (ISS) ≥ 16 were excluded. Patients were randomly divided into a study group (n = 24), who underwent IS therapy, and a control group (n = 26). All patients received the same analgesic protocol. Chest X-rays and pulmonary function tests (PFTs) were performed on the 5th and 7th days after trauma.

Results

The groups were considered demographically homogeneous. The mean age was 55.2 years and 68% were male. Mean pretreatment ISSs and mean number of ribs fractured were not significantly different (8.23 vs. 8.08 and 4 vs. 4, respectively). Of 50 patients, 28 (56%) developed pulmonary complications, which were more prevalent in the control group (80.7% vs. 29.2%; p = 0.001). Altogether, 25 patients had delayed hemothorax, which was more prevalent in the control group (69.2% vs. 29.2%; p = 0.005). Two patients in the control group developed atelectasis, one patient developed pneumothorax, and five patients required thoracostomy. PFT results showed decreased forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) in the control group. Comparing pre- and posttreatment FVC and FEV1, the study group had significantly greater improvements (p < 0.001).

Conclusions

In conclusion, the use of an IS reduced pulmonary complications and improved PFT results in patients with rib fractures. The IS is a cost-effective device for patients with rib fractures and its use has clinical benefits without harmful effects.

Trial registration

ClinicalTrials.gov, NCT04006587. Registered on 3 July 2019.
The effect of co supplementation of omega-3 and vitamin D on cardio metabolic risk factors and psychological distress in reproductive-aged women with prediabetes and hypovitaminosis D: a study protocol for a randomized controlled trial
Authors: Rajabi-Naeeni Masoumeh , Dolatian Mahrokh , Qorbani Mostafa , Vaezi Amir Abbas
Published: December 2019

Background

A prediabetic state is a risk factor for type 2 diabetes. There are no approved drugs to manage prediabetes. Among the supplements routinely used by individuals, vitamin D and omega-3 have been studied to reduce fasting blood sugar. However, their co-supplementation has not been studied in individuals with prediabetes. This randomized controlled trial is designed to determine the effects of these two supplements on fasting blood sugar, other cardio metabolic risk factors, and psychological distress in reproductive-aged women with prediabetes and hypovitaminosis D.

Methods/design

This 2 × 2 factorial, triple-blind, randomized, placebo-controlled, clinical trial will be done on 168 women of reproductive age diagnosed with prediabetes and hypovitaminosis D. Participants will be randomly assigned equally to four groups: (1) 1000 mg omega-3 fatty acid twice a day + vitamin D placebo every two weeks; (2) omega-3 fatty acid placebo twice a day + 50,000 IU vitamin D every two weeks; (3) 1000 mg omega-3 fatty acid twice a day + 50,000 IU vitamin D every two weeks; (4) omega-3 fatty acid placebo twice a day + vitamin D placebo every two weeks for eight weeks. At the beginning, participants will provide a self-reported questionnaire on the sociodemographic characteristics. At baseline and post-intervention visits, physical activity, Depression Anxiety Stress Scale 21 and Pittsburgh Sleep Quality Index, and a three-day food record will be collected for each individual. Blood pressure, weight, height, and waist circumference will also be measured.

At the beginning and at the end, a blood sample will be used for estimating serum glucose indices (fasting blood sugar and insulin, homeostasis model assessment-insulin resistance, homeostasis model assessment-beta cell function), lipids (triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol), and vitamin D status.

Data analysis using Kolmogorov–Smirnov test, paired t-test, one-way analysis of variance, and repeated measures analysis of variance will be conducted through SPSS-24 software.

Discussion

The primary aim of the present trial is to determine the effect of vitamin D and/or omega-3 on glycemic indices, lipid profiles, psychological distress, blood pressure, and anthropometric indices in prediabetic women with hypovitaminosis D. The results from this trial will provide evidence on the efficacy of these two supplements for preventing or delaying the onset of type 2 diabetes in high-risk individuals.

Trial registration

Iran Clinical Trials Registry,IRCT20100130003226N17. Registered on 9 February 2019.