bluuebunny/crossref_metadata_2025 huggingface dataset:
Local myocardial stiffness variations identified by high frame rate shear wave echocardiography
Authors: Strachinaru Mihai , Bosch Johan G. , Schinkel Arend F. L. , Michels Michelle , Feyz Lida , de Jong Nico , Geleijnse Marcel L. , Vos Hendrik J.
Published: September 2020

Background

Shear waves are generated by the closure of the heart valves. Significant differences in shear wave velocity have been found recently between normal myocardium and disease models of diffusely increased muscle stiffness. In this study we correlate in vivo myocardial shear wave imaging (SWI) with presence of scarred tissue, as model for local increase of stiffness. Stiffness variation is hypothesized to appear as velocity variation.

Methods

Ten healthy volunteers (group 1), 10 hypertrophic cardiomyopathy (HCM) patients without any cardiac intervention (group 2), and 10 HCM patients with prior septal reduction therapy (group 3) underwent high frame rate tissue Doppler echocardiography. The SW in the interventricular septum after aortic valve closure was mapped along two M-mode lines, in the inner and outer layer.

Results

We compared SWI to 3D echocardiography and strain imaging. In groups 1 and 2, no change in velocity was detected. In group 3, 8/10 patients showed a variation in SW velocity. All three patients having transmural scar showed a simultaneous velocity variation in both layers. Out of six patients with endocardial scar, five showed variations in the inner layer.

Conclusion

Local variations in stiffness, with myocardial remodeling post septal reduction therapy as model, can be detected by a local variation in the propagation velocity of naturally occurring shear waves.
Measurement properties of EQ-5D-3L and EQ-5D-5L in recording self-reported health status in older patients with substantial multimorbidity and polypharmacy
Authors: Bhadhuri Arjun , Kind Paul , Salari Paola , Jungo Katharina Tabea , Boland Benoît , Byrne Stephen , Hossmann Stefanie , Dalleur Olivia , Knol Wilma , Moutzouri Elisavet , O’Mahony Denis , Murphy Kevin D. , Wisselink Linda , Rodondi Nicolas , Schwenkglenks Matthias
Published: September 2020

Background

The EQ-5D-3L and EQ-5D-5L are two generic health-related quality of life measures, which may be used in clinical and health economic research. They measure impairment in 5 aspects of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The aim of this study was to assess the performance of the EQ-5D-3L and EQ-5D-5L in measuring the self-reported health status of older patients with substantial multimorbidity and associated polypharmacy.

Methods

Between 2017 and 2019, we administered EQ-5D-3L and EQ-5D-5L to a subset of patients participating in the OPERAM trial at 6 months and 12 months after enrolment. The OPERAM trial is a two-arm multinational cluster randomised controlled trial of structured medication review assisted by a software-based decision support system versus usual pharmaceutical care, for older people (aged ≥ 70 years) with multimorbidity and polypharmacy. In the psychometric analyses, we only included participants who completed the measures in full at 6 and 12 months. We assessed whether responses to the measures were consistent by assessing the proportion of EQ-5D-5L responses, which were 2 or more levels away from that person’s EQ-5D-3L response. We also compared the measures in terms of informativity, and discriminant validity and responsiveness relative to the Barthel Index, which measures independence in activities of daily living.

Results

224 patients (mean age of 77 years; 56% male) were included in the psychometric analyses. Ceiling effects reported with the EQ-5D-5L (22%) were lower than with the EQ-5D-3L (29%). For the mobility item, the EQ-5D-5L demonstrated better informativity (Shannon’s evenness index score of 0.86) than the EQ-5D-3L (Shannon’s evenness index score of 0.69). Both the 3L and 5L versions of EQ-5D demonstrated good performance in terms of discriminant validity, i.e. (out of all items of the EQ-5D-3L and EQ-5D-5L, the pain/discomfort and anxiety/depression items had the weakest correlation with the Barthel Index. Both the 3L and 5L versions of EQ-5D demonstrated good responsiveness to changes in the Barthel Index.

Conclusion

Both EQ-5D-3L and EQ-5D-5L demonstrated validity and responsiveness when administered to older adults with substantial multimorbidity and polypharmacy who were able to complete the measures.
Assessing how information is packaged in rapid reviews for policy-makers and other stakeholders: a cross-sectional study
Authors: Garritty Chantelle , Hamel Candyce , Hersi Mona , Butler Claire , Monfaredi Zarah , Stevens Adrienne , Nussbaumer-Streit Barbara , Cheng Wei , Moher David
Published: September 2020

Background

Rapid reviews (RRs) are useful products to healthcare policy-makers and other stakeholders, who require timely evidence. Therefore, it is important to assess how well RRs convey useful information in a format that is easy to understand so that decision-makers can make best use of evidence to inform policy and practice.

Methods

We assessed a diverse sample of 103 RRs against the BRIDGE criteria, originally developed for communicating clearly to support healthcare policy-making. We modified the criteria to increase assessability and to align with RRs. We identified RRs from key database searches and through searching organisations known to produce RRs. We assessed each RR on 26 factors (e.g. organisation of information, lay language use). Results were descriptively analysed. Further, we explored differences between RRs published in journals and those published elsewhere.

