bluuebunny/crossref_metadata_2025 huggingface dataset:
Corneal epithelial differentiation of human pluripotent stem cells generates ABCB5+ and ∆Np63α+ cells with limbal cell characteristics and high wound healing capacity
Authors: Vattulainen Meri , Ilmarinen Tanja , Viheriälä Taina , Jokinen Vilma , Skottman Heli
Published: December 2021

Background

Differentiation of functional limbal stem cells (LSCs) from human pluripotent stem cells (hPSCs) is an important objective which can provide novel treatment solutions for patients suffering from limbal stem cell deficiency (LSCD). Yet, further characterization is needed to better evaluate their immunogenicity and regenerative potential before clinical applications.

Methods

Human PSCs were differentiated towards corneal fate and cryopreserved using a clinically applicable protocol. Resulting hPSC-LSC populations were examined at days 10–11 and 24–25 during differentiation as well as at passage 1 post-thaw. Expression of cornea-associated markers including PAX6, ABCG2, ∆Np63α, CK15, CK14, CK12 and ABCB5 as well as human leukocyte antigens (HLAs) was analyzed using immunofluorescence and flow cytometry. Wound healing properties of the post-thaw hPSC-LSCs were assessed via calcium imaging and scratch assay. Human and porcine tissue-derived cultured LSCs were used as controls for marker expression analysis and scratch assays at passage 1.

Results

The day 24–25 and post-thaw hPSC-LSCs displayed a similar marker profile with the tissue-derived LSCs, showing abundant expression of PAX6, ∆Np63α, CK15, CK14 and ABCB5 and low expression of ABCG2. In contrast, day 10–11 hPSC-LSCs had lower expression of ABCB5 and ∆Np63α, but high expression of ABCG2. A small portion of the day 10–11 cells coexpressed ABCG2 and ABCB5. The expression of class I HLAs increased during hPSC-LSCs differentiation and was uniform in post-thaw hPSC-LSCs, however the intensity was lower in comparison to tissue-derived LSCs. The calcium imaging revealed that the post-thaw hPSC-LSCs generated a robust response towards epithelial wound healing signaling mediator ATP. Further, scratch assay revealed that post-thaw hPSC-LSCs had higher wound healing capacity in comparison to tissue-derived LSCs.

Conclusions

Clinically relevant LSC-like cells can be efficiently differentiated from hPSCs. The post-thaw hPSC-LSCs possess functional potency in calcium responses towards injury associated signals and in wound closure. The developmental trajectory observed during hPSC-LSC differentiation, giving rise to ABCG2+ population and further to ABCB5+ and ∆Np63α+ cells with limbal characteristics, indicates hPSC-derived cells can be utilized as a valuable cell source for the treatment of patients afflicted corneal blindness due to LSCD.

Graphical Abstract
The angiogenic properties of human amniotic membrane stem cells are enhanced in gestational diabetes and associate with fetal adiposity
Authors: Klid Sergiy , Algaba-Chueca Francisco , Maymó-Masip Elsa , Guarque Albert , Ballesteros Mónica , Diaz-Perdigones Cristina , Gutierrez Cristina , Vendrell Joan , Megía Ana , Fernández-Veledo Sonia
Published: December 2021

Background

An environment of gestational diabetes mellitus (GDM) can modify the phenotype of stem cell populations differentially according to their placental localization, which can be useful to study the consequences for the fetus. We sought to explore the effect of intrauterine GDM exposure on the angiogenic properties of human amniotic membrane stem cells (hAMSCs).

Methods

We comprehensively characterized the angiogenic phenotype of hAMSCs isolated from 14 patients with GDM and 14 controls with normal glucose tolerance (NGT). Maternal and fetal parameters were also recorded. Hyperglycemia, hyperinsulinemia and palmitic acid were used to in vitro mimic a GDM-like pathology. Pharmacological and genetic inhibition of protein function was used to investigate the molecular pathways underlying the angiogenic properties of hAMSCs isolated from women with GDM.

Results

Capillary tube formation assays revealed that GDM-hAMSCs produced a significantly higher number of nodes (P = 0.004), junctions (P = 0.002) and meshes (P < 0.001) than equivalent NGT-hAMSCs, concomitant with an increase in the gene/protein expression of FGFR2, TGFBR1, SERPINE1 and VEGFA. These latter changes were recapitulated in NGT-hAMSCs exposed to GDM-like conditions. Inhibition of the protein product of SERPINE1 (plasminogen activator inhibitor 1, PAI-1) suppressed the angiogenic properties of GDM-hAMSCs. Correlation analyses revealed that cord blood insulin levels in offspring strongly correlated with the number of nodes (r = 0.860; P = 0.001), junctions (r = 0.853; P = 0.002) and meshes (r = 0.816; P = 0.004) in tube formation assays. Finally, FGFR2 levels correlated positively with placental weight (r = 0.586; P = 0.028) and neonatal adiposity (r = 0.496; P = 0.014).

Conclusions

GDM exposure contributes to the angiogenic abilities of hAMSCs, which are further related to increased cord blood insulin and fetal adiposity. PAI-1 emerges as a potential key player of GDM-induced angiogenesis.
The usefulness of repeated CMR and FDG PET/CT in the diagnosis of patients with initial possible cardiac sarcoidosis
Authors: Mathijssen H. , Tjoeng T. W. H. , Keijsers R. G. M. , Bakker A. L. M. , Akdim F. , van Es H. W. , van Beek F. T. , Veltkamp M. V. , Grutters J. C. , Post M. C.
Published: December 2021

Background

Cardiac sarcoidosis (CS) diagnosis is usually based on advanced imaging techniques and multidisciplinary evaluation. Diagnosis is classified as definite, probable, possible or unlikely. If diagnostic confidence remains uncertain, cardiac imaging can be repeated. The objective is to evaluate the usefulness of repeated cardiac magnetic resonance imaging (CMR) and fluorodeoxyglucose positron emission tomography (FDG PET/CT) for CS diagnosis in patients with an initial “possible” CS diagnosis.

