bluuebunny/crossref_metadata_2025 huggingface dataset:
Pancreatic fibrosis, acinar atrophy and chronic inflammation in surgical specimens associated with survival in patients with resectable pancreatic ductal adenocarcinoma
Authors: Korpela Taija , Ristimäki Ari , Udd Marianne , Vuorela Tiina , Mustonen Harri , Haglund Caj , Kylänpää Leena , Seppänen Hanna
Published: January 2022

Background

Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies, is increasing in incidence. However, the stromal reaction pathophysiology and its role in PDAC development remain unknown. We, therefore, investigated the potential role of histological chronic pancreatitis findings and chronic inflammation on surgical PDAC specimens and disease-specific survival (DSS).

Methods

Between 2000 and 2016, we retrospectively enrolled 236 PDAC patients treated with curative-intent pancreatic surgery at Helsinki University Hospital. All pancreatic transection margin slides were re-reviewed and ﻿histological findings were evaluated applying international guidelines.

Results

DSS among patients with no fibrosis, acinar atrophy or chronic inflammation identified on pathology slides was significantly better than DSS among patients with fibrosis, acinar atrophy and chronic inflammation [median survival: 41.8 months, 95% confidence interval (CI) 26.0–57.6 vs. 20.6 months, 95% CI 10.3–30.9; log-rank test p = 0.001]. Multivariate analysis revealed that Ca 19–9 > 37 kU/l [hazard ratio (HR) 1.48, 95% CI 1.02–2.16], lymph node metastases N1–2 (HR 1.71, 95% CI 1.16–2.52), tumor size > 30 mm (HR 1.47, 95% CI 1.04–2.08), the combined effect of fibrosis and acinar atrophy (HR 1.91, 95% CI 1.27–2.88) and the combined effect of fibrosis, acinar atrophy and chronic inflammation (HR 1.63, 95% CI 1.03–2.58) independently served as unfavorable prognostic factors for DSS. However, we observed no significant associations between tumor size (> 30 mm) and the degree of perilobular fibrosis (p = 0.655), intralobular fibrosis (p = 0.587), acinar atrophy (p = 0.584) or chronic inflammation (p = 0.453).

Conclusions

Our results indicate that the pancreatic stroma is associated with PDAC patients’ DSS. Additionally, the more severe the fibrosis, acinar atrophy and chronic inflammation, the worse the impact on DSS, thereby warranting further studies investigating stroma-targeted therapies.
PIONEER-Panc: a platform trial for phase II randomized investigations of new and emerging therapies for localized pancreatic cancer
Authors: Douglas Julia E. , Liu Suyu , Ma Junsheng , Wolff Robert A. , Pant Shubham , Maitra Anirban , Tamm Eric P. , Bhosale Priya , Katz Matthew H. G. , Varadhachary Gauri R. , Koay Eugene J.
Published: January 2022

Background

Personalized and effective treatments for pancreatic ductal adenocarcinoma (PDAC) continue to remain elusive. Novel clinical trial designs that enable continual and rapid evaluation of novel therapeutics are needed. Here, we describe a platform clinical trial to address this unmet need.

Methods

This is a phase II study using a Bayesian platform design to evaluate multiple experimental arms against a control arm in patients with PDAC. We first separate patients into three clinical stage groups of localized PDAC (resectable, borderline resectable, and locally advanced disease), and further divide each stage group based on treatment history (treatment naïve or previously treated). The clinical stage and treatment history therefore define 6 different cohorts, and each cohort has one control arm but may have one or more experimental arms running simultaneously. Within each cohort, adaptive randomization rules are applied and patients will be randomized to either an experimental arm or the control arm accordingly. The experimental arm(s) of each cohort are only compared to the applicable cohort specific control arm. Experimental arms may be added independently to one or more cohorts during the study. Multiple correlative studies for tissue, blood, and imaging are also incorporated.

Discussion

To date, PDAC has been treated as a single disease, despite knowledge that there is substantial heterogeneity in disease presentation and biology. It is recognized that the current approach of single arm phase II trials and traditional phase III randomized studies are not well-suited for more personalized treatment strategies in PDAC. The PIONEER Panc platform clinical trial is designed to overcome these challenges and help advance our treatment strategies for this deadly disease.

Trial registration

This study is approved by the Institutional Review Board (IRB) of MD Anderson Cancer Center, IRB-approved protocol 2020-0075. The PIONEER trial is registered at the US National Institutes of Health (ClinicalTrials.gov) NCT04481204.
The impact of young age (< 40 years) on the outcome of a cohort of patients with primary non-metastatic breast cancer: analysis of 10-year survival of a prospective study
Authors: Bouferraa Youssef , Haibe Yolla , Chedid Andrea , Jabra Elio , Charafeddine Maya , Temraz Sally , Mukherji Deborah , El Saghir Nagi , Shamseddine Ali
Published: January 2022

Background

The role of young age (< 40 years) at diagnosis as an independent risk factor for adverse outcomes in female patients with breast cancer has been highlighted in several studies. In this prospective study, we assessed the difference in 10-year survival between two groups of patients diagnosed with non-metastatic breast cancer based on an age cutoff of 40 years. We also assessed the impact of factors including tumor characteristics, molecular markers and immunohistochemical markers on survival outcomes, highlighting the interaction of those variables with age.