Results

Certain criteria were well covered across the RRs (e.g. all aimed to synthesise research evidence and all provided references of included studies). Further, most RRs provided detail on the problem or issue (96%; n = 99) and described methods to conduct the RR (91%; n = 94), while several addressed political or health systems contexts (61%; n = 63). Many RRs targeted policy-makers and key stakeholders as the intended audience (66%; n = 68), yet only 32% (n = 33) involved their tacit knowledge, while fewer (27%; n = 28) directly involved them reviewing the content of the RR. Only six RRs involved patient partners in the process. Only 23% (n = 24) of RRs were prepared in a format considered to make information easy to absorb (i.e. graded entry) and 25% (n = 26) provided specific key messages. Readability assessment indicated that the text of key RR sections would be hard to understand for an average reader (i.e. would require post-secondary education) and would take 42 (± 36) minutes to read.

Conclusions

Overall, conformity of the RRs with the modified BRIDGE criteria was modest. By assessing RRs against these criteria, we now understand possible ways in which they could be improved to better meet the information needs of healthcare decision-makers and their potential for innovation as an information-packaging mechanism. The utility and validity of these items should be further explored.

Protocol availability

The protocol, published on the Open Science Framework, is available at: osf.io/68tj7
Policy dialogue and participation: a new way of crafting a national health financing strategy in Morocco
Authors: Akhnif El Houcine , Hachri Hafid , Belmadani Abdelouahab , Mataria Awad , Bigdeli Maryam
Published: September 2020

Background

Policy dialogue for health policies has started to gain importance in recent years, especially for complex issues such as health financing. Moroccan health financing has faced several challenges during the last years. This study aims to document the Moroccan experience in developing a consolidated health financing strategy according to the policy dialogue approach. It especially considers the importance of conceptualising this process in the Moroccan context.

Method

We documented the process of developing a health financing strategy in Morocco. It concerned four steps, as follows: (1) summarising health financing evidence in preparation of the policy dialogue; (2) organising the health policy dialogue process with 250 participants (government, private sector, NGOs, civil society, parliamentarians, technical and financial partners); (3) a technical workshop to formulate the strategy actions; and (4) an ultimate workshop for validation with decision-makers. The process lasted 1 year from March 2019 to February 2020. We have reviewed all documents related to the four steps of the process through our active participation in the policy debate and the documentation of two technical workshops to produce the strategy document.

Results

The policy dialogue approach showed its usefulness in creating convergence among all health actors to define a national shared vision on health financing in Morocco. There was a high political commitment in the process and all actors officially adopted recommendations on health financing actions. A strategy document produced within a collaborative approach was the final output. This experience also marked a shift from previous top-down approaches in designing health policies for more participation and inclusion. The evidence synthesis played a crucial role in facilitating the debate. The collaborative approach seems to work in favouring national consensus on practical health financing actions.

Conclusion

The policy dialogue process adopted for health financing in Morocco helped to create collective ownership of health financing actions. Despite the positive results in terms of national mobilisation around the health financing vision in Morocco, there is a need to institutionalise the policy dialogue with a more decentralised approach to consider subnational specificities.
Characterization of the expression and immunological impact of the transcriptional activator CREB in renal cell carcinoma
Authors: Friedrich Michael , Stoehr Christine , Jasinski-Bergner Simon , Hartmann Arndt , Wach Sven , Wullich Bernd , Steven André , Seliger Barbara
Published: September 2020

Background

The non-classical human leukocyte antigen (HLA)-G is a strong immunomodulatory molecule. Under physiological conditions, HLA-G induces immunological tolerance in immune privileged tissues, while under pathophysiological situations it contributes to immune escape mechanisms. Therefore, HLA-G could act as a potential immune checkpoint for future anti-cancer immunotherapies. Recent data suggest an aberrant expression of the cAMP response element binding protein (CREB) in clear cell renal cell carcinoma (ccRCC), which is correlated with tumor grade and stage. Furthermore, preliminary reports demonstrated a connection of CREB as a control variable of HLA-G transcription due to CREB binding sites in the HLA-G promoter region. This study investigates the interaction between CREB and HLA-G in different renal cell carcinoma (RCC) subtypes and its correlation to clinical parameters.

Methods

The direct interaction of CREB with the HLA-G promoter was investigated by chromatin immunoprecipitation in RCC cell systems. Furthermore, the expression of CREB and HLA-G was determined by immunohistochemistry using a tissue microarray (TMA) consisting of 453 RCC samples of distinct subtypes. Staining results were assessed for correlations to clinical parameters as well as to the composition of the immune cell infiltrate.

Results

There exists a distinct expression pattern of HLA-G and CREB in the three main RCC subtypes. HLA-G and CREB expression were the lowest in chromophobe RCC lesions. However, the clinical relevance of CREB and HLA-G expression differed. Unlike HLA-G, high levels of CREB expression were positively associated to the overall survival of RCC patients. A slightly, but significantly elevated number of tumor infiltrating regulatory T cells was observed in tumors of high CREB expression. Whether this small increase is of clinical relevance has to be further investigated.