Methods

We performed a retrospective cohort study in 35 patients diagnosed with possible CS by our multidisciplinary team (MDT), who received repeated CMR and FDG PET/CT within 12 months after diagnosis. Imaging modalities were scored on abnormalities suggestive for CS and classified as CMR+/PET+, CMR+/PET−, CMR−/PET+ and CMR−/PET−. Primary endpoint was final MDT diagnosis of CS.

Results

After re-evaluation, nine patients (25.7%) were reclassified as probable CS and 16 patients (45.7%) as unlikely CS. Two patients started immunosuppressive treatment after re-evaluation. At baseline, eleven patients (31.4%) showed late gadolinium enhancement (LGE) on CMR (CMR+) and 26 (74.3%) patients showed myocardial FDG-uptake (PET+). At re-evaluation, nine patients (25.7%) showed LGE (CMR+), while 16 patients (45.7%) showed myocardial FDG-uptake (PET+). When considering both imaging modalities together, 82.6% of patients with CMR−/PET+ at baseline were reclassified as possible or unlikely CS, while 36.4% of patients with CMR+ at baseline were reclassified as probable CS. Three patients with initial CMR−/PET+ showed LGE at re-evaluation.

Conclusion

Repeated CMR and FDG PET/CT may be useful in establishing or rejecting CS diagnosis, when initial diagnosis is uncertain. However, clinical relevance has to be further determined.
Supporting strategic health purchasing: a case study of annual health budgets from general tax revenue and social health insurance in Abia state, Nigeria
Authors: Mbachu Chinyere , Okeke Chinyere , Obayi Chinonso , Gatome-Munyua Agnes , Olalere Nkechi , Ogbonna Ikechi , Uzochukwu Benjamin , Onwujekwe Obinna
Published: December 2021

Background

Tracking general trends in strategic purchasing of health financing mechanisms will highlight where country demands may exist for technical support and where progress in being made that offer opportunities for regional learning. Health services in Abia State, Nigeria are funded from general tax-revenues (GTR), and a new state social health insurance scheme (SSHIS) is proposed to overcome the failings of the GTR and expand coverage of services. This study examined purchasing functions within the GTR and the proposed SSHIS to determine if the failings in GTR have been overcome, identify factors that shape health purchasing at sub-national levels, and provide lessons for other states in Nigeria pursuing a similar intervention.

Methods

Data was collected through document review and key informant interviews. Government documents were retrieved electronically from the websites of different organizations. Hard copies of paper-only files were retrieved from relevant government agencies and departments. Interviews were conducted with seven key personnel of the State Ministry of Health and State Health Insurance Agency. Thematic analysis of data was based on a strategic health purchasing progress tracking framework which delves into the governance arrangements and information architecture needed for purchasing to work well; and the core purchasing decisions of what to buy; who to buy from; and how to buy.

Results

There are differences in the purchasing arrangements of the two schemes. Purchaser-provider split does not exist for the GTR, unlike in the proposed SSHIS. There are no data systems for monitoring provider performance in the GTR-funded system, unlike in the SSHIS. Whereas GTR is based on a historical budgeting system, the SSHIS proposes to use a defined benefit package, which ensures value-for-money, as the basis for resource allocation. The GTR lacks private sector engagement, provider accreditation and contracting arrangements while the SSHIS will accredit and engage private providers through selective contracting. Likewise, provider payment is not linked to performance or adherence to established standards in the GTR, whereas provider payment will be linked to performance in the SSHIS.

Conclusions

The State Social Health Insurance has been designed to overcome many of the limitations of the budgetary allocation to health. This study provides insights into the enabling and constraining factors that can be used to develop interventions intended to strengthen the strategic health purchasing in the study area, and lessons for the other Nigeria states with similar characteristics and approaches.
Water surface object detection using panoramic vision based on improved single-shot multibox detector
Authors: Li Aofeng , Zhu Xufang , He Shuo , Xia Jiawei
Published: December 2021

In view of the deficiencies in traditional visual water surface object detection, such as the existence of non-detection zones, failure to acquire global information, and deficiencies in a single-shot multibox detector (SSD) object detection algorithm such as remote detection and low detection precision of small objects, this study proposes a water surface object detection algorithm from panoramic vision based on an improved SSD. We reconstruct the backbone network for the SSD algorithm, replace VVG16 with a ResNet-50 network, and add five layers of feature extraction. More abundant semantic information of the shallow feature graph is obtained through a feature pyramid network structure with deconvolution. An experiment is conducted by building a water surface object dataset. Results showed the mean Average Precision (mAP) of the improved algorithm are increased by 4.03%, compared with the existing SSD detecting Algorithm. Improved algorithm can effectively improve the overall detection precision of water surface objects and enhance the detection effect of remote objects.
Convergence of a distributed method for minimizing sum of convex functions with fixed point constraints
Authors: Ekkarntrong Nawarat , Arunrat Tipsuda , Nimana Nimit
Published: December 2021