Methods

A total of 119 female patients with newly diagnosed non-metastatic breast cancer were recruited at the American University of Beirut Medical Center (AUBMC) between July 2011 and May 2014. Patients were recruited and divided into 2 age groups (< 40 and ≥ 40 years). In addition to clinical characteristics, we assessed immunohistochemistry including estrogen, progesterone and HER2 receptors, p53, cyclin B1, vascular endothelial growth factor receptor (VEGFR), and ki-67. Germline BRCA mutations were also performed on peripheral blood samples. Patient and tumor characteristics were compared between the age groups. 10-year overall survival (OS) and disease-free survival (DFS) were estimated accordingly. Cox regression analysis was performed in order to assess the effect of the different variables on clinical outcomes.

Results

After a median Follow-up of 96 (13–122) months, the estimated 10-year OS was 98.6% for patients ≥40 as compared to 77.6% in patients < 40 (p = 0.001). A similar trend was found for 10-year DFS reaching 90% for patients ≥40 and 70.4% for those < 40 (p = 0.004). On multivariate analysis for DFS and OS, only younger age (< 40 years), higher stage and triple negative phenotype among other parameters assessed significantly affected the outcome in this cohort.

Conclusion

This prospective study confirms the association between younger age and adverse survival outcomes in patients with non-metastatic breast cancer. Future studies of the whole genome sequences may reveal the genomic basis underlying the clinical differences we have observed.
Prospective study evaluating dynamic changes of cell-free HPV DNA in locoregional viral-associated oropharyngeal cancer treated with induction chemotherapy and response-adaptive treatment
Authors: Rosenberg Ari J. , Izumchenko Evgeny , Pearson Alexander , Gooi Zhen , Blair Elizabeth , Karrison Theodore , Juloori Aditya , Ginat Daniel , Cipriani Nicole , Lingen Mark , Sloane Hillary , Edelstein Daniel L. , Keyser Kirsten , Fredebohm Johannes , Holtrup Frank , Jones Frederick S. , Haraf Daniel , Agrawal Nishant , Vokes Everett E.
Published: January 2022

Background

Human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) has a favorable prognosis which has led to efforts to de-intensify treatment. Response-adaptive de-escalated treatment is promising, however improved biomarkers are needed. Quantitative cell-free HPV-DNA (cfHPV-DNA) in plasma represents an attractive non-invasive biomarker for grading treatment response and post-treatment surveillance. This prospective study evaluates dynamic changes in cfHPV-DNA during induction therapy, definitive (chemo)radiotherapy, and post-treatment surveillance in the context of risk and response-adaptive treatment for HPV + OPC.

Methods

Patients with locoregional HPV + OPC are stratified into two cohorts: High risk (HR) (T4, N3, $$\ge$$
≥
20 pack-year smoking history (PYH), or non-HPV16 subtype); Low risk (LR) (all other patients). All patients receive induction chemotherapy with three cycles of carboplatin and paclitaxel. LR with ≥ 50% response receive treatment on the single-modality arm (minimally-invasive surgery or radiation alone to 50 Gy). HR with ≥ 50% response or LR with ≥ 30% and < 50% response receive treatment on the intermediate de-escalation arm (chemoradiation to 50 Gy with cisplatin). All other patients receive treatment on the regular dose arm with chemoradiation to 70 Gy with concurrent cisplatin. Plasma cfHPV-DNA is assessed during induction, (chemo)radiation, and post-treatment surveillance. The primary endpoint is correlation of quantitative cfHPV-DNA with radiographic response.

Discussion

A de-escalation treatment paradigm that reduces toxicity without compromising survival outcomes is urgently needed for HPV + OPC. Response to induction chemotherapy is predictive and prognostic and can select candidates for de-escalated definitive therapy. Assessment of quantitative cfHPV-DNA in the context of response-adaptive treatment of represents a promising reliable and convenient biomarker-driven strategy to guide personalized treatment in HPV + OPC.

Trial registration

This trial is registered with ClinicalTrials.gov on October 1st, 2020 with Identifier: NCT04572100.
Integration of breast cancer care in a middle-income country: learning from Suandok Breast Cancer Network (SBCN)
Authors: Chitapanarux Imjai , Onchan Wimrak , Wongmaneerung Panchaporn , Somwangprasert Areewan , Bunyoo Nongnuch , Ditsatham Chagkrit , Watcharachan Kirati , Charoentum Chaiyut , Sripan Patumrat , Chumachote Ausreeya , Maneesai Puttachart
Published: January 2022

Background

Breast cancer incidence in Northern Thailand has shown a continuous increase since records began in 1983. In 2002 the urgency of the situation prompted Maharaj Nakorn Chiang Mai Hospital to initiate the Suandok Breast Cancer Network (SBCN).

Methods

The SBCN is a not-for-profit organization in the university hospital which serves as a training and education center and provides highly specialized medical care for patients in Chiang Mai and in 5 provinces of northern Thailand, with the key mission of improving breast cancer care. The short-term goal was to overcome the barriers to engagement with breast cancer and its treatment and the long-term goal was to increase the overall survival rate of breast cancer patients in our region.

Results

We enrolled breast cancer patients treated at Maharaj Nakorn Chiang Mai Hospital between January 2006 and December 2015 and divided into 2 cohorts: 1485 patients who were diagnosed from 2006 to 2009 (cohort 1: early implementation of SBCN) and 2383 patients who were diagnosed from 2010 to 2015 (cohort 2: full implementation of SBCN). Criteria to measure improved cancer waiting time (CWT) would include: time to diagnosis, time to surgery, and time to radiotherapy. The 5-year overall survival (OS) of the cohort 2 was higher than that in cohort 1, at 73.8 (72.0–75.5) compared to 71.5 (69.2–73.7) (p-value = 0.03).