Conclusions

An interaction of CREB with the HLA-G promoter could be validated in RCC cell lines. Thus, for the first time the expression of CREB and its interaction with the HLA-G in human RCCs has been shown, which might be of clinical relevance.
Increased HIV-1 pretreatment drug resistance with consistent clade homogeneity among ART-naive HIV-1 infected individuals in Ethiopia
Authors: Kiros Mulugeta , Alemayehu Dawit Hailu , Geberekidan Eleni , Mihret Adane , Maier Melanie , Abegaz Woldaregay Erku , Mulu Andargachew
Published: September 2020

Background

The development of pretreatment drug resistance (PDR) is becoming an obstacle to the success of antiretroviral therapy (ART). Besides, data from developing settings including Ethiopia is still limited. Therefore, this study was aimed to assess HIV-1 genetic diversity and PDR mutations among ART-naive recently diagnosed HIV-1 infected individuals in Addis Ababa, Ethiopia.

Methods

Institutional based cross-sectional study was conducted from June to December 2018 in Addis Ababa among ART-naive recently diagnosed individuals. Partial HIV-1 pol region covering the entire protease (PR) and partial reverse transcriptase (RT) regions of 51 samples were amplified and sequenced using an in-house assay. Drug resistance mutations were examined using calibrated population resistance (CPR) tool version 6.0 from the Stanford HIV drug resistance database and the International Antiviral Society-USA (IAS-USA) 2019 mutation list.

Results

According to both algorithms used, 9.8% (5/51) of analyzed samples had at least one PDR Mutation. PDR mutations to Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) were the most frequently detected (7.8% and 9.8%, according to the CPR tool and IAS-USA algorithm, respectively). The most frequently observed NNRTIs-associated mutations common to both algorithms were K103N (2%), Y188L (2%), K101E (2%), and V106A (2%), while E138A (2%) was observed according to IAS-USA only. Y115F and M184V (mutations that confer resistance to NRTIs) dual mutations were detected according to both criteria in a single study participant (2%). PDR mutation to protease inhibitors was found to be low (only G73S; 2% according to the CPR tool). Phylogenetic analysis showed that 98% (50/51) of the study participants were infected with HIV-1C virus while one individual (2%) was infected with HIV-1A1 virus.

Conclusions

This study showed an increased level of PDR and persistence HIV-1C clade homogeneity after 15 years of the rollout of ART and 3 decades of HIV-1C circulation in Ethiopia, respectively. Therefore, we recommend routine baseline genotypic drug resistance testing for all newly diagnosed HIV infected patients before initiating treatment. This will aid the selection of appropriate therapy in achieving the 90% of patients having an undetectable viral load in consonance with the UN target.
Viruses of protozoan parasites and viral therapy: Is the time now right?
Authors: Barrow Paul , Dujardin Jean Claude , Fasel Nicolas , Greenwood Alex D. , Osterrieder Klaus , Lomonossoff George , Fiori Pier Luigi , Atterbury Robert , Rossi Matteo , Lalle Marco
Published: September 2020

Infections caused by protozoan parasites burden the world with huge costs in terms of human and animal health. Most parasitic diseases caused by protozoans are neglected, particularly those associated with poverty and tropical countries, but the paucity of drug treatments and vaccines combined with increasing problems of drug resistance are becoming major concerns for their control and eradication. In this climate, the discovery/repurposing of new drugs and increasing effort in vaccine development should be supplemented with an exploration of new alternative/synergic treatment strategies. Viruses, either native or engineered, have been employed successfully as highly effective and selective therapeutic approaches to treat cancer (oncolytic viruses) and antibiotic-resistant bacterial diseases (phage therapy). Increasing evidence is accumulating that many protozoan, but also helminth, parasites harbour a range of different classes of viruses that are mostly absent from humans. Although some of these viruses appear to have no effect on their parasite hosts, others either have a clear direct negative impact on the parasite or may, in fact, contribute to the virulence of parasites for humans. This review will focus mainly on the viruses identified in protozoan parasites that are of medical importance. Inspired and informed by the experience gained from the application of oncolytic virus- and phage-therapy, rationally-driven strategies to employ these viruses successfully against parasitic diseases will be presented and discussed in the light of the current knowledge of the virus biology and the complex interplay between the viruses, the parasite hosts and the human host. We also highlight knowledge gaps that should be addressed to advance the potential of virotherapy against parasitic diseases.
Influence of multiple apolipoprotein A-I and B genetic variations on insulin resistance and metabolic syndrome in obstructive sleep apnea
Authors: Li Xinyi , Fu Zhihui , Xu Huajun , Zou Jianyin , Zhu Huaming , Li Zhiqiang , Su Kaiming , Huai De , Yi Hongliang , Guan Jian , Yin Shankai
Published: September 2020

Background

The relationships between apolipoprotein A-I (APOA-I), apolipoprotein B (APOB) with insulin resistance, metabolic syndrome (MetS) are unclear in OSA. We aimed to evaluate whether the multiple single nucleotide polymorphism (SNP) variants of APOA-I and APOB exert a collaborative effect on insulin resistance and MetS in OSA.

Methods

Initially, 12 APOA-I SNPs and 30 APOB SNPs in 5259 subjects were examined. After strict screening, four APOA-I SNPs and five APOB SNPs in 4007 participants were included. For each participant, the genetic risk score (GRS) was calculated based on the cumulative effect of multiple genetic variants of APOA-I and APOB. Logistic regression analyses were used to evaluate the relationships between APOA-I/APOB genetic polymorphisms, insulin resistance, and MetS in OSA.