In this paper, we consider a distributed optimization problem of minimizing sum of convex functions over the intersection of fixed-point constraints. We propose a distributed method for solving the problem. We prove the convergence of the generated sequence to the solution of the problem under certain assumption. We further discuss the convergence rate with an appropriate positive stepsize. A numerical experiment is given to show the effectiveness of the obtained theoretical result.
The sub-supersolution method for a nonhomogeneous elliptic equation involving Lebesgue generalized spaces
Authors: Figueiredo Giovany M. , Razani A.
Published: December 2021

In this paper, a nonhomogeneous elliptic equation of the form$$\begin{aligned}& - \mathcal{A}\bigl(x, \vert u \vert _{L^{r(x)}}\bigr) \operatorname{div}\bigl(a\bigl( \vert \nabla u \vert ^{p(x)}\bigr) \vert \nabla u \vert ^{p(x)-2} \nabla u\bigr) \\& \quad =f(x, u) \vert \nabla u \vert ^{\alpha (x)}_{L^{q(x)}}+g(x, u) \vert \nabla u \vert ^{ \gamma (x)}_{L^{s(x)}} \end{aligned}$$−A(x,|u|Lr(x))div(a(|∇u|p(x))|∇u|p(x)−2∇u)=f(x,u)|∇u|Lq(x)α(x)+g(x,u)|∇u|Ls(x)γ(x)on a bounded domain Ω in${\mathbb{R}}^{N}$RN($N >1$N>1) with$C^{2}$C2boundary, with a Dirichlet boundary condition is considered. Using the sub-supersolution method, the existence of at least one positive weak solution is proved. As an application, the existence of at least one solution of a generalized version of the logistic equation and a sublinear equation are shown.
Observational case series: six neurosurgical patients with septic shock demonstrating clinical improvement after a combination of standard care and blood purification
Authors: Burov A. I. , Abramov T. A. , Kostritca N. S. , Korotkov D. S. , Danilov G. V. , Strunina Y. V. , Savin I. A.
Published: December 2021

Background

For patients with primary brain injury, septic shock is especially dangerous due to the possibility of secondary cerebral damage. The key factor of sepsis-associated brain injury is inflammatory mediators, pathogen and damage-associated molecular patterns (PAMPs, DAMPs) release. Theoretically, blood purification may be beneficial for patients with primary brain injury due to its possibility for fast removal of inflammatory mediators.

Case presentation

We report on six post-neurosurgery septic shock patients treated with combined blood purification (CBP), which included CRRT with high adsorption capacity membrane in combination with CytoSorb adsorber. Clinical improvement in the course of CBP was registered in all patients. Three patients had a stable clinical improvement; the other three patients had only a transient improvement due to underlying neurological and cardiac deficits aggravation. We observed septic shock reversal in four patients. The key observations of the case series are a significant decrease in MOF severity (measured by SOFA score) and in catecholamine need (not statistically significant). By the end of CBP we observed a significant decrease in blood lactate, PCT and IL-6 levels. Two patients demonstrated level of consciousness increase in the setting of CBP therapy measured by GCS and FOUR score.

Conclusion

This case series demonstrates that CBP therapy may have a role for septic shock patients with primary brain injury.
Associations between facet tropism and vertebral rotation in patients with degenerative lumbar disease
Authors: Ma Yachao , Huang Peipei , Tu Zhipeng , Yao Zhou , Wang Zhe , Luo Zhuojing , Hu Xueyu
Published: December 2021

Background

Vertebral rotation and facet tropism are very common in various lumbar degenerative diseases. Facet tropism means the presence of asymmetric angles on both sides of the facet joints. Studies have shown that facet tropism contributes to lumbar degenerative disease, and also inevitably leads to the asymmetry of movement and the imbalance of force, which may be possible to rotate the vertebral body. The aim of this study was to explore the correlation between lumbar vertebral rotation and facet tropism in patients with lumbar degenerative diseases.

Methods

A total of 198 patients with lumbar degenerative diseases from 2018 to 2019 were enrolled. Five hundred and seventy vertebral rotation angles and 1140 facet angles were measured. The vertebral bodies are divided into non-rotation group (Group A) and rotation group (Group B) with the vertebral rotation angle of 3° as the boundary. The information including gender, age, BMI (body mass index), bone mineral density, history of smoking, drinking, hypertension, diabetes, diagnosis, segment distribution, and degree of facet degeneration were also counted. Using inter-class correlation coefficients (ICC) to test the reliability of measurement results. Univariate and multivariate logistic regression analysis were used to analyze the relationship between vertebral rotation and facet tropism.

Results

The consistency of the ICC within the groups of the observers is above 0.8, with good agreement. The results of univariate analysis showed that facet tropism was significantly different between group A and group B (OR (odds ratio)  = 3.30, 95% CI  =  2.03–5.35, P  < 0.0001). Other significant factors were included as adjustment variables into the multivariate regression model. Three models were analyzed separately (Model 1: non-adjusted. Model 2: adjust for age; facet degeneration; Model 3: adjust for age; disease distribution; segment distribution; facet degeneration). The results showed that after adjusting the confounders, the correlation between facet tropism and vertebral rotation did not change (Model 1: OR  = 3.30, 95% CI  = 2.03–5.35, P  < 0.0001; Model 2: adjusted OR  = 2.87, 95% CI  = 1.66–4.97, P  = 0.0002, Model 3: adjusted OR  = 2.84, 95% CI  = 1.56–5.17, P  = 0.0006).

Conclusion

Current research demonstrates that there is an association between vertebral rotation and facet tropism, suggesting that vertebral rotation may also have a certain degree of correlation with lumbar degenerative diseases.
Functional outcome of 103 fractures of the proximal fifth metatarsal bone
Authors: Pflüger Patrick , Zyskowski Michael , Müller Michael , Kirchhoff Chlodwig , Biberthaler Peter , Crönlein Moritz
Published: December 2021

Background

Metatarsal fractures are common skeletal injuries of the lower extremity in adults. The majority involves the proximal fifth metatarsal bone. In the current literature, there still exists controversy regarding treatment recommendations for the different fracture entities.