Conclusions

Reasons behind the success of project include the uniformity of care encouragement, service network development and timely access to each step of breast cancer management. The model used in SBCN could be adopted as a learning guide to improve healthcare access and outcome for breast cancer patients in low- to middle-income countries.
Using Belgian pharmacy dispensing data to assess antibiotic use for children in ambulatory care
Authors: Dillen Hannelore , Burvenich Ruben , De Burghgraeve Tine , Verbakel Jan Y.
Published: January 2022

Background

The desired effect of antibiotics is compromised by the rapid escalation of antimicrobial resistance. Children are particularly at high-risk for unnecessary antibiotic prescribing, which is owing to clinicians’ diagnostic uncertainty combined with parents’ concerns and expectations. Recent Belgian data on ambulatory antibiotic prescribing practices for children are currently lacking. Therefore, we aim to analyse different aspects of antibiotic prescriptions for children in ambulatory care.

Methods

Pharmacy dispensing data on antibiotics for systematic use referring from 2010 to 2019 were retrieved from Farmanet, a database of pharmaceutical dispensations in community pharmacies. Population data were obtained from the Belgian statistical office (Statbel). Descriptive statistics were performed in Microsoft Excel. The Mann-Kendall test for trend analysis and the seasplot function for seasonality testing were conducted in R.

Results

The past decade, paediatric antibiotic use and expenditures have relatively decreased in Belgian ambulatory care with 35.5% and 44.3%, respectively. The highest volumes of antibiotics for children are prescribed by GPs working in Walloon region and rural areas, to younger children, and during winter. The most prescribed class of antibiotics for children are the penicillins and the biggest relative reduction in number of packages is seen for the sulfonamides and trimethoprim and quinolone antibacterials.

Conclusions

Paediatric antibiotic use has decreased in Belgian ambulatory care. Further initiatives are needed to promote prudent antibiotic prescribing in ambulatory care.
Time to death among HIV-infected under-five children after initiation of anti-retroviral therapy and its predictors in Oromiya liyu zone, Amhara region, Ethiopia: a retrospective cohort study
Authors: Weldemariam Sintayehu Argaw , Dagnew Zewdu , Tafere Yilkal , Bereka Tefera Marie , Bitewa Yibelu Bazezew
Published: January 2022

Background

Human Immunodeficiency Virus (HIV) is infection which mainly attacks immune system of an individual. Its disease progress is rapid in children and if treatment is not initiated nearly half of infected children will die by the second year of infection. In Ethiopia, nearly twenty four percent of HIV related death is happen to under-five children; however studies done in this specific age group are limited are with poor evidence of predictors.

Objectives

To determine time to death and identify predictors of death in HIV infected under- five children on antiretroviral therapy in Amhara regional state, Oromia ‘liyu’ zone, Northeast Ethiopia, from 2014 to 2019.

Methods

Institution based retrospective follow up study was conducted in 376 under-five HIV- infected children on antiretroviral therapy from January 2014 to December 2019 in health institutions in Oromia Liyu Zone, Amhara region, Ethiopia. Multivariable Cox-proportional hazard regression model was used to identify independent predictors of mortality in HIV- infected under-five children on antiretroviral therapy.

Result

At the end of follow up, 304 (80.85%) of HIV-infected children were alive, 39 (10.95%) were lost to follow up, 12 (3.19%) were transferred out and 21 (5.59%) were reported dead due to HIV/AIDS. The cumulative survival probabilities of children after 3, 6, 12, 24 and 36 months were 0.99, 0.98, 0.97, 0.89 and 0.87 respectively. The overall mean time to death was 19.7 months (95%CI = 18.74–20.67) with incidence of 5.9 deaths per 100 child-months (95%CI: 3.89–9.09). Children with severe malnutrition at baseline (AHR = 4.9; 95 CI: 1.04, 23.50), advanced WHO clinical stage at enrolment (AHR = 3.9; CI: 1.37, 10.88), poor adherence to ART (AHR = 6.56; CI: 3.33, 10.14) and with no history of Isoniazide prophylaxis were significantly associated to higher mortality events (AHR = 3.6; CI: 1.24, 10.18).

Conclusion

Death of HIV-infected under-five children on ART is high within the first one year after enrolment. The risk of death increased if the child was malnourished at beginning of treatment, had poor ART adherence, with advanced WHO clinical stages and lack of Isoniazide prophylaxis during their age of infancy.
Significance of the ‘line sign’ in the diagnosis of congenital imperforate anus on prenatal ultrasound
Authors: Yin Chan , Tong Lili , Nie Dan , Fei Zhihui , Tan Xiaoqun , Ma Mingxiang
Published: January 2022

Background

The prenatal diagnosis of foetal imperforate anus is difficult. Most previous studies have been case reports. To provide useful information for diagnosing foetal imperforate anus, a retrospective review of diagnostic approaches was conducted. Ultrasonography was performed in 19 cases of foetal imperforate anus from 2016 to 2019 at our prenatal diagnostic centre. The prenatal sonographic features and outcomes of each case were collected and evaluated.

Result

The anal sphincter of a normal foetus shows the ‘target sign’ on cross-sectional observation. Of the 19 cases of imperforate anus, 16 cases were diagnosed by the ultrasound image feature called the ‘line sign’. 1 case with tail degeneration was low type imperforate anus with the irregular ‘target sign’ not a real ‘target sign’. There was two false-negative case, in which the ‘target sign’ was found, but irregular.