Results

Serum APOB levels increased the risk of insulin resistance and MetS adjusting for age, gender and BMI [odds ratio (OR = 3.168, P < 0.001; OR = 6.098, P < 0.001, respectively]. APOA-I GRS decreased the risk of insulin resistance and MetS after adjustments (OR = 0.917, P = 0.001; OR = 0.870, P < 0.001, respectively). APOB GRS had no association with insulin resistance (OR = 1.364, P = 0.610), and had weak association with MetS after adjustments (OR = 1.072, P = 0.042). In addition, individuals in the top quintile of the APOA-I genetic score distribution had a lower risk of insulin resistance and MetS after adjustments (OR = 0.761, P = 0.007; OR = 0.637, P < 0.001, respectively).

Conclusions

In patients with OSA, cumulative effects of APOA-I genetic variations decreased the risk of insulin resistance and MetS, whereas multiple APOB genetic variations had no associations with insulin resistance and weak association with MetS.
Costing the implementation of public health interventions in resource-limited settings: a conceptual framework
Authors: Sohn Hojoon , Tucker Austin , Ferguson Olivia , Gomes Isabella , Dowdy David
Published: September 2020

Background

Failing to account for the resources required to successfully implement public health interventions can lead to an underestimation of costs and budget impact, optimistic cost-effectiveness estimates, and ultimately a disconnect between published evidence and public health decision-making.

Methods

We developed a conceptual framework for assessing implementation costs. We illustrate the use of this framework with case studies involving interventions for tuberculosis and HIV/AIDS in resource-limited settings.

Results

Costs of implementing public health interventions may be conceptualized as occurring across three phases: design, initiation, and maintenance. In the design phase, activities include developing intervention components and establishing necessary infrastructure (e.g., technology, standard operating procedures). Initiation phase activities include training, initiation of supply chains and quality assurance procedures, and installation of equipment. Implementation costs in the maintenance phase include ongoing technical support, monitoring and evaluation, and troubleshooting unexpected obstacles. Within each phase, implementation costs can be incurred at the site of delivery (“site-specific” costs) or more centrally (“above-service” or “central” costs). For interventions evaluated in the context of research studies, implementation costs should be classified as programmatic, research-related, or shared research/program costs. Purely research-related costs are often excluded from analysis of programmatic implementation.

Conclusions

In evaluating public health interventions in resource-limited settings, accounting for implementation costs enables more realistic estimates of budget impact and cost-effectiveness and provides important insights into program feasibility, scale-up, and sustainability. Assessment of implementation costs should be planned prospectively and performed in a standardized manner to ensure generalizability.
Can posterior stand-alone expandable cages safely restore lumbar lordosis? A minimum 5-year follow-up study
Authors: Kim Seung-Kook , Elbashier Ogeil Mubarak , Lee Su-chan , Choi Woo-Jin
Published: September 2020

Background

Lumbar lordosis (LL) can be restored, and screw-related complications may be avoided with the stand-alone expandable cage method. However, the long-term spinopelvic changes and safety remain unknown. We aimed to elucidate the long-term radiologic outcomes and safety of this technique.

Methods

Data from patients who underwent multi-level stand-alone expandable cage fusion and 80 patients who underwent screw-assisted fusion between February 2007 and December 2012, with at least 5 years of follow-up, were retrospectively analyzed. Segmental angle and translation, short and whole LL, pelvic incidence, pelvic tilt, sacral slope (SS), sagittal vertical axis, thoracic kyphosis, and presence of subsidence, pseudoarthrosis, retropulsion, cage breakage, proximal junctional kyphosis (PJK), and screw malposition were assessed. The relationship between local, lumbar, and spinopelvic effects was investigated. The implant failure rate was considered a measure of procedure effectiveness and safety.

Results

In total, 69 cases were included in the stand-alone expandable cage group and 150 cases in the control group. The stand-alone group showed shorter operative time (58.48 ± 11.10 vs 81.43 ± 13.75, P = .00028), lower rate of PJK (10.1% vs 22.5%, P = .03), and restoration of local angle (4.66 ± 3.76 vs 2.03 ± 1.16, P = .000079) than the control group. However, sagittal balance (0.01 ± 2.57 vs 0.50 ± 2.10, P = .07) was not restored, and weakness showed higher rate of subsidence (16.31% vs 4.85%, P = .0018), pseudoarthrosis (9.92% vs 2.42%, P = .02), cage, and retropulsion (3.55% vs 0, P = .01) than the control group.

Conclusions

Stand-alone expandable cage fusion can restore local lordosis; however, global sagittal balance was not restored. Furthermore, implant safety has not yet been proven.
Assessment of carotid artery stenosis and lower limb peripheral ischemia before coronary artery bypass grafting operations: a non-randomized clinical trial
Authors: Ali Ihab , Shokri Hoda , Abd Al Jawad Mohammed
Published: September 2020

Background

Atherosclerosis is a systemic disease affecting the coronary, carotid, and lower limb arteries. Cerebrovascular accidents and lower limb ischemia are devastating postoperative complications. We aimed to evaluate the role of non-selective routine arterial duplex scanning in patients undergoing coronary artery bypass grafting (CABG).

Methods

This non-randomized clinical trial included 360 patients scheduled for elective isolated CABG who were divided into two groups: low-risk (n = 180) and high-risk (n = 180). Both groups underwent preoperative carotid and lower limb ultrasound screening for associated arteriopathy.

Results

16 (8.9%) patients and 22 (12.2%) patients showed ≥70% carotid artery stenosis while 11 patients (6.1%) and 20 patients (11.1%) showed ≥50% lower limb arterial stenosis in the low-risk group and the high-risk group, respectively; though the difference was not statistically significant in both the cases (p > 0.1).