Methods

All patients suffering from single fractures to the proximal fifth metatarsal bone between 2003 and 2015 were enrolled in this retrospective analysis. Only patients with a minimum follow-up of 12 months were included. The fractures were classified according to Lawrence and Botte (L&B). Data were collected via patient registry, radiographs and a standardized questionnaire (Foot and Ankle Outcome Score = FOAS). For outcome analysis, the nonparametric Mann–Whitney U test was performed and Spearman’s rank correlation coefficient calculated.

Results

In total, the functional outcomes of 103 patients suffering from fractures to the proximal fifth metatarsal bone were analyzed. L&B type I fractures (n = 13) had a FAOS score of 91 ± 23, L&B type II (n = 67) presented a score of 91 ± 15 and L&B type III (n = 23) a score of 93 ± 11. Surgically treated patients with an L&B type II fracture had no statistically significant better functional outcome in comparison to conservative management (p = 0.89). Operatively treated L&B type III fractures tended to have a better functional score (p = 0.16). The follow-up time was 58 (min: 15; max: 164) months.

Conclusions

Overall, the functional outcome following fractures to the proximal fifth metatarsal bone is satisfactory. Conservatively treated L&B type II fractures showed an equivalent functional outcome compared to surgical management. Patients with an L&B type III fracture mainly were treated surgically, but difference in FAOS score did not reach level of significance.
Daratumumab and venetoclax in combination with chemotherapy provide sustained molecular remission in relapsed/refractory CD19, CD20, and CD22 negative acute B lymphoblastic leukemia with KMT2A-AFF1 transcript
Authors: Voruz Sophie , Blum Sabine , de Leval Laurence , Schoumans Jacqueline , Solly Françoise , Spertini Olivier
Published: December 2021

Relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) has a very poor prognosis with a median overall survival of four to nine months. Achieving a complete molecular response is most often required to obtain a sustained leukemia-free survival after allogeneic hematopoietic stem cell transplantation. Immunotherapies targeting CD19, CD20, or CD22 are very efficient in achieving this goal. However, in the absence of the expression of these immunotherapeutic targets by lymphoblasts, treatment options are extremely scarce. We report the successful treatment of a 26-year-old man who suffered R/R, CD19, CD20, and CD22 negative B-ALL targeting Bcl-2 and CD38 by combining venetoclax and daratumumab with chemotherapy.
The effect of two different types of forces on possible root resorption in relation to dentin phosphoprotein levels: a single-blind, split-mouth, randomized controlled trial
Authors: Ghaleb Sherifa , Tamish Nazla , ElKenany Walid , Guindi Myriam
Published: December 2021

Background

The purpose of this 2-arm-parallel split-mouth trial was to evaluate and compare the extent of possible root resorption using dentin phosphoprotein levels in gingival crevicular fluid between controlled continuous and intermittent orthodontic force groups.

Materials and methods

A sample of 16 maxillary first premolars from 8 patients requiring bilateral extractions of the upper first premolars as part of their orthodontic treatment were recruited. A buccally directed continuous force of 150 g, reactivated after 28 days, was applied to the upper first premolar on one side for 8 weeks. On the contralateral first premolar, a buccally directed intermittent force (21 days on, 7 days off) of the same magnitude was applied for the same period. Gingival crevicular fluid samples were collected at the beginning of the study, 1st, 3rd, 4th and 5th week, and at the end of the study to quantify and compare dentin phosphoprotein levels in both groups.

Results

Dentin phosphoprotein levels showed a higher concentration in the continuous force group than the intermittent force group in week 4 and 8 of sample collection; where the differences were statistically significant (95% CI 0.007–0.14; P < .04) and (95% CI 0.02–0.17; P < .04) respectively. No harm was observed.

Conclusions

Dentin phosphoprotein was found to be a useful early biomarker to detect and monitor root resorption, showing that the application of an intermittent orthodontic force caused less root resorption than a continuous force.

Trial registration

NCT04825665 ClinicalTrials.gov. Registered 1 April 2021—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04825665.
Intensive care unit versus high-dependency care unit for patients with acute heart failure: a nationwide propensity score-matched cohort study
Authors: Ohbe Hiroyuki , Matsui Hiroki , Yasunaga Hideo
Published: December 2021

Background

A structure and staffing model similar to that in general intensive care unit (ICUs) is applied to cardiac intensive care unit (CICUs) for patients with acute heart failure. However, there is limited evidence on the structure and staffing model of CICUs. The present study aimed to assess whether critical care for patients with acute heart failure in the ICUs is associated with improved outcomes than care in the high-dependency care units (HDUs), the hospital units in which patient care levels and costs are between the levels found in the ICU and general ward.

Methods

This nationwide, propensity score-matched, retrospective cohort study was performed using a national administrative inpatient database in Japan. We identified all patients who were hospitalized for acute heart failure and admitted to the ICU or HDU on the day of hospital admission from April 2014 to March 2019. Propensity score-matching analysis was performed to compare the in-hospital mortality between acute heart failure patients treated in the ICU and HDU on the day of hospital admission.