Conclusion

In this study, we find that the anus of a foetus with imperforate anus presents a ‘line sign’ on sonographic observation. The absence of the ‘target sign’ and then the presence of the ‘line sign’ can assist in the diagnosis of imperforate anus. The ‘line sign’ can be used as a secondary assessment to determine the type of the malformation following non visualization of the ‘target sign’. The higher the position of the imperforate anus is, the more obvious the ‘line sign’. It is worth noting that the finding of the short ‘line sign’ and irregularr ‘target sign’ can not ignore the low type imperforate anus.
Liver transplantation in a child with liver cirrhosis caused by langerhans cell histiocytosis: a case report
Authors: Wang Qi , Jin Shuguang , Xiang Bo , Chen Jing
Published: January 2022

Background

Langerhans cell histiocytosis (LCH) is a rare condition that has a variety of clinical manifestations. But LCH in children localized only in the hepatobiliary system is unusual.

Case presentation.

Here we reported a rare case of a 2-year-old boy who was serendipitously found to have elevated liver enzymes while undergoing treatment of a perianal abscess. After a period of earlier conservative treatment in another hospital, the perianal abscess had resolved but the levels of liver enzymes were still rising slowly. The child was then referred to our institution for a definitive diagnosis. After laboratory tests, imaging and pathological examinations, a diagnosis of liver cirrhosis and sclerosing cholangitis was established, although the cause was unclear. Subsequently, living-donor liver transplantation was performed due to deterioration in liver function. Following successful liver transplantation, a diagnosis of LCH localized only within the hepatobiliary system was finally confirmed, based on additional pathological and imaging investigation. Additionally, the BRAF V600E mutation in this patient was also confirmed. The child has now recovered without evidence of LCH recurrence.

Conclusions

LCH localized only within the hepatobiliary system is unusual. The presence of unexplainable sclerosing cholangitis and liver cirrhosis in any child should raise the suspicion of LCH.
Poor sleep quality is negatively associated with low cognitive performance in general population independent of self-reported sleep disordered breathing
Authors: Wang Zhongrong , Heizhati Mulalibieke , Wang Lin , Li Mei , Yang Zhikang , Lin Mengyue , Abudereyimu Reyila , Hong Jing , Yang Wenbo , Yao Ling , Liu Shasha , Hu Junli , Li Nanfang
Published: January 2022

Background

Sleep disordered breathing (SDB) plays a significant role in both sleep quality and cognition and whether it has an impact on the relationship between above two factors remains to be clear. The study aimed to explore the association between sleep quality and cognitive performance in general population by considering influence of sleep disordered breathing (SDB).

Methods

In this cross-sectional study, we enrolled subjects aged ≥ 18 years using a multi-stage random sampling method. Cognitive status was assessed using Mini Mental State Examination (MMSE) questionnaire, sleep quality using Pittsburgh Sleep Quality Index (PSQI) and SDB was assessed using No-SAS scale, respectively. Multi-variable logistic regression was applied to examine the association of sleep quality and cognitive performance. Subgroup analyses were performed in different age groups, and in those with and without SDB.

Results

Finally, 30,872 participants aged 47.5 ± 13.8 years with 53.5% women were enrolled, of whom 32.4% had poor sleep quality and 18.6% had low cognitive performance. Compared with good sleepers, subjects with poor sleep quality exhibited significantly higher presence of low cognitive performance (23.7% vs 16.2%, P < 0.001). Poor sleepers revealed 1.26 (95%CI: 1.16,1.36), 1.26 (1.08,1.46) and 1.25 (1.14,1.37) fold odds for low cognitive performance in general population and in subjects with and without self-reported SDB respectively. Stratified by age and SDB, the association was observed in young and middle-aged group without SDB (OR = 1.44, 95%CI: 1.30,1.59) and in the elderly group with SDB (OR = 1.30, 95%CI: 1.07,1.58).

Conclusions

Sleep quality is in a negative association with cognitive performance in general population independent of SDB, implying improvement of sleep disturbances is a potential objective of intervention strategies for cognitive protection at population level.
Anterior cervical corpectomy and fusion with stand-alone cages in patients with multilevel degenerative cervical spine disease is safe
Authors: Tohamy Mohamed H. , Osterhoff Georg , Abdelgawaad Ahmed Shawky , Ezzati Ali , Heyde Christoph-E.
Published: January 2022

Background

In case of spinal cord compression behind the vertebral body, anterior cervical corpectomy and fusion (ACCF) proves to be a more feasible approach than cervical discectomy. The next step was the placement of an expandable titanium interbody in order to restore the vertebral height. The need for additional anterior plating with ACCF has been debatable and such technique has been evaluated by very few studies. The objective of the study is to evaluate radiographic and clinical outcomes in patients with multilevel degenerative cervical spine disease treated by stand-alone cages for anterior cervical corpectomy and fusion (ACCF).

Methods

Thirty-one patients (66.5 ± 9.75 years, range 53–85 years) were analyzed. Visual Analog Scale (VAS) and the 10-item Neck Disability Index (NDI) were assessed preoperatively and during follow-up on a regular basis after surgery and after one year at least. Assessment of radiographic fusion, subsidence, and lordosis measurement of Global cervical lordosis (GCL); fusion site lordosis (FSL); the anterior interbody space height (ant. DSH); the posterior interbody space height (post. DSH); the distance of the cage to the posterior wall of the vertebral body (CD) were done retrospectively. Mean clinical and radiographic follow-up was 20.0 ± 4.39 months.