Conclusion

Routine preoperative peripheral arterial screening by sonography is a feasible and effective strategy to avoid unnecessary post CABG complications.

Trial registration

NCT03516929, Registered in 24 th of April 2018.
Hejie Zhitong prescription promotes sleep and inhibits nociceptive transmission-associated neurotransmitter activity in a rodent migraine model
Authors: Wang Xinna , Zhao Hongfei , Liu Liming , Niu Ping , Zhai Chao , Li Jinjian , Xu Qiaoli , Zhao Dexi
Published: September 2020

Background

Migraine is painful disease in which neurotransmitters related to pain transmission play an important role. Hejie Zhitong prescription (HJZT) has been used in the clinic as an effective prescription for the treatment of migraine for many years. Our team aimed to further explore its antimigraine mechanism based on previous research results and to explore the inhibitory effect of HJZT on the transmission of pain related to nitroglycerine (NTG)-induced migraine as well as the synergistic effect of HJZT with pentobarbital sodium on promoting sleep.

Methods

Sixty mice were randomly assigned to groups and received the corresponding interventions. Sleep latency and sleep time were recorded to calculate the incidence of sleep. Forty-eight Wistar rats were randomly assigned and administered an intervention corresponding to their group. Calcitonin gene-related peptide (CGRP), serotonin (5-HT), substance P (SP), and cholecystokinin (CCK) levels were measured using ELISAs. Levels of the cannabinoid receptor type 1 (CB1R) and cyclooxygenase-2 (COX-2) protein were assessed using immunohistochemistry. The expression of the CGRP and CCK mRNAs in the midbrain and trigeminal ganglion (TG) were measured using real-time quantitative PCR.

Results

HJZT promoted the occurrence of sleep in mice. HJZT downregulated COX-2 expression in the midbrain and TG of rats but upregulated the expression of the CB1R, and decreased the plasma level of the CGRP protein and expression of its mRNA in the midbrain and TG. It also downregulated the expression of the CCK mRNA in the midbrain and TG. The high-dose HJZT treatment increased plasma 5-HT levels, but did not induce changes in the plasma levels of the SP or CCK protein.

Conclusions

HJZT exerts a synergistic effect with pentobarbital sodium on promoting sleep. As for anti-migraine, HJZT can inhibits the expression of nociceptive transmission-associated neurotransmitters, including 5-HT, CGRP and CCK, which may be related to its upregulation of CB1R and downregulation of COX-2.
Clinical characteristics of patients from Quebec, Canada, with Morquio A syndrome: a longitudinal observational study
Authors: Moisan Lina , Iannuzzi David , Maranda Bruno , Campeau Philippe M. , Mitchell John J.
Published: September 2020

Background

Morquio A syndrome is a rare, autosomal recessive, progressively debilitating disorder, with multi-system impairments and high medical burden. Quebec, Canada has a large Morquio A population, which is considered unique due to the presence of founder pathogenic variants. The objectives of this study were to document the genetic and clinical heterogeneity of patients with Morquio A in Quebec, to better characterize the phenotype of those with the French Canadian founder pathogenic variant (NM_000512.5: c.1171A>G, p.Met391Val), and to describe the natural history of the patients treated with elosulfase alfa enzyme replacement therapy. Patients with Morquio A were genotyped for pathogenic variants in the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. Clinical data were retrospectively collected from medical charts of patients and included medical history, height, physical examination, respiratory function tests, electrocardiogram, echocardiogram, endurance in the 6-min walk test (6MWT), and activities of daily living (ADL) as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ). Longitudinal data were collected retrospectively and prospectively for patients treated with elosulfase alfa.

Results

A total of 33 patients, aged 5–63 years, were included in the analysis. Patients with the founder pathogenic variant (n = 17) generally exhibited a non-classical form of Morquio A. As compared with patients with a non-founder pathogenic variant (n = 16), these patients were generally taller, had greater endurance and were better able to perform ADL. However, they still had significant musculoskeletal disease. Most of the 26 patients treated with elosulfase alfa, regardless of pathogenic variant, showed improvements in endurance and ADL. After 5 to 12 months of treatment, the mean improvement from baseline in the 6MWT was 23% and 10 of 14 patients improved in at least one MPS-HAQ domain. Endurance and ADL generally continued to improve or maintained stable in the long term (up to 7 years). Four out of 19 treated patients with echocardiogram data at follow-up showed progression of cardiac disease.

Conclusions

In Quebec, Canada, Morquio A frequently manifests as a non-classical form of the syndrome due to a founder effect. Patients treated with elosulfase alfa generally show long-term improvement or stability in endurance and function, regardless of pathogenic variant.
Clinical significance of serum anti-granulocyte–macrophage colony-stimulating factor autoantibodies in patients with sarcoidosis and hypersensitivity pneumonitis
Authors: Katayama Kanako , Hirose Masaki , Arai Toru , Hatsuda Kazuyoshi , Tachibana Kazunobu , Sugawara Reiko , Sugimoto Chikatoshi , Kasai Takahiko , Akira Masanori , Inoue Yoshikazu
Published: September 2020