Results

Of 202,866 eligible patients, 78,646 (39%) and 124,220 (61%) were admitted to the ICU and HDU, respectively, on the day of admission. After propensity score matching, there was no statistically significant difference in in-hospital mortality between patients who were admitted to the ICU and HDU on the day of admission (10.7% vs. 11.4%; difference, − 0.6%; 95% confidence interval, − 1.5% to 0.2%). In the subgroup analyses, there was a statistically significant difference in in-hospital mortality between the ICU and HDU groups among patients receiving noninvasive ventilation (9.4% vs. 10.5%; difference, − 1.0%; 95% confidence interval, − 1.9% to − 0.1%) and patients receiving intubation (32.5% vs. 40.6%; difference, − 8.0%; 95% confidence interval, − 14.5% to − 1.5%). There were no statistically significant differences in other subgroup analyses.

Conclusions

Critical care in ICUs was not associated with lower in-hospital mortality than critical care in HDUs among patients with acute heart failure. However, critical care in ICUs was associated with lower in-hospital mortality than critical care in HDUs among patients receiving noninvasive ventilation and intubation.
Tide-induced magnetic signals and their errors derived from CHAMP and Swarm satellite magnetometer observations
Authors: Saynisch-Wagner Jan , Baerenzung Julien , Hornschild Aaron , Irrgang Christopher , Thomas Maik
Published: December 2021

Satellite-measured tidal magnetic signals are of growing importance. These fields are mainly used to infer Earth’s mantle conductivity, but also to derive changes in the oceanic heat content. We present a new Kalman filter-based method to derive tidal magnetic fields from satellite magnetometers: KALMAG. The method’s advantage is that it allows to study a precisely estimated posterior error covariance matrix. We present the results of a simultaneous estimation of the magnetic signals of 8 major tides from 17 years of Swarm and CHAMP data. For the first time, robustly derived posterior error distributions are reported along with the reported tidal magnetic fields. The results are compared to other estimates that are either based on numerical forward models or on satellite inversions of the same data. For all comparisons, maximal differences and the corresponding globally averaged RMSE are reported. We found that the inter-product differences are comparable with the KALMAG-based errors only in a global mean sense. Here, all approaches give values of the same order, e.g., 0.09 nT-0.14 nT for M2. Locally, the KALMAG posterior errors are up to one order smaller than the inter-product differences, e.g., 0.12 nT vs. 0.96 nT for M2.

Graphical Abstract
The initial learning curve for the ROSA® Knee System can be achieved in 6-11 cases for operative time and has similar 90-day complication rates with improved implant alignment compared to manual instrumentation in total knee arthroplasty
Authors: Vanlommel Luc , Neven Enrico , Anderson Mike B. , Bruckers Liesbeth , Truijen Jan
Published: December 2021

Purpose

The purpose of this study was to determine the learning curve for total operative time using a novel cutting guide positioning robotic assistant for total knee arthroplasty (raTKA). Additionally, we compared complications and final limb alignment between raTKA and manual TKA (mTKA), as well as accuracy to plan for raTKA cases.

Methods

We performed a retrospective cohort study on a series of patients (n = 180) that underwent raTKA (n = 90) using the ROSA Total Knee System or mTKA (n = 90) by one of three high-volume (> 200 cases per year) orthopaedic surgeons between December 2019 and September 2020, with minimum three-month follow-up. To evaluate the learning curve surgical times and postoperative complications were reviewed.

Results

The cumulative summation analysis for total operative time revealed a change point of 10, 6, and 11 cases for each of three surgeons, suggesting a rapid learning curve. There was a significant difference in total operative times between the learning raTKA and both the mastered raTKA and mTKA groups (p = 0.001) for all three surgeons combined. Postoperative complications were minimal in all groups. The proportion of outliers for the final hip-knee-ankle angle compared to planned was 5.2% (3/58) for the mastered raTKA compared to 24.1% (19/79) for mTKA (p = 0.003). The absolute mean difference between the validated and planned resections for all angles evaluated was < 1 degree for the mastered raTKA cases.

Conclusion

As the digital age of medicine continues to develop, advanced technologies may disrupt the industry, but should not disrupt the care provided. This cutting guide positioning robotic system can be integrated relatively quickly with a rapid initial learning curve (6-11 cases) for operative times, similar 90-day complication rates, and improved component positioning compared to mTKA. Proficiency of the system requires additional analysis, but it can be expected to improve over time.

Level of evidence

Level III Retrospective Therapeutic Cohort Study.
Non-coding RNAs and chromatin: key epigenetic factors from spermatogenesis to transgenerational inheritance
Authors: Cheuquemán Carolina , Maldonado Rodrigo
Published: December 2021

Cellular fate and gene expression patterns are modulated by different epigenetic factors including non-coding RNAs (ncRNAs) and chromatin organization. Both factors are dynamic throughout male germ cell differentiation on the seminiferous tubule, despite the transcriptional inactivation in the last stages of spermatogenesis. Sperm maturation during the caput-to-cauda transit on the epididymis involves changes in chromatin organization and the soma-to-germ line transference of ncRNAs that are essential to obtain a functional sperm for fertilization and embryo development. Here, the male environment (diseases, drugs, mental stress) is crucial to modulate these epigenetic factors throughout sperm maturation, affecting the corresponding offspring. Paternal transgenerational inheritance has been directly related to sperm epigenetic changes, most of them associated with variations in the ncRNA content and chromatin marks. Our aim is to give an overview about how epigenetics, focused on ncRNAs and chromatin, is pivotal to understand spermatogenesis and sperm maturation, and how the male environment impacts the sperm epigenome modulating the offspring gene expression pattern.
The therapeutic potential of mesenchymal stem cells in treating osteoporosis
Authors: Chen Tianning , Yang Tieyi , Zhang Weiwei , Shao Jin
Published: December 2021