Results

VAS-neck (p = 0.001) and VAS-arm (p < 0.001) improved from preoperatively to postoperatively. The NDI improved at the final follow-up (p < 0.001). Neither significant subsidence of the cages nor significant loss of lordotic correction were seen. All patients showed a radiographic union of the surgically addressed segments at the last follow up.

Conclusions

Application of a stand-alone expandable cage in the cervical spine after one or two-level ACCF without additional posterior fixation or anterior plating is a safe procedure that results in fusion. Neither significant subsidence of the cages nor significant loss of lordotic correction were seen.

Trial registration

Retrospectively registered. According to the Decision of the ethics committee, Jena on 25th of July 2018, that this study doesn’t need any registration. https://www.laek-thueringen.de/aerzte/ethikkommission/registrierung/.
Hybrid surgery with PEEK rods for lumbar degenerative diseases: a 2-year follow-up study
Authors: Zhao Yao , Xu Beiyu , Qi Longtao , Li Chunde , Yue Lei , Yu Zhengrong , Wang Shijun , Sun Haolin
Published: January 2022

Background

Finite element analyses and biomechanical tests have shown that PEEK rods promote fusion and prevent adjacent segment degeneration. The purpose of this study was to evaluate the effects and complications of hybrid surgery with PEEK rods in lumbar degenerative diseases.

Methods

From January 2015-December 2017, 28 patients who underwent lumbar posterior hybrid surgery with PEEK rods were included in the study. The patients were diagnosed with lumbar disc herniation, lumbar spinal stenosis, or degenerative grade I spondylolisthesis. Before the operation and at the last follow-up, the patients completed lumbar anteroposterior and lateral X-ray, dynamic X-ray, MRI examinations. In addition, at the last follow-up the patients also completed lumbar CT examinations. The radiographic parameters, clinical visual analog scale (VAS) score and Oswestry disability index (ODI) score were compared.

Results

The average age of the patients was 44.8 ± 12.6 years, and the average follow-up duration was 26.4 ± 3.6 months. The VAS score improved from 6.3 ± 1.6 to 1.0 ± 0.9, and the ODI score decreased from 38.4 ± 10.8 to 6.8 ± 4.6. The fusion rate of the fused segment was 100%. There were no significant changes in the modified Pfirrmann classifications or disc height index for the nonfused segments and the upper adjacent segments from pre- to postoperatively. No cases of screw loosening, broken screws, broken rods or other mechanical complications were found.

Conclusion

Hybrid surgery with PEEK rods for lumbar degenerative diseases can yield good clinical results and effectively reduce the incidence of complications such as adjacent segment diseases.
Bone marrow aspirate concentrate versus platelet-rich plasma for treating knee osteoarthritis: a one-year non-randomized retrospective comparative study
Authors: El-Kadiry Abed El-Hakim , Lumbao Carlos , Salame Natasha , Rafei Moutih , Shammaa Riam
Published: January 2022

Background

Knee osteoarthritis (OA) is a debilitating condition affecting human body biomechanics and quality of life. Current standard care for knee OA leads to trivial improvement and entails multiple adverse effects or complications. Recently, investigational cell therapies injected intra-articularly, such as bone marrow aspirate concentrate (BMAC) and platelet-rich plasma (PRP), have shown safety and therapeutic potency providing patients with pain relief. In the current retrospective comparative study, we investigated the differences in pain and functional improvements in patients with symptomatic knee OA receiving intra-articular injections of BMAC vs PRP.

Methods

Pain and functionality scores were measured at baseline and at different time points post-injection over 12 months, using 3 self-administered, clinically validated questionnaires: the visual analogue scale (VAS) for assessing pain intensity, the knee injury and osteoarthritis outcome score (KOOS) for evaluating functionality and knee-related quality of life, and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) for evaluating physical function. The repeated-measures general linear model with Sidak test for pairwise comparisons was used to investigate the influence of the treatment on the score evolution within groups (between baseline and each time point) and between groups (overall).

Results

The BMAC group (n = 26 knees) significantly improved in VAS, KOOS, and WOMAC scores between baseline and 12 months (57.4, 75.88, and 73.95% mean score improvement, respectively). In contrast, the PRP group (n = 13 knees) witnessed nonsignificant improvement in all scores. BMAC, in comparison to PRP, induced significant improvement in outcomes by 29.38% on the VAS scale, 53.89% on the KOOS scale, and 51.71% on the WOMAC scale (P < .002, P < .01, P < .011, respectively).

Conclusions

Intra-articular autologous BMAC injections are safe, effective in treating pain, and ameliorate functionality in patients with symptomatic knee OA to a greater extent than PRP injections.

Graphical abstract

Intra-articular autologous BMAC therapy is safe and provides more relief to patients with symptomatic knee osteoarthritis compared to PRP therapy.
Two-year clinical and economic burden, risk and outcomes following application of software-assisted hexapod ring fixation systems
Authors: Reid J. Spence , Vanderkarr Mollie , Ray Bidusee , Chitnis Abhishek , Holy Chantal E. , Sparks Charisse
Published: January 2022

Background

Multiplanar external fixation systems that employ software-assisted deformity correction consist of rings connected by angled struts, defined as hexapod ring fixators (HRF). Costs and outcomes associated with the application of HRFs are not well documented. This study was designed to provide a nationwide baseline understanding of the clinical presentation, risks, outcomes and payer costs, and healthcare resource utilization (HCU) of patients requiring application of an HRF, from the day of, and up to 2 years, post-application.