Background

Anti-granulocyte–macrophage colony-stimulating factor autoantibody (GMAb) has been recognized as a diagnostic biomarker for autoimmune pulmonary alveolar proteinosis (aPAP). The aims of this study were to know the incidence of increased level of serum GMAb in granulomatous lung diseases (sarcoidosis and hypersensitivity pneumonitis [HP]) and to clarify the role of GMAb. Consecutive individuals diagnosed with sarcoidosis (n = 92) and HP (n = 45) at National Hospital Organization Kinki-Chuo Chest Medical Center were retrospectively analyzed. We measured serum GMAb levels at the diagnosis. Cut-off values of GMAb discriminating aPAP (n = 110) from healthy controls (n = 31) were determined by receiver operating characteristic (ROC) curve analysis. We compared the clinical features of sarcoidosis and HP patients with GMAb levels above the cut-off value (“Elevated-GMAb”) with those of patients whose GMAb levels below the cut-off value (“Low-GMAb”). Radiological and pathological findings in elevated-GMAb patients were re-evaluated to elucidate the role of GMAb in granulomatous lung diseases.

Results

Analysis of ROC indicated a sensitivity and specificity of 100% at GMAb level of 3.33 μg/mL for discriminating aPAP from healthy controls (area under curve = 1.000, p < 0.0001). The percentages of elevated-GMAb sarcoidosis and HP patients were 5.4% (n = 5) and 11.1% (n = 5), respectively. The number of comorbid sarcoidosis and HP patients with aPAP was two and one, respectively. Elevated-GMAb sarcoidosis patients presented with significantly higher serum levels of Krebs von den Lungen (KL)-6, surfactant protein-D (SP-D), lactate dehydrogenase, and the requirement of systemic corticosteroid therapy. Elevated-GMAb HP patients demonstrated older age, higher serum KL-6, SP-D, carcinoembryonic antigen, and cytokeratin fragment 21-1 levels, and a higher percentage of lymphocytes in bronchoalveolar lavage than low-GMAb patients. A subset of patients presented with radiological and pathological findings characteristic of aPAP.

Conclusions

We demonstrated the percentage of elevated-GMAb sarcoidosis and HP patients who presented with several features suggestive of aPAP. Elevated-GMAb sarcoidosis and HP patients without definitive aPAP diagnosis may have subclinical or early-stage aPAP and may not necessarily indicate false positives. Upon diagnosis of sarcoidosis or HP, measurement of GMAb may be useful in detecting possible comorbidity of subclinical or early-onset aPAP.
The SPARKLE registry: protocol for an international prospective cohort study in patients with alpha-mannosidosis
Authors: Hennermann Julia B. , Guffon Nathalie , Cattaneo Federica , Ceravolo Ferdinando , Borgwardt Line , Lund Allan M. , Gil-Campos Mercedes , Tylki-Szymanska Anna , Muschol Nicole M.
Published: September 2020

Background

Alpha-mannosidosis is a lysosomal storage disorder caused by reduced enzymatic activity of alpha-mannosidase. SPARKLE is an alpha-mannosidosis registry intended to obtain long-term safety and effectiveness data on the use of velmanase alfa during routine clinical care in patients with alpha-mannosidosis. It is a post-approval commitment to European marketing authorization for Velmanase alfa (Lamzede®), the first enzyme replacement therapy for the treatment of non-neurologic manifestations in patients with mild to moderate alpha-mannosidosis. In addition, SPARKLE will expand the current understanding of alpha-mannosidosis by collecting data on the clinical manifestations, progression, and natural history of the disease in treated and untreated patients, respectively.

Results

The SPARKLE registry is designed as a multicenter, multinational, noninterventional, prospective cohort study of patients with alpha-mannosidosis, starting patient enrollment in 2020. Patients will be followed for up to 15 years. Safety and effectiveness as post-authorization outcomes under routine clinical care in patients with treatment will be evaluated. The primary safety outcomes are the rate of adverse events (anti-velmanase alfa-immunoglobulin G antibody development, infusion-related reactions, and hypersensitivity). Secondary safety outcomes include the evaluation of medical events, change in vital signs, laboratory tests, physical examination, and electrocardiogram results. The primary effectiveness outcome is a global treatment response rate, evaluated as the individual aggregate of single endpoints from pharmacodynamic, functional, and quality-of-life effectiveness outcomes; secondary effectiveness outcomes are to characterize the population of patients with alpha-mannosidosis with regard to clinical manifestation, progression, and natural history of the disease. Any patient in the European Union with a diagnosis of alpha-mannosidosis who is willing to participate will likely be eligible for inclusion in the registry. Publications to disseminate scientific insights from the registry are planned.

Conclusion

This study will provide real-world data on the long-term safety and effectiveness of velmanase alfa in patients with alpha-mannosidosis during routine clinical care and increase the understanding of the natural course, clinical manifestations, and progression of this ultra-rare disease.
GPR68 deletion impairs hippocampal long-term potentiation and passive avoidance behavior
Authors: Xu Yuanyuan , Lin Mike T. , Zha Xiang-ming
Published: September 2020