Osteoporosis (OP), a common systemic metabolic bone disease, is characterized by low bone mass, increasing bone fragility and a high risk of fracture. At present, the clinical treatment of OP mainly involves anti-bone resorption drugs and anabolic agents for bone, but their long-term use can cause serious side effects. The development of stem cell therapy and regenerative medicine has provided a new approach to the clinical treatment of various diseases, even with a hope for cure. Recently, the therapeutic advantages of the therapy have been shown for a variety of orthopedic diseases. However, these stem cell-based researches are currently limited to animal models; the uncertainty regarding the post-transplantation fate of stem cells and their safety in recipients has largely restricted the development of human clinical trials. Nevertheless, the feasibility of mesenchymal stem cells to treat osteoporotic mice has drawn a growing amount of intriguing attention from clinicians to its potential of applying the stem cell-based therapy as a new therapeutic approach to OP in the future clinic. In the current review, therefore, we explored the potential use of mesenchymal stem cells in human OP treatment.
Indocyanine green fluorescence to ensure perfusion in middle segment-preserving pancreatectomy: a case report
Authors: Iguchi Tomohiro , Iseda Norifumi , Hirose Kosuke , Ninomiya Mizuki , Honboh Takuya , Maeda Takashi , Sawada Fumi , Tachibana Yu-ichi , Akashi Tetsuro , Sekiguchi Naotaka , Sadanaga Noriaki , Matsuura Hiroshi
Published: December 2021

Background

Middle segment-preserving pancreatectomy (MSPP) is an alternative to total pancreatectomy that allows for the preservation of the endocrine and exocrine functions of the pancreas. However, maintaining perfusion to the pancreatic remnant is of critical importance. We describe the first case to our knowledge in which indocyanine green (ICG) fluorescence was used to confirm perfusion to the pancreatic remnant during MSPP.

Case presentation

A 79-year-old man with diabetes mellitus was referred to our hospital for treatment of a pancreatic tumor. Computed tomography revealed a hypovascular mass in the uncus of the pancreas and dilatation of the main pancreatic duct, measuring 13 mm in the tail of the pancreas. He was diagnosed with cancer of the pancreatic uncus via endoscopic ultrasound and fine-needle aspiration revealed a mixed-type intraductal papillary mucinous neoplasm (IPMN), along with high-risk stigmata in the tail of the pancreas. We performed MSPP and the length of the pancreatic remnant was 4.6 cm. The dorsal pancreatic artery was preserved and perfusion to the pancreatic remnant was confirmed by ICG fluorescence. Histopathological examination showed a pancreatic ductal adenocarcinoma in the uncus (pT1cN1M0, pStage 2B) and IPMN in the tail of the pancreas. The postoperative course was complicated by a grade B pancreatic fistula, but this was successfully treated with conservative management. The patient was transferred to a hospital 33 days after surgery. Insulin administration was necessary, but C-peptide was detectable and blood glucose was relatively well-controlled. He did not exhibit any exocrine dysfunction when pancreatic enzyme supplementation was administered.

Conclusion

ICG fluorescence can be used to evaluate perfusion to the pancreatic remnant during MSPP.
Influence of vitreomacular interface score on treatment outcomes of anti-VEGF therapy for neovascular age-related macular degeneration
Authors: Miyata Manabu , Ooto Sotaro , Yamashiro Kenji , Tamura Hiroshi , Uji Akihito , Miyake Masahiro , Muraoka Yuki , Takahashi Ayako , Tsujikawa Akitaka
Published: December 2021

Background

To quantitatively evaluate the vitreomacular interface of eyes with neovascular age-related macular degeneration (AMD) and to investigate its association with the 1-year treatment outcome following intravitreal injections of aflibercept (IVA).

Methods

This prospective observational case series included 59 eyes of 59 consecutive patients with treatment-naïve neovascular AMD who were treated with three monthly IVA and subsequent four bi-monthly IVA and were followed up for 1 year. We estimated posterior vitreous detachment at 1, 9, and 25 macular points within an area of 6 × 6 mm2 at the center of the fovea using the built-in enhanced vitreous visualization mode of swept-source optical coherence tomography. One year after the initial IVA, we classified the eyes into either wet or dry groups.

Results

The wet and dry groups included 12 and 47 eyes, respectively. The resistance rate against IVA was 20.3%. The 25-point interface score was higher in the wet group than in the dry group (23.0 ± 4.3 vs. 18.6 ± 9.8, P = 0.03), whereas there were no significant between-group differences in the 9-point and 1-point scores (P = 0.21, and 0.47, respectively) or in the other studied parameters. Multivariable analysis revealed that the 25-point vitreomacular interface score was strongly correlated with subfoveal choroidal thickness (P = 0.02, β =  − 0.31).