Methods

Patients with HRF application (“index”) between 2007 and 2019 within the IBM Marketscan® Commercial Claims database were identified and categorized based on diagnosis: acquired deformity, arthropathy, congenital deformity, deep infection, nonunion, fracture, and other post-operative fracture sequelae. Demographics, comorbidities at index, complications post-index, HCU, and payments were analyzed. Payments were estimated using a generalized linear model and were adjusted for inflation to the 2020 consumer price index. Rates of deep infection and amputation were estimated up to 2 years post-index using Poisson regressions, and risk factors for each were estimated using logistic regression models.

Results

Six hundred ninety-five patients were included in our study (including 219 fractures, 168 congenital deformities, 68 deep infections, 103 acquired deformities). Comorbidities at index were significantly different across groups: less than 2% pediatrics vs 18% adults had 3 or more comorbidities, < 1% pediatric vs 29% adults had diabetes. Index payments ranged from $39,250–$75,350, with 12-months post-index payments ranging from $14,350 to $43,108. The duration of the HRF application ranged from 96 days to 174 days. Amputation was observed in patients with deep infection (8.9, 95% confidence interval (CI): 3.2–23.9%), nonunion (5.0, 95%CI: 1.6–15.4%) or fracture (2.7, 95%CI: 0.9–7.6%) at index. Complicated diabetes was the main predictor for deep infection (odds ratio (OR): 5.14, 95%CI: 2.50–10.54) and amputation (OR: 5.26, 95%CI: 1.79–15.51).

Conclusions

Findings from this longitudinal analysis demonstrate the significant heterogeneity in patients treated with HRF, and the wide range in treatment intensity, payments, and outcomes. Risks for deep infection and amputation were primarily linked to the presence of complicated diabetes at the time of HRF application, suggesting a need for careful management of comorbid chronic conditions in patients requiring HRF for orthopedic care.
Polymorphism of MMP-3 gene and imbalance expression of MMP-3 / TIMP-1 in articular cartilage are associated with an endemic osteochondropathy, Kashin- Beck disease
Authors: Shi Bohui , Guo Xiong , Iv Aili , Zhang Zengtie , Shi Xiaowei
Published: January 2022

Background

The etiology of Kashin-Beck disease (KBD), an endemic osteochondropathy, is largely unknown. Matrix metalloproteinase-3 (MMP-3) plays a central role in the initiation and progression of cartilage destruction, however, no study has reported on the relationship between KBD and MMP-3. The objective of this study was to explore the polymorphism of MMP-3 gene and expression of MMP-3 / TIMP-1(Tissue inhibitors of matrixmetalloproteinases-1) in the pathogenesis of KBD.

Methods

Single nucleotide polymorphism (SNP) genotyping was conducted in 274 KBD cases and 248 healthy controls for eight SNPs in MMP-3 using the Sequenom MassARRAY system. Additionally, the expression of MMP-3、TIMP-1 in different layers of the articular cartilage was analyzed by immunohistochemistry for 22 KBD patients, 15 osteoarthritis (OA) patients and 21 controls.

Results

The results showed that six SNPs (rs520540、rs591058、rs679620、rs602128、rs639752 and rs678815) in MMP-3 were associated with the increased risk of KBD, however, after Bonferroni correction, only the SNP rs679620 in the recessive model remained significant difference (OR = 2.31, 95%CI = 1.29–4.14, P = 0.0039), homozygous for “T” allele have a risk for KBD than “C” allele carriers. Moreover, the percentages of cells expressing MMP-3 in articular cartilage were significantly higher in the KBD and OA groups than in the controls (t = 5.37 and 4.19, P<0.01). While the KBD and OA groups had lower levels of TIMP-1 positive staining compared with the controls (t = 5.23and 5.06, P<0.01). And there was no significant different between KBD and OA for the levels of MMP-3 and TIMP-1 positive staining (t = 0.05and 0.28, P>0.05).

Conclusions

MMP-3 is associated with the susceptibility of KBD, and the imbalance expression of MMPs / TIMPs leading to cartilage degradation may play an important role in cartilage degradation and osteoarthritis formation in OA and KBD.
Complexities of interprofessional identity formation in dental hygienists: an exploratory case study
Authors: Imafuku Rintaro , Nagatani Yukiko , Yamada Saeko
Published: January 2022

Background

In a super-aging society, medical-dental collaboration is increasingly vital for comprehensive patient care. Particularly in dysphagia rehabilitation and perioperative oral functional management, dental hygienists’ active involvement is pivotal to interprofessional collaborative practice. Despite this societal expectation, dental hygienists’ experiences and perceptions of interprofessional collaboration have not been explored. This study aims to investigate dental hygienists’ interprofessional identity formation and perceptions of interprofessional collaboration. Specifically, it was explored from the perspectives of dental hygiene students and hospital dental hygienists.

Methods

This study is underpinned by Wenger’s social theory of learning, which focuses on identity as a component in the process of learning in communities. Semi-structured interviews were conducted with 11 dental hygiene students in their final year at a technical college and five dental hygienists engaging in interprofessional care at a university hospital in Japan. The narrative data were analysed using an inductive approach to thematic analysis to extract themes regarding the identification of self in interprofessional teams.

Results

Dental hygiene students found several barriers to the collaboration, including power relation and conceptual hierarchy, limited understanding of other professional roles, and differences in language and jargon. They viewed themselves as inferior in the interprofessional team. This resulted from their limited knowledge about general health and less responsibility for problems directly related to patient life and death. However, they could ultimately perceive the negative experiences positively as challenges for the future through reflection on learning in clinical placements. Contrarily, dental hygienists did not have such negative perceptions as the students did. Rather, they focused on fulfilling their roles as dental professionals in the interprofessional team. Their identities were formed through actively involving, coordinating their activity, and creating new images of the world and self in inter-professional communities of practice.