Increased neural activities reduced pH at the synaptic cleft and interstitial spaces. Recent studies have shown that protons function as a neurotransmitter. However, it remains unclear whether protons signal through a metabotropic receptor to regulate synaptic function. Here, we showed that GPR68, a proton-sensitive GPCR, exhibited wide expression in the hippocampus, with higher expression observed in CA3 pyramidal neurons and dentate granule cells. In organotypic hippocampal slice neurons, ectopically expressed GPR68-GFP was present in dendrites, dendritic spines, and axons. Recordings in hippocampal slices isolated from GPR68−/− mice showed a reduced fiber volley at the Schaffer collateral-CA1 synapses, a reduced long-term potentiation (LTP), but unaltered paired-pulse ratio. In a step-through passive avoidance test, GPR68−/− mice exhibited reduced avoidance to the dark chamber. These findings showed that GPR68 contributes to hippocampal LTP and aversive fear memory.
Management of Achilles and patellar tendinopathy: what we know, what we can do
Authors: Aicale Rocco , Oliviero Antonio , Maffulli Nicola
Published: September 2020

Tendinopathies are challenging conditions frequent in athletes and in middle‐aged overweight patients with no history of increased physical activity. The term “tendinopathy” refers to a clinical condition characterised by pain, swelling, and functional limitations of tendons and nearby structures, the effect of chronic failure of healing response. Tendinopathies give rise to significant morbidity, and, at present, only limited scientifically proven management modalities exist. Achilles and patellar tendons are among the most vulnerable tendons, and among the most frequent lower extremity overuse injuries. Achilles and patellar tendinopathies can be managed primarily conservatively, obtaining good results and clinical outcomes, but, when this approach fails, surgery should be considered. Several surgical procedures have been described for both conditions, and, if performed well, they lead to a relatively high rate of success with few complications. The purpose of this narrative review is to critically examine the recent available scientific literature to provide evidence‐based opinions on these two common and troublesome conditions.
Patient with ovarian insufficiency: baby born after anticancer therapy and re-transplantation of cryopreserved ovarian tissue
Authors: Isachenko Vladimir , Morgenstern Bernd , Todorov Plamen , Isachenko Evgenia , Mallmann Peter , Hanstein Bettina , Rahimi Gohar
Published: September 2020

Background

The second major cause of death is cancer. In fact, the effectiveness of anticancer treatments and positive long-term prognosis for young women has increased. However, the problem of post-cancer infertility plays a significant role, because chemotherapy can be gonadotoxic and lead to the functional death of ovaries. There is potential key solution to this problem: cryopreservation of ovarian tissue before cancer therapy with re-implantation after convalescence. Data regarding cryopreservation and re-transplantation of ovarian tissue from patients with ovarian insufficiency is limited. The aim of this treatment was the re-transplantation of cryopreserved ovarian tissue after anticancer therapy of patient with ovarian insufficiency (56 IU/l FSH, 8 ng/l β-estradiol, < 1.1 ng/ml anti-Mullerian hormone, 1 primary follicle per 10mm3).

Case presentation

After the operation, four tissue fragments (10–16 × 8–13 × 1.0–1.2 mm) were cooled to 5 °C in the freezing medium (culture medium+ 6% ethylene glycol+ 6% dimethyl sulfoxide+ 0.15 M sucrose) for 24 h, frozen and thawed. Freezing was performed in four standard 5 ml cryo-vials with ice formation at − 9 °C, cooling from − 9 to − 34 °C at a rate of − 0.3 °C/min and plunging at − 34 °C into liquid nitrogen. After thawing in a 100 °C (boiling) water bath, the removal of cryoprotectants was performed in 0.5 M sucrose with 20 min. exposure in sucrose and 30 min. stepping rehydration. After thawing of one cryo-vial, part (5 mm3) of experimental ovarian tissue after 7 day in vitro culture was histological evaluated and two ovarian fragments (8 × 7 × 1.0 mm and 7 × 6 × 1.0 mm) were re-transplanted. The quantity of follicles after cryopreservation and in vitro culture was not increased (P > 0.1): it was found 1 primordial follicle in 5 mm3 of tissue. Thirty seven days after the re-transplantation of ovarian tissue, the restoration of the menstrual cycle of Patient W. was noted. Three months after the transplantation, the patient became spontaneously pregnant and delivered a healthy baby girl at term.

Conclusions

Described protocol of conventional cryopreservation of ovarian tissue can be used for treatment of patients with ovarian insufficiency.
Online health information seeking behaviours of parents of children undergoing surgery in a pediatric hospital in Rome, Italy: a survey
Authors: Russo Luisa , Campagna Ilaria , Ferretti Beatrice , Pandolfi Elisabetta , Ciofi Degli Atti Marta Luisa , Piga Simone , Jackson Sally , Rizzo Caterina , Gesualdo Francesco , Tozzi Alberto E.
Published: September 2020

Background

People increasingly search online for health information. Particularly, parents of patients often use the Internet as a source for health information. We conducted a survey to investigate the online searching behavior of parents of patients < 18 years, admitted for surgery in an Italian pediatric hospital.

Methods

The cross-sectional survey was nested in a prospective cohort study on surgical procedures. Parents of patients undergoing surgical procedures at Bambino Gesù Children’s Hospital, Rome, Italy, were enrolled and contacted by phone after the procedure. We recorded socio-demographic data, sex, length of stay following surgery, proximity of residence to the hospital, use of the internet to search for information on the surgery before and after the intervention and effect of information found online.

Results

The majority (91%) of parents of children undergoing surgical intervention used the internet. Of these, 74.3% of parents searched for information before surgery, and 26.1% searched for information after. Most parents searched for information on the care provider’s website. Two thirds of parents reported that information found online had increased their understanding of the child’s condition. Multivariate analyses indicated that families living far from the hospital (> 43 km) were more likely to search for health information (OR 2.3; 95% CI 1.34–4.00), as were families of patients undergoing a major surgery (OR = 2.1; 95% CI 1.04–4.11).