Conclusions

Our findings suggest that wide-ranged separation of the posterior vitreous membrane from the retina induces poor response to IVA.
Update on surgical management of complex macular holes: a review
Authors: Abdul-Kadir Mohd-Asyraaf , Lim Lik Thai
Published: December 2021

Modern surgical interventions effectively treat macular holes (MHs) more than 90%. Current surgical treatment for MHs is pars plana vitrectomy with epiretinal membrane, internal limiting membrane (ILM) peeling, gas endotamponade, and prone posturing postoperatively. However, a small subset of MHs imposes challenges to surgeons and frustrations on patients. A narrative review was performed on the surgical treatment of challenging MHs including large and extra-large MHs, myopic MHs with or without retinal detachment, and chronic and refractory MHs. There are robust data supporting inverted ILM flap as the first-line treatment for large idiopathic MHs and certain secondary MHs including myopic MHs. In addition, several studies had shown that ILM flap manipulations in combination with surgical adjuncts increase surgical success, especially in difficult MHs. Even in eyes with limited ILM, surgical options included autologous retinal graft, human amniotic membrane, and creation of a distal ILM flap that can assist in MH closure even though the functional outcome may be affected by the MH chronicity. Despite relative success anatomically and visually after each technique, most techniques require a long-term study to analyze their safety profile and to establish any morphological changes of the MH plug in the closed MHs.
A bridging assay for detection and characterization of anti-drug antibodies to dostarlimab, a new anti-PD-1 therapeutic monoclonal antibody
Authors: Patterson Marilyn , Beausang Lee Anne , Rup Bonita , Bowsher Ronald R. , Krug Kim , Melhem Murad , Lu Sharon
Published: December 2021

Dostarlimab (JEMPERLI) is a humanized anti-programmed death 1 (PD-1) immunoglobulin (Ig)G4-kappa monoclonal antibody that binds to the PD-1 receptor and competitively inhibits binding of its ligands, PD-L1 and PD-L2. Dostarlimab was recently approved in the USA and the European Union. Because dostarlimab is a macromolecular therapeutic, it has the potential to elicit the formation of anti-drug antibodies, which have the capability to impact the drug’s safety and efficacy and to alter pharmacokinetics. The immunogenic potential of dostarlimab remains unknown, and it was therefore necessary to develop analytical assays to detect and characterize anti-drug antibodies as a key component in the mitigation of immunogenicity risk. Here, we present the development and optimization of a 3-tiered electrochemiluminescense bridging assay for the investigation of dostarlimab clinical immunogenicity. In this work, the full details of the method, statistical data analysis and cut point determinations, assay performance during clinical sample analysis, and associated regulatory expectations are discussed. The full validation of this 3-tier anti-drug antibody assay enabled dostarlimab immunogenicity evaluation in clinical studies. Trial registration: Clinicaltrials.gov, NCT02715284. Registered 9 March 2016
Tuberculosis in the middle of COVID-19 in Morocco: efforts, challenges and recommendations
Authors: Bouaddi Oumnia , Hasan Mohammad Mehedi , Sahito Abdul Moiz , Shah Pritik A. , Mohammed Abdelrahman Zaki Ali , Essar Mohammad Yasir
Published: December 2021

Tuberculosis (TB) is a deadly infectious disease that kills approximately 1.5 million people per year and is among the most frequent respiratory infections in developing countries. Morocco has made significant progress in the control and management of TB during the past 30 years thanks to its National Plan for Tuberculosis and the continuous support of national and international partners. While tremendous efforts were undertaken to tilt the balance against the COVID-19 pandemic, new challenges resurfaced with regard to long-standing health problems amongst which is TB. The spill-over effect of the COVID-19 pandemic disrupted health service delivery globally, threatening to reverse years of progress made on the TB control front. In Morocco, this crisis highlighted deep shortcomings within the national health system and in the adopted approach to TB control. This article discusses national efforts to get back on track with regard to TB management, the multitude of challenges that co-emerged with the onset of COVID-19 and lays down key recommendations to implement in order to build back a TB control plan that is resilient in the face of health hazards.
A demographic profile of cervical injury: an Indonesian single tertiary hospital study with 6 months to 1-year follow-up
Authors: Widhiyanto Lukas , Japamadisaw Aliefio , Hernugrahanto Kukuh Dwiputra
Published: December 2021

Background

Spinal cord injury (SCI) can cause considerable morbidity and mortality. Until now there is no spinal cord injury profile in Indonesia. Therefore, this study aims to provide an overview of the spinal cord injury profile as well as to analyze the functional outcome at the sixth month and the first year.

Results

Most spinal cord injury cases were traumatic SCI (67.5%). Meanwhile, non-traumatic SCI was 32.5%. The mean age of patients who had traumatic SCI was 41.9 ± 17.4 years while non-traumatic SCI patients was 48.4 ± 13.7 with a significant difference (p < 0.05). Most cases occurred in men rather than women with significant differences based on the type of injury (p < 0.05). Traffic accidents were the most common cause of cervical injuries (47.1%). Surgery was the most common treatment modality in cervical injury cases (60.4%) with the posterior approach being the preferred approach in most operative measures (72.4%). Respiratory failure was the leading cause of death (48.9%). The mean LOS of patients with traumatic SCI was 28.8 ± 14.3 days while the mean LOS of non-traumatic SCI patients was 44.7 ± 28.7 with a significant difference (p < 0.05). There was significance difference between the initial outcome and after the sixth month to first year follow-up (p < 0.05).

Conclusions

This study demonstrated the epidemiology and characteristics of spinal cord injury which mostly had a good neurological outcome.
Health-Related Quality of Life in Metastatic, Hormone-Sensitive Prostate Cancer: ENZAMET (ANZUP 1304), an International, Randomized Phase III Trial Led by ANZUP
Authors: Stockler Martin R. , Martin Andrew J. , Davis Ian D. , Dhillon Haryana M. , Begbie Stephen D. , Chi Kim N. , Chowdhury Simon , Coskinas Xanthi , Frydenberg Mark , Hague Wendy E. , Horvath Lisa G. , Joshua Anthony M. , Lawrence Nicola J. , Marx Gavin M. , McCaffrey John , McDermott Ray , McJannett Margaret , North Scott A. , Parnis Francis , Parulekar Wendy R. , Pook David W. , Reaume M. Neil , Sandhu Shahneen , Tan Alvin , Tan Thean Hsiang , Thomson Alastair , Vera-Badillo Francisco , Williams Scott G. , Winter Diana G. , Yip Sonia , Zhang Alison Y. , Zielinski Robert R. , Sweeney Christopher J. ,   for the ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: December 2021

PURPOSE

We previously reported that enzalutamide improved overall survival when added to standard of care in metastatic, hormone-sensitive prostate cancer. Here, we report its effects on aspects of health-related quality of life (HRQL).