Conclusions

Interprofessional identity is relational as well as experiential, which is developed in complex and socially dynamic processes across intra- and inter-professional communities of practice. Engagement, imagination, and alignment are essential aspects of their interprofessional identities, which inform conceptual foundations of interprofessional education and collaborative practice in health care.
Mannheimia haemolytica serovars associated with respiratory disease in cattle in Great Britain
Authors: Mason Colin , Errington Jane , Foster Geoffrey , Thacker Jennifer , Grace Oliver , Baxter-Smith Katharine
Published: January 2022

Background

Mannheimia haemolytica is commonly associated with respiratory disease in cattle worldwide as a cause of fibrinous pneumonia, bronchopneumonia and pleuritis. M. haemolytica is further subdivided into 12 serovars, however not all are considered to be pathogenic in cattle. The study aim was to determine the most common serovars of M. haemolytica associated with respiratory disease in cattle in Great Britain, which is currently unknown and could be useful information for clinicians when considering preventative strategies.

Results

One hundred four M. haemolytica isolates isolated from bovine clinical pathology and post-mortem samples from pneumonia cases between 2016 and 2018 were tested using a multiplex PCR assay to identify M. haemolytica serovars A1, A2 and A6. 46 isolates (44.2%) typed as M. haemolytica serovar A1, 31 (29.8%) as M. haemolytica serovar A2 and 18 isolates (17.3%) as M. haemolytica serovar A6. Nine isolates (8.7%) were not A1, A2 or A6 so were considered to belong to other serovars or were not typable.

Conclusion

This study highlights the importance of M. haemolytica serovars other than A1 which may be responsible for respiratory disease in cattle and could help guide the veterinarian when making choices on preventative vaccination programmes.
A genomic mutation spectrum of collecting duct carcinoma in the Chinese population
Authors: Zhang Huaru , Lu Xiaojun , Huang Gang , Hua Meimian , Zhang Wenhui , Wang Tao , Huang Liqun , Wang Ziwei , Chen Qing , Li Jing , Yang Qing , Yang Guosheng
Published: January 2022

Background

Renal collecting duct carcinoma (CDC) is a rare and lethal subtype of renal cell carcinoma (RCC). The genomic profile of the Chinese population with CDC remains unclear. In addition, clinical treatments are contradictory. In this study, we aimed to identify the genomic mutation spectrum of CDC in the Chinese population.

Methods

Whole-exome sequencing was performed using the Illumina Novaseq™ 6000 platform. MuTect2 detects single-nucleotide variants (SNVs) and small scale insertions/deletions (INDELs). The identified mutations were annotated with ANNOVAR and validated by Sanger sequencing. Control-FREEC was used to detect copy number variation (CNV), and GISTIC was applied to detect frequently mutated altered regions. These data were compared with associated The Cancer Genome Atlas cohorts.

Results

Ten normal-matched CDC patients were included. The mean tumour mutation burden was 1.37 Mut/Mb. Six new recurrent somatic mutated genes were identified, includingRBM14,MTUS1,GAK,DST,RNF213andXIRP2(20% and 2 of 10, respectively), and validated by Sanger sequencing. In terms of common mutated genes,SETD2was altered in both CDC and other RCC subtypes but not in bladder urothelial carcinoma (BLCA);CDKN2Awas a driver gene in both CDC (SNV: 10%, 1 of 10) and BLCA but not in other RCC subtypes. Next, 29 amplifications and 6 deletions of recurrent focal somatic CNVs were identified by GISTIC2.0, which displayed differences from kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP) and BLCA cohorts. Of note,CDKN2A(CNV alteration: 30%, 3 of 10) andCDKN2A-AS1were the only overlapping genes of these four cohorts. Importantly, theCDKN2Amutation in our cohort differed from previous studies in urinary carcinomas. Moreover,CDKN2A-altered cases had significantly worse overall survival than wild-type cases in both KIRC and KIRP cohorts. In addition, the most frequently altered genomic pathway of our CDC cohort was theCDKN2A-mediated p53/RB1 pathway.

Conclusions

Our study offers the first genomic spectrum of the Chinese population with CDC, which differs from that of the Western population. The alteredCDKN2A-mediated p53/RB1 pathway might provide new insight into potential therapeutic targets for CDC patients.
Correction to: Long non-coding RNA UCA1 promotes malignant phenotypes of renal cancer cells by modulating the miR-182-5p/DLL4 axis as a ceRNA
Authors: Wang Wei , Hu Wentao , Wang Ya , An Yong , Song Lei , Shang Panfeng , Yue Zhongjin
Published: January 2022

An amendment to this paper has been published and can be accessed via the original article.
On-treatment blood TMB as predictors for camrelizumab plus chemotherapy in advanced lung squamous cell carcinoma: biomarker analysis of a phase III trial
Authors: Jiang Tao , Chen Jianhua , Xu Xingxiang , Cheng Ying , Chen Gongyan , Pan Yueyin , Fang Yong , Wang Qiming , Huang Yunchao , Yao Wenxiu , Wang Rui , Li Xingya , Zhang Wei , Zhang Yanjun , Hu Sheng , Guo Renhua , Shi Jianhua , Wang Zhiwu , Cao Peiguo , Wang Donglin , Fang Jian , Luo Hui , Geng Yi , Xing Chunyan , Lv Dongqing , Zhang Yiping , Yu Junyan , Cang Shundong , Zhang Yaxi , Zhang Jiao , Yang Zeyu , Shi Wei , Zou Jianjun , Zhou Caicun , Ren Shengxiang
Published: January 2022

Background

Camrelizumab plus chemotherapy significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone as first-line treatment in advanced lung squamous cell carcinoma (LUSC) in the phase III trial (CameL-sq), which has become an option of standard-of-cares for Chinese patients with advanced LUSC. However, the predictive biomarkers remain unknown.