Conclusions

Parents of children undergoing surgery often search online for information on their child’s intervention, in particular those whose child is scheduled for a major surgery and those living far from the hospital. A survey like the present one allows to understand parents’ information needs, to better guide them in online information seeking and to better tailor information provided on the care provider’s website.
Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence
Authors: Wang Denian , Xiao Fei , Feng Zhongxue , Li Min , Kong Lingmiao , Huang Luping , Wei Yong’gang , Li Hongyu , Liu Fei , Zhang Haili , Zhang Wei
Published: September 2020

Background

Sunitinib, a receptor tyrosine kinase (RTK) inhibitor that targets multiple receptors such as vascular endothelial growth factor receptors (VEGFRs), was approved for cancer treatment in 2006. However, it was unsuccessful in treating certain cancers, particularly metastatic breast cancer (MBC), and the mechanism underlying this “sunitinib resistance” remains unclear. Herein, we investigated whether the sunitinib-associated inferior survival benefit in MBC was due to sunitinib-induced endothelial cell (EC) injury or EC senescence.

Methods

4T1 murine breast cancer cells were used as the main breast tumor model for it produces a highly metastatic solid tumor that can spontaneously metastasize to the lung, which closely mimics highly metastatic human breast cancer. Senescence-associated β-galactosidase (SA-β-Gal, immunohistochemistry [IHC]-staining), P16, P53, and P57 (immunoblotting) were used as markers of cell senescence. A protein array containing 25 senescence-associated chemokines and the transwell chemotaxis assay were used to examine whether sunitinib increases inflammatory chemokine secretion which attracts tumor cells via chemokinesis. Flow cytometry and IHC were used to detect whether the sunitinib-induced senescent ECs recruit cancer-associated inflammatory myeloid cells. Finally, the spontaneous metastatic model was used to monitor whether sunitinib causes the formation of “pre-metastatic niche” which promotes MBC to metastasize to the lungs.

Results

We demonstrated that sunitinib induced a senescence-like endothelial cell (EC) phenotype. Inflammatory chemokine secretion and VCAM1 expression were significantly increased in senescent ECs, resulting in tumor cell (TC) chemotaxis and TC/EC interactions. Meanwhile, EC senescence caused loosening of EC junctions, facilitating TC transmigration through the endothelial barrier. Sunitinib-induced senescent ECs also recruited cancer-associated myeloid cells to form a “pre-metastatic niche”-like microenvironment. Alterations at the molecular level and in the tissue environment ultimately led to an increase in distant metastasis.

Conclusion

Although sunitinib was designed to target the EC directly, the increase in tumor metastasis may ironically be due to sunitinib “correctly” playing its role. Our findings suggest that we should carefully weigh the pros and cons before using sunitinib and other antiangiogenic drugs that directly target the ECs.
Manual acupuncture versus sham acupuncture and usual care for the prevention of primary dysmenorrhea (PD): study protocol for a randomized controlled trial
Authors: Yu Lingling , Liu Shiqin , Zheng Cuihong , Liu Wenhua , Wang Hua , Liang Fengxia , Lu Wei , Xu Shabei , Wang Wei
Published: September 2020

Background

Primary dysmenorrhea (PD) is a leading cause of dysmenorrhea among adolescent girls. Manual acupuncture may be considered as an effective treatment for PD, but high-quality evidence remains limited. This trial aims to evaluate the efficacy and safety of acupuncture for the prevention of PD as compared with sham acupuncture and usual care.

Methods/design

This is a three-arm, randomized, controlled clinical trial in which the patients, assessors, and statisticians will be blinded. A total of 300 acupuncture-naive patients who were diagnosed as PD will be randomly allocated to the verum acupuncture, sham acupuncture, or usual care groups in a 2:2:1 ratio. Patients in the verum acupuncture group will receive manual acupuncture at specific acupuncture points with penetrating needling, while those in the sham acupuncture group will receive non-penetrating needling at non-acupuncture points. They will be given five sessions over a menstrual cycle for 3 menstrual cycles. Patients in the usual care group will receive health education and informed to receive manual acupuncture for free after waiting for 7 menstrual cycles. The primary outcome will be the change from baseline in the Cox Menstrual Symptom Scale Score (CMSS). The secondary outcomes will be the changes in Massachusetts General Hospital Acupuncture Sensation Scale (MASS), visual analog scale (VAS), Short-Form McGill Pain Questionnaire 2 (SF-MPQ-2), Pittsburgh Sleep Quality Index (PSQI), Beck Anxiety Inventory (BAI), Beck Depression Inventory II (BDI- II), Acupuncture Expectancy Scale (AES), 60-item NEO Personality Inventory-Short Form (NEO-FFI), and acute medication intake. The adverse events will be recorded at every visit. The analyses will be performed base on a full analysis set (FAS) and a per-protocol set (PPS).

Discussion

This study may provide high-quality evidence regarding the efficacy and safety of manual acupuncture for PD. In addition, the results of this study will help to identify the efficacy of acupuncture due to the specific effects of acupuncture or placebo effects of acupuncture ritual.

Trial registration

Clinical Trials.gov NCT02783534. Registered on 26 May 2016