METHODS

HRQL was assessed with the European Organisation for Research and Treatment of Cancer core quality-of-life questionnaire and QLM-PR25 at weeks 0, 4, 12, and then every 12 weeks until progression. Scores from week 4 to 156 were analyzed with repeated measures modeling to calculate group means and differences. Deterioration-free survival was from random assignment until the earliest of death, clinical progression, discontinuation of study treatment, or a worsening of 10 points or more from baseline in fatigue, physical function, cognitive function, or overall health and quality of life (OHQL). HRQL scores range from 0 (lowest possible) to 100 (highest possible).

RESULTS

HRQL was assessed in 1,042 of 1,125 participants (93%). Differences in means favored control over enzalutamide for fatigue (5.2, 95% CI, 3.6 to 6.9; P < .001), cognitive function (4.0, 95% CI, 2.5 to 5.5; P < .001), and physical function (2.6, 95% CI, 1.3 to 3.9; P < .001), but not OHQL (1.2, 95% CI, −0.2 to 2.7; P = .1). Deterioration-free survival rates at 3 years, and log-rank P values comparing the whole distributions, favored enzalutamide over control for OHQL (31% v 17%; P < .0001), cognitive function (31% v 20%; P = .001), and physical function (31% v 22%; P < .001), but not fatigue (24% v 18%; P = .16). The effects of enzalutamide on HRQL were independent of baseline characteristics.

CONCLUSION

Enzalutamide was associated with worsening of self-reported fatigue, cognitive function, and physical function, but not OHQL. Enzalutamide was associated with improved deterioration-free survival for OHQL, physical function, and cognitive function because delays in disease progression outweighed early deteriorations in these aspects of HRQL.
Parietal epithelial cells maintain the epithelial cell continuum forming Bowman's space in focal segmental glomerulosclerosis
Authors: Miesen Laura , Bándi Péter , Willemsen Brigith , Mooren Fieke , Strieder Thiago , Boldrini Eva , Drenic Vedran , Eymael Jennifer , Wetzels Roy , Lotz Johannes , Weiss Nick , Steenbergen Eric , van Kuppevelt Toin H. , van Erp Merijn , van der Laak Jeroen , Endlich Nicole , Moeller Marcus J. , Wetzels Jack F. M. , Jansen Jitske , Smeets Bart
Published: December 2021

In the glomerulus, Bowman's space is formed by a continuum of glomerular epithelial cells. In focal segmental glomerulosclerosis (FSGS), glomeruli show segmental scarring, a result of activated parietal epithelial cells (PECs) invading the glomerular tuft. The segmental scars interrupt the epithelial continuum. However, non-sclerotic segments seem to be preserved even in glomeruli with advanced lesions. We studied the histology of the segmental pattern in Munich Wistar Frömter rats, a model for secondary FSGS. Our results showed that matrix layers lined with PECs cover the sclerotic lesions. These PECs formed contacts with podocytes of the uninvolved tuft segments, restoring the epithelial continuum. Formed Bowman's spaces were still connected to the tubular system. In biopsies of patients with secondary FSGS, we also detected matrix layers formed by PECs, separating the uninvolved from the sclerotic glomerular segments. PECs have a major role in the formation of glomerulosclerosis; we show here that in FSGS they also restore the glomerular epithelial cell continuum that surrounds Bowman's space. This process may be beneficial and indispensable for glomerular filtration in the uninvolved segments of sclerotic glomeruli.
Acute haemorrhage rate in 28,000 Out-of-Hours CT heads
Authors: Hocking Katherine C , Wright Catriona R , Alhun Utku , Hughes Frances , Balian Vartan J , Kabuli Mohammed A K , Tse George , McGonnell Maria , Chopra Annu , Kotnis Nikhil , Connelly Daniel , Alabed Samer
Published: December 2021

Objectives:

The aim of this paper is to assess the acute haemorrhage rate in patients who had CT head investigation out-of-hours with and without trauma and compare the rates of haemorrhage between warfarin and DOACs, at a busy teritary teaching hospital.

Methods:

All CT heads performed between January 2008 and December 2019 were identified from the radiology information system (RIS) at Sheffield Teaching Hospitals (STH), with the requesting information being available from January 2015. The clinical information was assessed for the mention of trauma or anticoagulation, and the reports were categorised into acute and non-acute findings.

Results:

Between 2008 and 2019 the number of scans increased by 63%, with scans performed out of hours increasing by 278%. Between 2015 and 2019, the incidence of acute ICH was similar over the 5-year period, averaging at 6.9% and ranging from 6.1 to 7.6%. The rate of detection of acute haemorrhage following trauma was greater in those not anticoagulated (6.8%), compared with patients on anticoagulants such as warfarin (5.2%) or DOACs (2.8%).

Conclusions:

Over 12 years, there has been a significant increase in the number of CT heads performed at STH. The rate of ICH has remained steady over the last 5 years indicating a justified increase in imaging demand. However, the incidence of ICH in patients prescribed DOACs is lower than the general population and those on warfarin.

Advances in knowledge:

This finding in a large centre should prompt discussion of the risk of bleeding with DOACs in relation to CT head imaging guidelines.