Methods

Tumor tissue samples at baseline, and peripheral blood samples at baseline (pretreatment) and after two cycles of treatment (on-treatment) were prospectively collected from 270 LUSC patients from the CameL-sq study. Blood tumor mutation burden (bTMB) and its dynamics were analyzed to explore their predictive values.

Results

Pretreatment bTMB was not associated with objective response, PFS and OS in camrelizumab or placebo plus chemotherapy groups. Low on-treatment bTMB was associated with significantly better objective response (73.8% vs 27.8%, P < 0.001), PFS (median, 9.1 vs 4.1 months; P < 0.001) and OS (median, not reached vs 8.0 months; P < 0.001) in camrelizumab plus chemotherapy group whereas it did not correlate with objective response and PFS in chemotherapy alone group. Importantly, on-treatment bTMB level could discriminate patients of initially radiological stable disease who would long-term benefit from camrelizumab plus chemotherapy (low vs high, median OS, 18.2 vs 7.8 months; P = 0.001). Combing on-treatment bTMB and its dynamics improved the ability for predicting the efficacy of camrelizumab plus chemotherapy.

Conclusion

On-treatment bTMB together with its dynamics could serve as a predictive biomarker for camrelizumab plus chemotherapy in patients with advanced LUSC.

Trial registration

ClinicalTrials.gov identifier: NCT03668496.
Fit for purpose. Co-production of complex behavioural interventions. A practical guide and exemplar of co-producing a telehealth-delivered exercise intervention for people with stroke
Authors: Ramage Emily R. , Burke Meredith , Galloway Margaret , Graham Ian D. , Janssen Heidi , Marsden Dianne L. , Patterson Amanda J. , Pollack Michael , Said Catherine M. , Lynch Elizabeth A. , English Coralie
Published: January 2022

Background

Careful development of interventions using principles of co-production is now recognized as an important step for clinical trial development, but practical guidance on how to do this in practice is lacking. This paper aims (1) provide practical guidance for researchers to co-produce interventions ready for clinical trial by describing the 4-stage process we followed, the challenges experienced and practical tips for researchers wanting to co-produce an intervention for a clinical trial; (2) describe, as an exemplar, the development of our intervention package.

Method

We used an Integrated Knowledge Translation (IKT) approach to co-produce a telehealth-delivered exercise program for people with stroke. The 4-stage process comprised of (1) a start-up planning phase with the co-production team. (2) Content development with knowledge user informants. (3) Design of an intervention protocol. (4) Protocol refinement.

Results and reflections

The four stages of intervention development involved an 11-member co-production team and 32 knowledge user informants. Challenges faced included balancing conflicting demands of different knowledge user informant groups, achieving shared power and collaborative decision making, and optimising knowledge user input. Components incorporated into the telehealth-delivered exercise program through working with knowledge user informants included: increased training for intervention therapists; increased options to tailor the intervention to participant’s needs and preferences; and re-naming of the program. Key practical tips include ways to minimise the power differential between researchers and consumers, and ensure adequate preparation of the co-production team.

Conclusion

Careful planning and a structured process can facilitate co-production of complex interventions ready for clinical trial.

﻿Graphical Abstract
Bilirubin ameliorates murine atherosclerosis through inhibiting cholesterol synthesis and reshaping the immune system
Authors: Wen Guanmei , Yao Leyi , Hao Yali , Wang Jinheng , Liu Jinbao
Published: January 2022

Atherosclerosis is a chronic inflammatory disease caused mainly by lipid accumulation and excessive inflammatory immune response. Although the lipid-lowering and cardioprotective properties of bilirubin, as well as the negative relationship between bilirubin and atherosclerosis, were well documented, it is not yet clear whether bilirubin can attenuate atherosclerosis in vivo. In this study, we investigated the role of bilirubin in improving atherosclerosis. We found that mildly elevated bilirubin significantly reduced the risk factors of atherosclerosis, such as plasma glucose, total cholesterol, and low-density lipoprotein cholesterol, and the formation of atherosclerotic plaques, liver total cholesterol, and cholesterol ester concentration in apolipoprotein E-deficient (ApoE−/−) mice fed a western-type (high fat) diet. It was further found that bilirubin could promote the degradation of 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), a rate-limiting enzyme for endogenous cholesterol synthesis. Using mass cytometry-based high dimensional single cell analysis, we observed a decrease of natural killer cells and an increase of dendritic cells and myeloid-derived suppressor cells, which all are closely associated with atherosclerosis risk factors and contribute to the improvement of atherosclerosis, in ApoE−/− mice treated with bilirubin. By in-depth analysis, modulation of multiple spleen or peripheral blood T cell clusters exhibiting either positive or negative correlations with total cholesterol or low-density lipoprotein cholesterol was detected after bilirubin treatment. In this study, we demonstrate that bilirubin serves as a negative regulator of atherosclerosis and reduces atherosclerosis by inhibiting cholesterol synthesis and modulating the immune system.